2.2.1.1. Death

Mineral Oil Hydraulic Fluids. No studies were located regarding death in humans after inhalation exposure to mineral oil hydraulic fluids.

Several water-in-oil emulsion hydraulic fluids (Houghto-Safe 5047F, Sunsafe F, Pyroguard A-443, and Quintolubric 95830W) produced no deaths or clinical signs of toxicity in rats within 14 days of single 4-hour exposures to aerosol concentrations ranging from 110 to 210 mg/m³ (Kinkead et al. 1987a, 1988). No deaths were reported in Fischer-344 rats during a 90-day continuous exposure (23 hours/day) to 1.0 mg/m³ Houghto-Safe 5047F (Kinkead et al. 1991). A U.S. military fluid designated as MLH-5606 likewise produced no deaths in rats within 14 days of single 6-hour exposures to an aerosol concentration of 1,148 mg/m³ (Kinkead et al. 1985). Additional information on lethality of mineral oil hydraulic fluids in animals after inhalation exposure was not located. The available mineral oil hydraulic fluid studies (presented in Table 2-1 and Figure 2-1) were not designed to examine lethality, and probably did not use high enough concentrations to cause death.

Table 2-1

Levels of Significant Exposure to Mineral Oil Hydraulic Fluids - Inhalation.

Figure 2-1

Levels of Significant Exposure to Mineral Oil Hydraulic Fluids - Inhalation.

Table 2-2

Levels of Significant Exposure to Organophosphate Ester Hydraulic Fluids - Inhalation.

Figure 2-2

Levels of Significant Exposure to Organophosphate Ester Hydraulic Fluids - Inhalation.

Table 2-3

Levels of Significant Exposure to Polyalphaolefin Hydraulic Fluids - Inhalation.

Figure 2-3

Levels of Significant Exposure to Polyalphaolefin Hydraulic Fluids - Inhalation. Acute (≤14 days)

Organophosphate Ester Hydraulic Fluids. No studies were located regarding death in humans after inhalation exposure to organophosphate ester hydraulic fluids.

Single 4-hour exposures to aerosols of U.S. military fluids Durad MP280 and Fyrquel 220 produced no deaths in male rats at respective concentrations of 6,190 and 5,790 mg/m³and female rats exposed to 6,350 and 6,310 mg/m³, respectively (Gaworski et al. 1986; Kinkead et al. 1992a). Daily 4-hour exposures over an 11-day period caused death to a single rabbit exposed to 2,000 mg/m³ of Cellulube 220 (Carpenter et al. 1959).

Intermediate-duration inhalation exposures to aerosols of a few organophosphate ester hydraulic fluids (Durad MP280 and trial phosphate ester”) produced lethal neurotoxic effects in chickens and rabbits (MacEwen and Vemot 1983; Siegel 1965). Rats and hamsters appear to be less susceptible to the neurotoxic action of organophosphate esters; tests of several organophosphate fluids produced no deaths in rats exposed to substantial aerosol concentrations.

Aerosols of Cellulube 220 produced deaths associated with severe dyspnea and mild diarrhea in one of two rabbits exposed to 2,000 mg/m³ for ≤4 hours/day, 5 days/week for 11 or 22 days (Carpenter et al. 1959). Continuous exposure for ~30-160 days to aerosols of a triaryl phosphate U.S. military hydraulic fluid (see Table 3-2), at concentrations ≤110 mg/m³, produced no deaths in dogs or rats, but deaths associated with severe neurotoxic symptoms occurred in chickens exposed to concentrations ≥23 mg/m³ and in rabbits exposed to 102 mg/m³ (Siegel et al. 1965). Aerosols of Durad MP280 or Fyrquel 220 (continuous exposure for 90 days) produced no deaths in rats or hamsters exposed to 100 mg/m³. Deaths associated with lethargy, cachexia, and head droop occurred in rabbits exposed to 101 mg/m³ Durad MP280, but not in rabbits exposed to 100 mg/m³ Fyrquel 220 (MacEwen and Vemot 1983). Some of the Durad MP280-exposed rabbits were also infected with Pasteurella, which may have contributed to neurological symptoms. No deaths occurred in rats exposed to cyclotriphosphazene at 990 mg/m³, 6 hours/day, 5 days/week for 21 days (Kinkead et al. 1989a, 1990) or in rats exposed to aerosols of Skydrol 500B-4 at concentrations ≤300 mg/m³, 6 hours/day, 5 days/week for 13 weeks (Healy et al. 1992; Monsanto 1987a, 1987b, 1989). The LOAEL values for death are presented in Table 2-2 and Figure 2-2.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding death in humans after inhalation exposure to polyalphaolefin hydraulic fluids.

The LC₅₀ values (single 4-hour exposures) for male and female rats, respectively, were determined for several U.S. military polyalphaolefin hydraulic fluids as follows: DTNSRDC N501, 2, 390 and 1,670 mg/m³ (MacEwen and Vemot 1983); MIL-H-83282LT, 2,130 and 1,500 mg/m³ (Kinkead et al. 1992b); and B85-174, 1,620 and 1,390 mg/m³ (Kinkead et al. 1987b). Kinkead et al. (1992b) speculated from observations of pulmonary edema in the dead rats that deaths were caused by acute respiratory irritation. Several other U.S. military fluids produced no deaths in rats within 14 days of single 4-hour exposures to the following aerosol concentrations: DTNSRDC N527, 5, 470 mg/m³; DTNSRDC N448, 10, 720 mg/m³; DTNSRDC N518,5,350 mg/m³; DTNSRDC N517, 5, 430 mg/m³; and DTNSRDC N525, 5, 470 mg/m³ (MacEwen and Vemot 1983). These acute-duration LOAEL values for death are recorded in Table 2-3 and Figure 2-3.

2.2.1.2. Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Tables 2-1, 2-2, and 2-3 and plotted in Figures 2-1, 2-2, and 2-3 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively. Data for systemic effects (respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, and ocular) from chicken studies were not presented in the LSE tables or figures because the appropriateness of nonmammalian models for human systemic effects is not known. However, chickens have been shown to be a sensitive species for neurological effects, and data from chickens are included in both the LSE tables and figures.

2.2.1.3. Immunological and Lymphoreticular Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding immunological effects in humans or animals after inhalation exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding immunological effects in humans after inhalation exposure to organophosphate ester hydraulic fluids.

Information regarding immunological effects in animals is restricted to histopathological examination of organs with immune functions (thymus, spleen, lymph nodes) after intermediate-duration inhalation exposures of up to 90 days. No treatment-related lesions in these tissues was reported in rats exposed to ≤900 mg/m³ cyclotriphosphazene (Kinkead et al. 1989b, 1990). No lesions were seen in the spleen of rats exposed to 260 mg/m³ Fyrquel 220 or 251 mg/m³ Durad MP280 (Gaworski et al. 1986; MacEwen and Vernot 1983), or 300 mg/m³ Skydrol 500B-4 (Healy et al. 1992; Monsanto 1987a, 1987a, 1989). Similar results were reported for the spleen in both hamsters and rabbits exposed to ≤260 mg/m³ Fyrquel220 or 251 mg/m³ Durad MP280 for 21 days (Gaworski et al. 1986; MacEwen and Vemot 1983). It should be noted that the 90-day NOAELs for Durad MP280 and Fyrquel 220 in rats, hamsters, and rabbits were based on gross pathology only (MacEwen and Vernot 1983). The NOAEL values for immunological effects are recorded in Table 2-2 and plotted in Figure 2-2.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding immunological effects in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids.

2.2.1.4. Neurological Effects

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in each species and duration category are recorded in Tables 2-1, 2-2, and 2-3 and plotted in Figures 2-1, 2-2, and 2-3 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively.

Mineral Oil Hydraulic Fluids. No studies were located regarding neurological effects in humans after inhalation exposure to mineral oil hydraulic fluids. There are reports of neurological effects in humans occupationally exposed to mineral oil hydraulic fluids; however dermal contact was expected to have been the primary route of exposure (see Section 2.2.3.4).

Information regarding neurological effects in animals after inhalation exposure to mineral oil hydraulic fluids is limited to two rat studies in which no symptoms of acute neurotoxicity or delayed neuropathy were seen in rats within 14 days of aerosol exposure. (These studies did not specifically look for neurological effects.) One study exposed Fischer 344 rats for 4 hours to water-in-oil emulsion hydraulic fluids at concentrations ranging from 110 to 210 mg/m³ (Pyroguard A-443, Houghto-Safe 5047F, Quintolubric 9583OW, and Sunsafe F) (Kinkead et al. 1987a, 1988). The second study exposed rats to 1,148 mg/m³ of MIL-H-5606 for 6 hours (Kinkead et al. 1985).

Organophosphate Ester Hydraulic Fluids. The principal adverse effect of exposure to organophosphate esters is neurotoxicity. Organophosphate esters have been synthesized that-are preferentially toxic to insects compared to mammals; these are widely used as insecticides (e.g., chlorpyrifos, diazinon). Acute toxicity to organophosphate esters is mediated by the inhibition of neural acetylcholinesterase. Neural acetylcholinesterase is present at cholinergic synapses throughout the central and peripheral nervous systems, and is responsible for hydrolyzing acetylcholine released from the pre-synaptic terminal. If this enzyme is inhibited, acetylcholine accumulates in the synapse, resulting in increased firing of the post-synaptic neuron or increased neuroeffector activity. The consequences of increased cholinergic activity in the parasympathetic autonomic nervous system (muscarinic receptors) can include increased salivation, lacrimation, perspiration, miosis, nausea, vomiting, diarrhea, excessive bronchial secretions, bradycardia, frequent micturition, and incontinence. The effects of increased neuroeffector activity on skeletal muscles (nicotinic receptors) can include muscle fasciculations, cramps, muscle weakness, and depolarization-type paralysis. Effects on cholinergic synapses in the central nervous system (predominantly muscarinic) can result in drowsiness, fatigue, mental confusion, headache, convulsions, and coma (see Table 2-10). These classical symptoms of organophosphate ester neurotoxicity increase in severity and rapidity of onset in a dose-dependent manner (Ecobichon 1991).

Acetylcholinesterase is also present in erythrocytes where it is known as erythrocyte acetylcholinesterase. Both forms of acetylcholinesterase are produced by the same gene (Taylor et al. 1993). In in vitro assays, erythrocyte and neural acetylcholinesterase are inhibited to roughly the same extent by exposure to many organophosphate esters. Measurement of erythrocyte acetylcholinesterase is used as a surrogate of the inhibition of neural acetylcholinesterase. A cholinesterase capable of hydrolyzing acetylcholine is also produced by the liver and circulates in the blood. This enzyme, called plasma cholinesterase or butyrylcholinesterase, can also be inhibited by organophosphate esters and is often used as a marker for exposure. The endogenous substrate of this enzyme is unknown. This enzyme is often inhibited by organophosphate esters at lower levels of exposure than required to inhibit neural or erythrocyte acetylcholinesterase. Erythrocyte acetylcholinesterase activity is located in the erythrocyte membrane and can be differentiated from plasma cholinesterase by sedimenting the erythrocytes from whole blood. Measurement of “whole blood cholinesterase” reflects both plasma and erythrocyte activity.

Exposure to organophosphate esters can also cause a syndrome referred to as organophosphate-induced delayed neuropathy (OPIDN). This is a syndrome observed in humans and some animal models after exposure to certain organophosphate esters, for example tri-ortho-cresyl phosphate (Johnson 1981). The initial clinical signs are disturbances of gait, usually seen at least a week after exposure has begun. Severe cases can result in ataxia and paralysis. A characteristic “dying-back” type degeneration of motor fibers is seen upon histopathological examination. The biochemical mechanism of OPIDN is unknown at the present time. This syndrome does not appear to be closely correlated with neural acetylcholinesterase inhibition, but rather an enzyme activity referred to as “neurotoxic esterase” (NTE). The endogenous substrate of this enzyme activity is unknown. This syndrome can be reproduced in chickens, but not in rats or mice (Abou-Donia and Lapadula 1990).

One study was located regarding neurological effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Workers in an aryl phosphate manufacturing plant were not found to have neurological deficits even with decades of potential exposure (Reade 1982).

Information regarding neurological effects in animals after acute inhalation exposure to organophosphate ester hydraulic fluids is limited to reports of a decrease in whole blood cholinesterase in mice exposed to 757 mg/m³ of triphenyl phosphate (Sutton et al. 1960) and of head droop, generalized weakness, and decreased whole blood cholinesterase activity in one of two rabbits exposed to aerosols of 2,000 mg/m³ Cellulube 220,4 hours/day, 5 days/week for 11 days (Carpenter et al. 1959). Transient, mild lethargy after 4-hour exposures to aerosols of Durad MP280 and Fyrquel 220 has been observed (Gaworski et al. 1986; Kinkead et al. 1992a).

Several organophosphate ester hydraulic fluids have produced neurological effects in several animal species after intermediate inhalation exposure (see Table 2-2).

Aerosols of Skydrol 500B-4 produced transient excessive salivation in rats exposed to 300 mg/m³, 6 hours per day, 5 days per week for 6 or 13 weeks; this effect was not observed with exposure to 100 mg/m³ by the same protocol (Healy et al. 1992; Monsanto 1987a, 1987b, 1989). Plasma cholinesterase activity (a marker for organophosphate ester exposure) was decreased 60% in this group; erythrocyte acetylcholinesterase was not measured in this study. Aerosols of Cellulube 220 produced decreased whole blood cholinesterase activity (13–57%) in rabbits exposed to 2,000 mg/m³ for 4 hours/day, 5 days/week for 22 days; exposure for 2 hours/day produced no clinical signs of neurotoxicity in two rabbits (Carpenter et al. 1959). No overt signs of neurotoxicity or histological alterations of brain or sciatic nerve tissues were observed in rats exposed to cyclotriphosphazene at 990 mg/m³, 6 hours/day, 5 days/week for 21 days (Kinkead et al. 1989a, 1990).

Continuous exposure for ≈30-160 days to aerosols of a triaryl phosphate U.S. military hydraulic fluid, triaryl phosphate (see Table 3-1), produced paralysis in rabbits and chickens after exposure to 102 mg/m³ and 23 mg/m³, respectively, but not after exposure to respective concentrations of 34 mg/m³ or 4.4 mg/m³ (Siegel et al. 1965). Continuous exposure to triaryl phosphate at 110, 103, or 4.4 mg/m³, respectively, produced no signs of neurotoxicity in rats after 36 days, dogs after 99 days, or monkeys after 108 days (Siegel et al. 1965). Intermittent exposure (8 hours/day, 5 days/week for 30 exposures) to 50 mg/m³ triaryl phosphate produced no neurotoxic signs in squirrel monkeys (Siegel et al. 1965). Aerosols of Durad MP280 (continuous exposure for 90 days) produced kyphosis (a deformity of the spine characterized by extensive flexion) and a decrease in the tail tip curl reflex in rats and anorexia, lethargy, cachexia, and head droop in rabbits after exposure to 101 mg/m³; exposure to 10.3 mg/m³ produced no signs of neurotoxicity in these species (MacEwen and Vernot 1983). Hamsters similarly exposed to 101 mg/m³ Durad MP280 showed no evidence of neurotoxicity in this study. Aerosols of Fyrquel 220 (continuous exposure for 90 days) likewise produced kyphosis in rats at 100 mg/m³, but no clinical signs of neurotoxicity in rabbits or hamsters at 100 mg/m³ (MacEwen and Vernot 1983). Because of the uncertainty that the kyphosis observed in rats is a neurological or muscular effect, this effect has been discussed in both sections.

The studies by Siegel et al. (1965) and MacEwen and Vemot (1983) also included intermittent exposure experiments (8 or 6 hours/day, respectively, for 5 days/week) for shorter durations (30 exposures or 21 days, respectively). Neither Fyrquel 220 (260 mg/m³) nor Durad MP280 (251 mg/m³) produced signs of neurotoxicity in rats, rabbits, or hamsters with the intermittent exposure protocol (MacEwen and Vemot 1983). No evidence of neurotoxicity was observed in rats exposed to ≤300 mg/m³ Skydrol500B-4 intermittently for 6 or 13 weeks (Healy et al. 1992; Monsanto 1987a, 1987b, 1989). The intermittent protocol used by Siegel et al. (1965) produced no signs of neurotoxicity in rabbits or dogs at 50 mg/m³ triaryl phosphate. It produced delayed peripheral neuropathy in chickens at 50 mg/m³ but not at 25 mg/m³.

No information was located regarding neurological effects in animals after chronic inhalation exposure to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding neurological effects in humans after inhalation exposure to polyalphaolefin hydraulic fluids.

In a series of acute lethality studies, lethargy and inactivity were noted in rats exposed for 4 hours to lethal concentrations of DTNSRDC N501 (6,430 mg/m³) (MacEwen and Vemot 1983). Kyphosis was observed in rats exposed to 880-5,030 mg/m³ of a polyalphaolefin hydraulic fluid designated as B85-174 (Kinkead et al. 1987b). Because of the uncertainty of whether the kyphosis is a neurological or muscular effect, this effect is discussed in both-the Musculoskeletal Effects and Neurological Effects sections. No other information was located on neurological effects in animals after inhalation exposure to polyalphaolefin hydraulic fluids.

2.2.1.5. Reproductive Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding reproductive effects in humans or animals after inhalation exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding reproductive effects in humans after inhalation exposure to organophosphate ester hydraulic fluids.

Testicular atrophy was observed upon gross necropsy after male rats were continuously exposed for 90 days to an aerosol concentration of 101 mg/m³ Durad MP280, but not in rats exposed to 10.3 mg/m³ (MacEwen and Vemot 1983). Testicular atrophy was not observed in male rats continuously exposed for 90 days to an aerosol concentration of 100 mg/m³ Fyrquel 220 (MacEwen and Vemot 1983).

Male and female rats showed no treatment-related gross or histological reproductive tract alterations when exposed by inhalation 6 hours/day, 5 days/week for 3 weeks to a 990 mg/m³ aerosol of cyclotriphosphazene (Kinkead et al. 1989a, 1990), or aerosol concentrations of Skydrol 500B-4 ≥300 mg/m³, 6 hours/day, 5 days/week for 13 weeks (Healy et al. 1992; Monsanto 1987a, 1987b, 1989).

Likewise, no treatment-related gross reproductive tract alterations after intermediate-duration exposure were observed in male or female rabbits or in male hamsters continuously exposed to aerosols of Fyrquel220 at concentrations ≤100 mg/m³ (MacEwen and Vemot 1983). Two male rabbits exposed for 1-4 hours/day, 4-5 days/week, for 11-26 days to 2,000 mg/m³ aerosol of Cellulube 220 (Carpenter et al. 1959) showed no histological evidence for effects on reproductive tissues. No acute or chronic inhalation studies examining reproductive effects in animals were located.

The highest NOAEL values and all LOAEL values from each reliable study for reproductive effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding reproductive effects in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids.

2.2.1.6. Developmental Effects

No studies were located regarding developmental effects in humans or animals after inhalation exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or polyalphaolefin hydraulic fluids.

2.2.1.7. Genotoxic Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after inhalation exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after inhalation exposure to organophosphate ester hydraulic fluids. Genotoxicity studies for organophosphate ester hydraulic fluids are discussed in Section 2.5.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids.

2.2.1.8. Cancer

Mineral Oil Hydraulic Fluids. Studies regarding cancer in humans or animals after inhalation exposure to mineral oil hydraulic fluids were limited to a single case-control study that examined associations between subjectively reported occupational exposure to petroleum-derived liquids and cancer at particular sites among 3,726 male cancer patients (Siemiatycki et al. 1987a). The study found no convincing associations between occupational exposure to hydraulic fluids and cancer at any site. This study is discussed in more detail in Section 2.2.3.8, because, while inhalation exposure was probable for the subject occupations, the authors reported that the exposure route was more often dermal contact.

No studies were located regarding cancer in animals after inhalation exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding cancer in humans or animals after inhalation exposure to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding cancer in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids.

2.2.2.1. Death

Mineral Oil Hydraulic Fluids. A 14-month-old boy ingested ≈5-10 cc of automobile automatic transmission fluid thought to have been composed primarily (75-80%) of mineral oil (Perrot and Palmer 1992). The child developed pneumonia, pneumothorax (presence of gas in the pleural cavity), hemorrhaging in the intestines, and a distended abdomen and eventually died 4 weeks after ingestion. Postmortem examination revealed scattered subserosal hemorrhage in the small and large intestine and the omentum, as well as focal edema, hemorrhage, and lipoid/oil droplets in the lung, and proliferation of alveolar macrophages. The presence of lipoid/oil droplets in the lung suggest that the transmission fluid was aspirated. Additional information was not located on lethality of mineral oil hydraulic fluids in humans after oral exposure.

Several water-in-oil emulsion hydraulic fluids (Houghto-Safe 5047F, Sunsafe F, Pyroguard A-443, and Quintolubric 95830W) produced no deaths or clinical signs of toxicity at single gavage dosage levels of 5,000 mg/kg in rats observed for 14 days (Kinkead et al. 1987a, 1988). Single gavage doses of a U.S. military fluid designated as MIL-H-5606 at 4,500 mg/kg (5 mL/kg) also produced no deaths in rats observed for 14 days (Kinkead et al. 1985). Additional information on lethality of mineral oil hydraulic fluids in animals after oral exposure was not located. No studies showing LOAEL values for lethality are shown in Table 2-4 or Figure 2-4.

Table 2-4

Levels of Significant Exposure to Mineral Oil Hydraulic Fluids - Oral.

Figure 2-4

Levels of Significant Exposure to Mineral Oil Hydraulic Fluids - Oral.

Table 2-5

Levels or significant Exposure to Organopnospnate Ester Hydraulic Fluids - Oral.

Figure 2-5

Levels of Significant Exposure to Organophosphate Ester Hydraulic Fluids - Oral.

Table 2-6

Levels of Significant Exposure to Polyalphaolefin Hydraulic Fluids - Oral.

Figure 2-6

Levels of Significant Exposure to Polyalphaolefin Hydraulic Fluids - Oral.

Organophosphate Ester Hydraulic Fluids. Reports of organophosphate poisonings in the United States, India, and South Africa date back to the 1930s when tri-ortho-cresyl phosphate was either inadvertently mixed with cooking oils or was an adulterant of an alcohol-containing extract, Jamaica Ginger (Goldstein et al. 1988). Few deaths are reported, but polyneuritis and paralysis are common to these outbreaks.

Acute oral exposure to several organophosphate ester hydraulic fluids produced deaths in rabbits, chickens, and cows. The deaths were associated with severe cholinergic symptoms or symptoms of organophosphorus induced delayed neuropathy (OPIDN). (See Section 2.2.2.4 for further details on the neurological effects.)

Single oral gavage doses of several organophosphate ester hydraulic fluids produced deaths in rats. LD₅₀ values are reported for rats at >8,400 mg/kg for triaryl phosphates, 2,400 mg/kg for dibutyl phenyl phosphate, and 1,400 mg/kg for tributyl phosphate (Johannsen et al. 1977). No deaths were reported for rats at the highest administered dosage levels which were: Durads 300, 550B, 116, and 220B, 5,000 mg/kg (FMC 1990a); Durad MP280,5,775 mg/kg (Gaworski et al. 1986); and Cellulube 220 (two rats tested), 20,000 mg/kg (Dollahite and Pierce 1969). Single gavage doses of 34,500 mg/kg Pydraul 50E produced deaths in 3 of 10 rats from unspecified causes, but a dosage level of 28,750 mg/kg produced no deaths (FMC 1978a). No deaths were reported in rats orally exposed to a cyclotriphosphazene-based fluid at ≤5,000 mg/kg (Kinkead et al. 1992c; MacEwen and Vemot 1985).

Cellulube 220 produced deaths (including animals killed due to morbidity) associated with severe cholinergic symptoms and paralysis that developed within 5 days in four of five rabbits after administration of single doses of 7,500 mg/kg, but no deaths were produced after two rabbits received doses of 6,000 mg/kg (Dollahite and Pierce 1969). Lethal cholinergic toxicity after 6 days was observed in one of two rabbits exposed daily to 120 mg/kg/day of Cellulube 220 for 2-14 days (Carpenter et al. 1959).

The actual composition of the Cellulube 220 was not reported in either the Dollahite or Carpenter studies, so the large difference in doses causing death can not be explained. Deaths were also reported in 5 of 5 pregnant Wistar rats after 5-6 daily doses of 800 mg/kg tributyl phosphate beginning on gestation day 7 (Noda et al. 1994).

The acute oral LD₅₀ values for Skydrol 500B-4, Skydrol LD-4, tributyl phosphate, and dibutyl phenyl phosphate in chickens were 2,559, 2,594, 1,500 or 1,800, and <2,000 mg/kg, respectively; deaths occurred within 1-3 days with severe cholinergic symptoms (Carrington et al. 1989; Johannsen et al. 1977; Monsanto 1987c, 1987d). Lethal single gavage doses of 300 and 5,000 mg/kg were associated with severe neurotoxicity (paralysis, and inability to stand) in chickens treated with Fyrquel 150 (Stauffer Chemical Co. 1971) and Fyrquel 220 (FMC 1977a), respectively.

A single gavage dose of 5,000 mg/kg Fyrquel 150 produced lethal cholinergic symptoms in a calf; dosage levels of 500 and 1,000 mg/kg also produced cholinergic signs in adult cows. Death resulted from paralysis about 20 days after dosing (Beck et al. 1977). A calf died 30 days after a single dose of 7,700 mg/kg Cellulube 220; decreased erythrocyte acetylcholinesterase was observed (time of onset not reported) and axonal degeneration and demyelination in the peripheral and central nervous systems were observed beginning 19 days after dosing (Dollahite and Pierce 1969).

Intermediate-duration oral exposure to Durad 110 produced deaths in chickens associated with the delayed development of neuropathy at dosage levels of 4,000 mg/kg/day in a 28-day study and 90 mg/kg/day in a 90-day study (FMC 1986). At 100 mg/kg/day over a 13-week period, 2 of 12 male and 1 of 12 female rats died with exposure to tri-n-butyl phosphate (Healy et al. 1995). Dietary administration of Pydraul 90E for 90 days providing daily doses of 50 mg/kg/day produced no chemical-related deaths in rats (Monsanto 1979). An organophosphate ester hydraulic fluid designated MIL-H-83306 also caused death in 4 of 4 rats exposed by gavage to 1,000 mg/kg over a 26-day period (Mattie et al. 1993).

Gavage exposure to 2,900 mg/kg/day tricresyl phosphate for 16 days, 5 days a week, resulted in death in 5 of 10 male and 7 of 10 female Fischer 344 rats (NTP 1994). Deaths occurred in 5 of 10 male and 10 of 10 female B₆C₃F₁ mice at 1,450 mg/kg/day in a parallel study. No deaths occurred in rats in 13-week feeding (≤770 mg/kg/day) or gavage studies (5 days a week, 5 800 mg/kg/day) or in 2-year feeding studies at ≤15 mg/kg/day (NTP 1994). Similar results were obtained in mice where the highest doses were 1,050 mg/kg/day (13-week feeding), 800 mg/kg/day (13-week gavage), and 37 mg/kg/day (2-year feeding).

All LOAEL values for each reliable study for death in each species and duration category are recorded in Table 2-5 and plotted in Figure 2-5.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding death in humans after oral exposure to polyalphaolefin hydraulic fluids.

A U.S. military polyalphaolefin hydraulic fluid, MIL-H-83282LT, produced no deaths in adult leghorn chickens when two gavage doses of 5,000 mg/kg were administered separated by 21 days; a 21 -day observation period followed the second dose administration (Kinkead et al. 1992b). Single gavage 5 ml/kg (≈4,250 mg/kg) doses of another U.S. military fluid, MIL-H-83282, produced no deaths in rats within 14 days of dosing (Kinkead et al. 1985). No deaths occurred within 14 days of dosing in other groups of rats treated with one of several other U.S. military polyalphaolefin hydraulic fluids (designated as B85-174 and DTNSRDC Nos. N448, N501, N5 17, N5 18, N525, and N527) at single gavage dosage levels of 5 mL/kg (≈4,250 mg/kg) or 5,000 mg/kg (Kinkead et al. 1987b; MacEwen and Vemot 1983). No other information was located regarding deaths in animals after oral exposure to polyalphaolefin hydraulic fluids.

2.2.2.2. Systemic Effects

The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Tables 2-4, 2-5, and 2-6 and are plotted in Figures 2-4, 2-5, and 2-6 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively. Because of the uncertainty on whether chickens are a good model for human systemic effects (respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal, and ocular), these data are not listed in the LSE tables or figures. However, chickens have been shown to be sensitive models for neurotoxicity, and data from chickens are included in the LSE tables and figures. Some of the systemic effects resulting from oral exposure to the organophosphate ester hydraulic fluids are most likely secondary to their anticholinesterase activity.

2.2.2.3. Immunological and Lymphoreticular Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding immunological or lymphoreticular effects in humans or animals after oral exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding immunological or lymphoreticular effects in humans after oral exposure to organophosphate ester hydraulic fluids.

Rats exposed for 6 weeks to 2.5 mg/kg/day of tricresyl phosphate showed decreased serum antibody titers to tetanus and decreased immunoglobin levels (Banerjee et al. 1992). In a 16-day gavage study with tricresyl phosphate, serious effects on immunological/lymphoreticular tissues were observed (NTP 1994). Male and female rats that received 2900 mg/kg/day tricresyl phosphate had increased incidences of lymphoid depletion and necrosis of the spleen, thymus and the mandibular lymph node; the severity of these lesions ranged from mild to marked (NTP 1994). Significantly reduced thymus weight was observed at 1,450 mg/kg/day. Necrosis of the spleen, thymus, and mandibular lymph node and lymphoid depletion of the thymus were also observed in mice at 2,900 mg/kg/day (NTP 1994). The NOAEL value in this study was 1,452 mg/kg/day. At reduced doses in subsequent studies, histological examination of bone marrow, spleen, thymus and mandibular and mesenteric lymph nodes revealed no treatment-related lesions in Fischer 344 rats and B₆C₃F₁ mice orally exposed to tricresyl phosphate (NTP 1994). Dosing regimens (highest doses in mg/kg/day in parenthesis) were as follows: 13-week feeding (rats 770, mice 1,050); 13-week gavage, 5 days a week (rats 800, mice 800); and 2-year feeding (rats 15, mice 37).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding immunological or lymphoreticular effects in humans after oral exposure to polyalphaolefin hydraulic fluids.

Histopathological analysis of the thymus, lymph nodes, and spleen of rats exposed to 1,000 mg/kg/day MIL-H-83282 or MIL-H-83282LT for 4 weeks revealed no treatment-related changes in these tissues (Mattie et al. 1993).

2.2.2.4. Neurological Effects

The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in each species and duration category are recorded in Tables 2-4, 2-5, and 2-6 and plotted in Figures 2-4, 2-5, and 2-6 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively.

Mineral Oil Hydraulic Fluids. No studies were located regarding neurological effects in humans after oral exposure to mineral oil hydraulic fluids.

Mineral oil hydraulic fluids sometimes contain organophosphate ester additives; however, no symptoms of acute cholinergic toxicity or delayed neuropathy were seen in several studies with animals treated with single oral doses of mineral oil hydraulic fluids. Single gavage doses of several hydraulic fluids at doses of ≈5,000 mg/kg produced no clinical signs of neurotoxicity within 14 days of dosing in Fischer 344 rats; tested fluids include several water-in-oil emulsion types of hydraulic fluids (Pyroguard A-443, Houghto-Safe 5047F, Quintolubric 9583OW, and Sunsafe F) (Kinkead et al. 1987a, 1988) and a U.S. military MIL-H-5606 fluid (Kinkead et al. 1985). Single gavage doses of a MIL-H-5606 hydraulic fluid (5 mL/kg or ≈4,500 mg/kg) produced no clinical signs of acute neurotoxicity or delayed neuropathy in Leghorn chickens within 21 days of dosing, nor did it produce histological changes in peripheral or central nervous system (tissues examined were not specified) like those produced in positive control chickens treated with 500 mg/kg tri-ortho-cresyl phosphate (Kinkead et al. 1985).

No studies were located regarding neurological effects in animals after intermediate or chronic-duration oral exposures to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. A brief overview of organophosphate ester neurotoxicity is presented in Section 2.2.1.4.

A number of human poisonings have been reported, dating back to the 1930s in which the primary effects of tricresyl phosphates were neurological (Goldstein et al. 1988; Senanayake and Jeyaratnam 1981; Srivastava et al. 1990). Though doses are difficult to ascertain, estimated exposure to 50-100 mg/kg/day resulted in facial weakness, severe dysarthria (difficulty of speech due to muscular control problems stemming from central or peripheral nerve damage), loss of reflexes and myoclonic jerking in a 4-year-old boy (Goldstein et al. 1988) and polyneuropathy in young Sri Lankan girls (Senanayake and Jeyaratnam 1981) exposed to 5-10 mg/kg/day for 14 days. The boy fully recovered in 5 weeks. One year after ingesting 5-7 doses of tricresyl phosphate, the young women still reported reduced muscular strength. Abou-Donia and Lapadula (1990) have estimated that there have been more than 40,000 cases of OPIDN. More than 20,000 cases occurred in the United States in the 1930s as a result of people consuming a contaminated extract of ginger called “Jamaican Ginger.” Subsequent analysis revealed that these cases of delayed neuropathy were caused by the presence of a specific isomer of tricresyl phosphate, tri-ortho-cresyl phosphate (TOCP), in the extract.

Many of the studies on the neurological effects of oral exposure to organophosphate ester hydraulic fluids in animals have employed chickens as models instead of the more commonly used rodent models. For reasons that are not well understood, organophosphate-induced delayed neuropathy can be induced in chickens and cats, but not in mice or rats (Abou-Donia and Lapadula 1990).

Several organophosphate ester hydraulic fluids produced neurological effects, including acute cholinergic toxicity and signs of organophosphate-induced delayed neuropathy (OPIDN), in chickens after acute gavage administration (see Table 2-5). Fyrquel EHC produced incoordination, inability to stand and eventually ataxia in chickens after a single dose of 11,350 mg/kg (Stauffer Chemical Co. 1980); spinal cord lesions with minor signs of neuropathy at 5,000 mg/kg and ataxia at 10,000 mg/kg (Mortensen and Ladefoged 1992); and decreased activities of brain neurotoxic esterase and plasma cholinesterase without signs of neurotoxicity at 1,140 mg/kg (Stauffer Chemical Co. 1981). Brain neurotoxic esterase activity was reduced 94% by a single dose of 11,350 mg/kg Fyrquel EHC, a dose which produced ataxia (Stauffer Chemical Co. 1980). Chickens dosed with either tributyl phosphate or dibutyl phenyl phosphate exhibited apparent cholinergic signs (salivation, diarrhea, impaired respiration) for 2-4 days after single doses near the LD₅₀ for these compounds but did not show significant reduction in brain acetylcholinesterase or further signs of neurotoxicity (Canington et al. 1989). Tributoxyethyl phosphate significantly inhibited brain acetylcholinesterase (45%), but neither acute cholinergic signs nor further signs of neurotoxicity developed. Inhibition of NTE and motor incoordination were observed in chickens receiving a single oral dose of 11,700 mg/kg isopropyl triphenyl phosphate (Sprague et al. 1984), but OPIDN did not develop. Reofos 65 produced minor histological changes in peripheral nerves without cholinergic symptoms or signs of delayed neuropathy at doses ≤5,000 mg/kg (Mortensen and Ladefoged 1992).

Tricresyl phosphate caused ataxia, axonal degeneration and reduction of NTE at 60 mg/kg/day over 10 weeks in chickens (Freudenthal et al. 1993). Skydrol LD-4 and Skydrol 500B-4 produced decreased activities of brain neurotoxic esterase (−46%), brain acetylcholinesterase (−18%), and plasma butyrylcholinesterase (−78%), as well as cholinergic symptoms at respective LD₅₀ levels of 2,594 and 2,559 mg/kg in chickens. No clear signs of delayed neuropathy developed in survivors at doses as high as 5,000 mg/kg (Monsanto 1987c, 1987d). U.S. military fluids designated as Durad MP280 and Cellulube 220 produced distinct clinical signs of OPIDN (ataxia and paralysis) in chickens after 5 days of dosing with 240 and 60 mg/kg/day, respectively (Carpenter et al. 1959; Gaworski et al. 1986). A tricresyl phosphate fluid designated TCP-1 caused leg and wing weakness and paralysis in chickens receiving 240 mg/kg/day for 5 days (Friess et al. 1959). Fyrquel 220 and Fyrquel 150 each produced distinct clinical signs of OPIDN in chickens after 5-day administrations of respective doses of 5,000 mg/kg/day (FMC 1977a) and 240 mg/kg/day (Stauffer Chemical Co. 1971). Fyrquel 220 at a dose of 420 mg/kg/day had no effect (FMC 1977a). Fourteen days of tricresyl phosphate exposure in mice caused cholinergic signs such as piloerection, tremors, and lethargy at 2,275 mg/kg/day, but not OPIDN (Chapin et al. 1988)

Another group of organophosphate ester hydraulic fluids produced no signs of neurotoxicity in chickens following acute gavage administration. Fluids that produced no neurotoxic signs in chickens (with the maximum dose level at which they were tested in parenthesis) included U.S. military fluids MIL-H-19457B and MIL-H-19457(3 (420 mg/kg/day for 5 days [Gaworski et al. 1986; Kinkead et al. 1989b]), Pydraul 50E (20,000 mg/kg/day for 3 days [Monsanto 19791 and 5,000 mg/kg/day for 4 or 5 days [Ciba-Geigy 1973; FMC 1977b]), Pydraul 29ELT (20,000 mg/kg/day for 3 days [Monsanto 1979]), and Pydraul 90E (20,000 mg/kg/day for 3 days [Monsanto 19791). Each of these studies provided sufficient periods (>18 days) to observe signs of delayed neuropathy.

Administration of organophosphate ester hydraulic fluids has produced neurological effects in-species other than chickens. Cellulube 220 produced delayed hindlimb paralysis in two goats 19-36 days after single doses of 5,000 or 10,000 mg/kg, and incoordination, accompanied with demyelination and axonal swelling in peripheral nerves, and increased cellularity in dorsal and ventral spinal nerve roots in a calf 19 days after a single dose of 7,700 mg/kg (Dollahite and Pierce 1969). Beck et al. (1977) observed acute signs of cholinesterase inhibition (diarrhea, rapid respiration, salivation, miosis) that eventually led to death in calves given 500, 1,000, or 2,000 mg/kg/day Fyrquel 150 by gavage for 10 days. The dose level did not influence the onset or severity of clinical signs. Delayed hindlimb paralysis developed in two cows given single gavage doses of 500 or 1,000 mg/kg Fyrquel 150; histological examination of the spinal cord revealed axonal degeneration and demyelination (Beck et al. 1977). The onset of hindlimb paralysis was observed after the cessation of cholinesterase effects on either day 15 or 19.

No clinical signs of neurotoxicity were observed in rats after acute gavage administration in lethality studies of several organophosphate ester hydraulic fluids tested at dose levels as high as 5,000 mg/kg. Tested materials included Durad 300 (FMC 1990a), Durad 110 (FMC 1990a), Durad 220B (FMC 1990a), Durad 550B (FMC 1992a), and a cyclotriphosphazene based fluid (Kinkead et al. 1992c; MacEwen and Vemot 1985). Durad 125 produced an 85% inhibition of serum cholinesterase in rats, without producing cholinergic signs (tremors, diarrhea) like those produced in positive controls treated with tri-ortho-cresyl phosphate (FMC 1991a). Cellulube 220, a fluid that produced definite signs of delayed neuropathy in goats and cows, produced no signs of neurotoxicity in rats treated with 20,000 mg/kg (Dollahite and Pierce 1969).

No studies were located regarding neurological effects in animals after chronic oral exposure to organophosphate ester hydraulic fluids, but three hydraulic fluids have been tested for neurological effects in animals after intermediate dose administration. In a 90-day dietary study, administration of 50 mg/kg/day Pydraul90E to albino rats produced no effects on brain, plasma, or red blood cell cholinesterase activities, compared with controls, and no histological effects. The report did not mention the extent of the histological examination nor the occurrence of clinical signs of neurotoxicity (Monsanto 1979). In a 28day study with domestic chickens gavaged daily with Durad 110, an increased incidence of chickens with clinical signs of ataxia was observed at 1,333 mg/kg/day, but not at 444 mg/kg/day (FMC 1986). In a 90-day gavage study with Durad 110, chickens treated with 90 mg/kg/day displayed an increased incidence of ataxia and axonal damage in the spinal cord and peripheral nerves. The NOAEL for neurological effects was 20 mg/kg/day (FMC 1986). Cellulube 220 administered at a dose level of ≈8,333 mg/kg/day three times over a 56-day period produced incoordination in a calf after the last dose administration; axonal swelling in the peripheral nervous system was observed (Dollahite and Pierce 1969).

Neurological effects have also been observed with several organophosphate esters used currently or formerly in hydraulic fluids. Dibutyl phenyl phosphate decreased erythrocyte and brain acetylcholinesterase levels in female rats exposed by feed for 91 days at 250 mg/kg/day but not at 50 mg/kg/day (Healy et al. 1991). Male rats similarly exposed were unaffected. In Fischer 344 rats receiving tricresyl phosphate by gavage for 16 days, decreased activity and grip strength were noted in females at 1,450 mg/kg/day and in males at 2,900 mg/kg/day (NTP 1994); no-effect levels were 730 mg/kg/day in females and 1,450 mg/kg/day in males. Thirteen-week exposures by gavage or feed in this strain of rats at ≤800 mg/kg/day tricresyl phosphate had no effect on neurological parameters or histology of brain, spinal cord or sciatic nerve (NTP 1994). In a 2-year feeding study with tricresyl phosphate in rats (0, 3, 6, or 13 mg/kg/day in males; 0,4,7, or 15 mg/kg/day in females), no histological evidence of treatment-related damage to nervous system tissues (brain, spinal cord, and sciatic nerve) was observed (NTP 1994).

Tricresyl phosphate exposure by feed for 13 weeks resulted in tremors in male B6C3F, mice receiving 900 mg/kg/day and decreased forelimb grip strength at 380 mg/kg/day (NTP 1994). Female mice exposed at 530 mg/kg/day also showed decreased hindlimb strength along with histopathological evidence of axonal degeneration in the spinal cord and sciatic nerve. NOAELs in this study were 180 mg/kg/day in males and 230 mg/kg/day in females. Tricresyl phosphate was more potent for inducing neurological effects when given by gavage. A 13-week exposure by gavage (5 days a week) produced multifocal degeneration of the spinal cord and sciatic nerve at 100 mg/kg/day (NTP 1994). No histologic evidence of treatment-related damage to brain, spinal cord, or sciatic nerve was seen in mice after a 2-year feed exposure to ≤37 mg/kg/day tricresyl phosphate (NTP 1994).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding neurological effects in humans after oral exposure to polyalphaolefin hydraulic fluids.

In a series of acute lethality studies on U.S. military fluids, single gavage doses (4,250 or 5,000 mg/kg) of one of several polyalphaolefin hydraulic fluids did not produce signs of neurological toxicity in rats within 14 days of dosing. Tested materials included fluids designated as DTNSRDC Nos. N448, N501, N517, N518, N525, and N527 (MacEwen and Vemot 1983); B85-174 (Kinkead et al. 1987b); MIL-H-83282LT (Kinkead et al. 1992b); MIL-H-83282 (Kinkead et al. 1985). Single gavage doses of MIL-H-83282 (7.5 mL/kg or 6,375 mg/kg) or MIL-H-83282LT (5,000 mg/kg) did not produce delayed neuropathy in Leghorn chicken hens within 21 days of dosing (Kinkead et al. 1985, 1992b). No other information was located on neurological effects in animals after oral exposure to polyalphaolefin hydraulic fluids.

2.2.2.5. Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after oral exposure to mineral oil hydraulic fluids or to polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding reproductive effects in humans after oral exposure to organophosphate ester hydraulic fluids.

Data suggestive of adverse reproductive effects after an assumed acute oral exposure to organophosphate ester hydraulic fluids are restricted to an observation of reduced lactation and delayed estrus with no coincident gross lesions in cows that ingested grass contaminated with Fyrquel 150 (Beck et al. 1977).

There are a number of studies of intermediate duration which note reproductive effects in experimental animals. Rats exposed to 400 mg/kg/day tricresyl phosphate and 1,900 mg/kg/day butylated triphenyl phosphate for 40 days by gavage showed hypertrophy and vacuolization of ovarian interstitial cells (Latendresse et al. 1993). These results are supported by a study in which rats exposed by gavage for 20,40, and 60 days showed lipidosis in ovarian interstitial cells at 400 mg/kg/day tricresyl phosphate and 1,700 mg/kg/day butylated triphenyl phosphate, as well as testicular degeneration and decreased testicular weight at 400 mg/kg/day tricresyl phosphate (Latendresse et al. 1994a). An increase in abnormal sperm morphology and necrosis of seminiferous tubules were noted in male rats exposed to 100 mg/kg/day tricresyl phosphate by gavage, while decreased fertility and vacuolar cytoplasmic alteration of ovarian interstitial cells were noted in female rats exposed at 200 mg/kg/day to this compound for 66 days (Carlton et al. 1987). Latendresse et al. (1994b) reported decreased numbers of litters in rats exposed by gavage to 600, 1,000, and 1,700 mg/kg/day butylated triphenyl phosphate and 400 mg/kg/day tricresyl phosphate for 98 days. In the same study, 100% infertility, decreased testicular and epididymal weights, and increased ovarian weights were seen at 400 mg/kg/day tricresyl phosphate; and abnormal estrous cycles and decreased uterine weights were noted in female rats exposed to 1,000 mg/kg/day butylated triphenyl phosphate, all for 106 days. Decreased mating and fertility indices and decreased number of live pups per litter were seen after 105 days of exposure to 124 mg/kg/day in the feed (Chapin et al. 1988) but not at 62.5 mg/kg/day.

Reproductive changes in rats and mice were found in intermediate- and chronic-duration oral studies performed with tricresyl phosphate by the National Toxicology Program (NTP 1994). Ovarian interstitial cell hypertrophy was a common finding in both species and occurred at the lowest doses tested in rats in a 13-week feeding study in rats (65 mg/kg/day) and a 13-week gavage study (50 mg/kg/day). In mice, this sign was observed at 50 mg/kg/day in a 13-week gavage study. These effects were seen at all doses tested, but did not increase in severity with dose. Interstitial cell cytoplasmic vacuolization was observed at 530 mg/kg/day in a 13-week feeding study, but hypertrophy was not. Seminiferous tubule atrophy was observed in rats at 430 mg/kg/day in 13-week feeding studies and at 400 mg/kg/day in 13-week gavage studies. Similar results were seen in mice treated by gavage, but not in mice exposed to tricresyl phosphate by feeding (NTP 1994).

In contrast, several studies did not report reproductive effects. Laham et al. (1985) reported no significant changes in the testes or ovaries in rats exposed by gavage to a high dose of 350 mg/kg/day tri-n-butyl phosphate for 18 weeks. No gross or histological alterations in the reproductive tract after acute oral exposure were observed in male rabbits gavaged with 480 mg/kg Cellulube 220 (Carpenter et al. 1959) or in chickens given ≤420 mg/kg of MIL-H-19457B or MIL-H-19457C (Kinkead et al. 1989b). No changes in gonad weight or histology were observed in male or female rats after oral exposure to Pydraul90E at a dietary concentration of 50 mg/kg/day for 90 days (Monsanto 1979).

In a 2-year feeding study in rats, ovarian interstitial cell hyperplasia was observed in rats exposed to 15 mg/kg/day tricresyl phosphate, but no effect was seen at 7 mg/kg/day (NTP 1994). No effects on male reproductive tissues were seen at ≤13 mg/kg/day. No effects on reproductive tissues in either sex were observed in 2-year feeding studies in mice (27 mg/kg/day in males, 37 mg/kg/day in females).

A neurotoxic isomer of tricresyl phosphate (tri-ortho-cresyl phosphate) altered testicular morphology and function as well as reproductive function after oral exposure in rats (Somkuti et al. 1987a, 1987b) (see Section 2.5).

2.2.2.6. Developmental Effects

No studies were located regarding developmental effects in humans or animals after oral exposure to mineral oil hydraulic fluids or to polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding developmental effects in humans after oral exposure to organophosphate ester hydraulic fluids.

Data suggestive of adverse developmental effects after an assumed acute oral exposure to organophosphate ester hydraulic fluids are restricted to an observation of retarded growth in calves of cows with reduced lactation, and “abnormal” growth in a calf of a cow that showed moderate ataxia, after the cows ingested grass probably contaminated with Fyrquel 150 (Beck et al. 1977).

None of the calves of 10 cows showed clinical signs of neurotoxicity after the cows were orally exposed to an unknown quantity of a Fyrquel hydraulic fluid reclamation waste that according to the authors possibly contained tri-ortho-cresyl phosphate (TOCP), and that was applied liberally to their backs one time as a treatment for ringworm (Julian et al. 1976). The cows were seen licking their backs and the backs of other cows; thus, the cows were orally and dermally exposed to organophosphate ester hydraulic fluids.

With acute-duration exposure to tricresyl phosphate and dibutyl phenyl phosphate, decreased litter size and pup survivability were found at 400 mg/kg/day (Carleton et al. 1987) and 50 mg/kg/day (Healy et al. 1991), respectively. Exposure to Santicizer 154 caused no developmental changes in the offspring of rats treated with ≤2,000 mg/kg/day for 14 days (Robinson et al. 1986). An 8% decrease in pup weight was reported in the offspring of rats treated during gestation with 1,000 mg/kg/day Phosflex 51 B, although the authors considered this effect to be secondary to maternal toxicity (Stauffer 1982). Increased incidence of rudimentary lumbar ribs were noted in offspring of rat dams treated with tributyl phosphate at 500 mg/kg/day over gestation days 7-17 (Noda et al. 1986). Dibutyl phenyl phosphate, a component of some organophosphate ester hydraulic fluids, decreased the postnatal survival of rat pups. Decreased survival to day 4 was observed in the F_1a pups (first litter) of rats exposed to 50 or 250 mg/kg/day and F_1b pups (second litter) of rats exposed to 5 or 50 mg/kg/day (but not to 250 mg/kg/day). The number of live offspring at weaning was also diminished in the F_1a pups in 50 and 250 mg/kg/day groups and F₂, pups of the 250 mg/kg/day group. In an attempt to determine if the reduced survival was due to in utero effects, the F_1b pups of the 250 mg/kg/day pups were cross-fostered with control pups. Reduced survival at day 4 and weaning was observed in the control pups raised by the high-dose rats. Decreased body weight gains were observed in the F, dams (parental) exposed to 250 mg/kg/day and F₁, dams exposed to 50 and 250 mg/kg/day. Effects on control pups, potentially exposed via treated dams are equivocal. Although surviva1 was reduced, the cause is not clear (Healy et al. 1991). Additionally, no changes were seen in the type or incidence of developmental anomalies observed in the pups of male and female rats that had been orally exposed to triphenyl phosphate, another component of some organophosphate ester hydraulic fluids at doses ≤ 690 mg/kg/day for 91 days, including through mating and gestation (Welsh et al. 1987).

No intermediate- or chronic-duration oral studies examining developmental effects in animals were located.

2.2.2.7. Genotoxic Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after oral exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding genotoxic effects in humans after oral exposure to organophosphate ester hydraulic fluids.

The incidence of nuclear anomalies in bone marrow interphase cells significantly increased (p<0.05) in Chinese hamsters gavaged on 2 consecutive days with 2,500 and 5,000 mg/kg/day of Reofos 50 (Ciba-Geigy 1984a), but not in those dosed with 1,250 mg/kg/day. The types of anomalies used in scoring were single “Howell-Jolly” bodies, fragments of nuclei in erythrocytes, micronuclei in erythroblasts, micronuclei in leucopoietic cells, and polyploidal cells.

Administration of single doses of ≤5,000 mg/kg Reofos 50 in sodium-carboxymethyl cellulose or Reolube HYD46 in arachid oil by gavage oil to four male and four female Chinese hamsters did not induce significant increases in sister chromatid exchanges in bone marrow cells (Ciba-Geigy 1983b, 1984b). Other genotoxicity studies for organophosphate ester hydraulic fluids are discussed in Section 2.5.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after oral exposure to polyalphaolefin hydraulic fluids.

2.2.2.8. Cancer

Mineral Oil Hydraulic Fluids. No studies were located regarding cancer in humans or animals after oral exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding cancer in humans after oral exposure to organophosphate ester hydraulic fluids.

A 2-year carcinogenicity bioassay of tricresyl phosphate in mice and rats showed no evidence of carcinogenicity in these species (NTP 1994). Doses (consumed in feed) were 137 mg/kg/day in mice and ≤15 mg/kg/day in rats. Dietary administration of tributyl phosphate was associated with transitional and squamous cell carcinomas of the bladder in rats after 2 years of exposure at 143.3 mg/kg/day (FMC 1994a). An increased incidence of hepatocellular adenomas in the liver was observed in mice after dietary administration of 455 mg/kg/day tributyl phosphate for 18 months (FMC 1994b).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding cancer in humans or animals after oral exposure to polyalphaolefin hydraulic fluids.

2.2.3.1. Death

Mineral Oil Hydraulic Fluids. No studies were located regarding death in humans after dermal exposure to mineral oil hydraulic fluids.

Several water-in-oil emulsion hydraulic fluids (Houghto-Safe 5047F, Sunsafe F, Pyroguard A-443, and Quintolubric 95830W) produced no deaths or signs of toxicity in rabbits within 14 days of single 24-hour exposures to occluded doses of 2,000 mg/kg spread evenly onto the backs and sides of the animals (Kinkead et al. 1987a, 1988). A U.S. military fluid designated as MIL-H-5606 likewise produced no deaths in rabbits within 14 days of 24-hour exposures to occluded doses of 1,800 mg/kg spread evenly onto the backs and sides of the animals (Kinkead et al. 1985). Additional information on lethality of mineral oil hydraulic fluids in animals after oral exposure was not located. -.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding death in humans after dermal exposure to organophosphate ester hydraulic fluids.

Table 2-7

Levels of Significant Exposure to Mineral Oil Hydraulic Fluids - Dermal.

Table 2-8

Levels of Significant Exposure to Organophosphate Ester Hydraulic Fluids - Dermal.

Table 2-9

Levels of Significant Exposure to Polyalphaolefin Hydraulic Fluids - Dermal.

No deaths occurred in rats after dermal exposure to Durad 220B, Durad 300, or Durad 110 under occluded conditions for 24 hours at dosage levels of 2,000 mg/kg (FMC 1990a). Dermal exposure to 2,890 mg/kg doses of a cyclotriphosphazene hydraulic fluid for 24 hours under occluded conditions likewise produced no deaths in rabbits (Kinkead et al. 1992c; MacEwen and Vemot 1985). Deaths associated with severe cholinergic symptoms and symptoms of delayed neuropathy occurred in a group of 50 cattle treated dermally with about 1.52 L of waste from reclamation of a Fyrquel hydraulic fluid (Julian et al. 1976). The material was poured over the backs of the animals as a ringworm treatment. Exposure was expected to have been by the oral route as well as by dermal contact, because the cows were seen licking their backs or the backs of other cows; 14 of 50 cows died within 4 weeks of exposure. The authors stated that this fluid may have been contaminated with tri-ortho-cresyl phosphate.

Johannsen and colleagues (1977) report dermal LD₅₀ values for rabbits at levels of >3,700 mg/kg for a group of triaryl phosphates, >5,000 mg/kg for dibutyl phenyl phosphate, 5,000 mg/kg for both asymmetrical and symmetrical triaryls, and >3,100 mg/kg for tributyl phosphate. This study looked at structural activity relationships for the organophosphate esters.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding death in humans after dermal exposure to polyalphaolefin hydraulic fluids.

Several U.S. military polyalphaolefin hydraulic fluids (designated as B85-174, MJL-H-83282, MLL-H-83282, and DTNSBDC Nos. N448, N501, N5 17, N5 18, N525, and N527) produced no deaths in rabbits within 14 days of single 24-hour occluded exposures to either 2,000 mg/kg (B85-174 and MJL-H-83232LT) or 5 mL/kg (= 1,700 mg/kg; the remaining fluids were applied at this level) (Kinkead et al. 1987b; MacEwen and Vemot 1983). The test materials were spread evenly over the backs and sides of the animals.

2.2.3.2. Systemic Effects

The highest NOAEL and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Tables 2-7, 2-8, and 2-9 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively.

2.2.3.3. Immunological and Lymphoreticular Effects

The highest NOAEL values and all LOAEL values for each reliable study for immunological effects in each species and duration category are recorded in Tables 2-7, 2-8, and 2-9 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively.

Mineral Oil Hydraulic Fluids. No studies were located regarding immunological effects in humans after dermal exposure to mineral oil hydraulic fluids.

In guinea pig assays for skin sensitization, 4 of 5 tested mineral oil hydraulic fluids (Pyroguard A-443, Sunsafe F, Houghto-Safe 5047F, and MIL-H-5606) displayed no activity; the remaining fluid, Quintolubric 95830W, displayed only weak skin sensitization (skin sensitization occurred in only 1 of 10 guinea pigs) (Kinkead et al. 1985, 1987a, 1988). No other studies were located regarding immunological effects in animals after dermal exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No dermal sensitization was observed in a study of human subjects (46 females and 7 males) exposed dermally to 0.2 mL Skydrol 500B-4 for three 24-hour periods per week for 5 weeks (Monsanto 1980). No other studies were located regarding immunological effects in humans after dermal exposure to organophosphate ester hydraulic fluids. Two case reports of skin sensitization to triphenyl phosphate were found. A woman developed eczema from her eyeglasses containing the phosphate (Carlsen et al. 1986), and a carpenter tested positive to an allergy patch test, where a 5% petrolatum solution of triphenyl phosphate was applied after exposure to a glue containing it (Camarassa and Serra-Baldfich 1992).

No skin sensitization was seen in guinea pigs treated with four doses of 0.1 mL of a cyclotriphosphazenebased hydraulic fluid on the skin of the forelegs (Kinkead et al. 1992c; MacEwen and Vernot 1985). Thymus weight decreases (both absolute and relative to body weight) were observed, without histological alterations, in rabbits dermally exposed to 6-hour doses of cyclotriphosphazene ≤1,000 mg/kg, 5 days/week for 21 days (Kinkead et al. 1989c, 1990). No other studies regarding immunological effects in animals after dermal exposure were located.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding immunological effects in humans after dermal exposure to polyalphaolefin hydraulic fluids.

Two U.S. military polyalphaolefin hydraulic fluids, MJL-H83232LT and B85-174, displayed skin sensitization activity in guinea pigs (Kinkead et al. 1987b, 1992b). Seven other polyalphaolefin hydraulic fluids did not produce skin sensitization in guinea pig assays; tested materials were designated as MIL-H-83282 (Kinkead et al. 1985) and DTNSDR Nos. N448, N501, N517, N518, N525, and N527 (MacEwen and Vernot 1983). No other studies were located regarding immunological effects in animals after dermal exposure to polyalphaolefin hydraulic fluids.

2.2.3.4. Neurological Effects

The highest NOAEL values and all LOAEL values for each reliable study for neurological effects in each species and duration category are recorded in Tables 2-7, 2-8, and 2-9 for mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, and polyalphaolefin hydraulic fluids, respectively.

Mineral Oil Hydraulic Fluids. Weakness in the hands and the absence of tendon reflexes developed in a man whose skin was exposed heavily to mineral-oil-based hydraulic fluids on a daily occupational basis for ≈2 years. Reportedly, his hands and arms “were always wet with fluid,” and his clothes were often saturated with fluid (Järvholm et al. 1986). The fluid, to which the man was exposed for an unspecified number of months prior to the appearance of neurotoxic signs, contained ≈0.5% isopropylated triphenyl phosphate and <50 ppm tri-ortho-cresyl phosphate (TOCP) according to the manufacturer’s analysis. A coincidental association between polyneuropathy and exposure to hydraulic fluid in this case could not be excluded. Neurological examination of eight men who worked with mineral-oil-based hydraulic fluids for 3 months to 13 years revealed subtle electromyographical effects in several muscles of four of the men (“a reduced number of motor unit potentials”), but no such effects were observed in eight nonexposed male controls (Järvholm et al. 1986). Reportedly, the exposed men in this study were less heavily exposed to hydraulic fluids than the man who developed arm weakness and absence of tendon reflexes. The two reports provide limited evidence that dermal exposure to certain mineral-oil-based hydraulic fluids may produce neurological effects. Other studies on neurological effects in humans following dermal exposure to mineral-oil-based hydraulic fluids were not located.

In acute toxicity studies, rabbits exposed to 2,000 mg/kg occluded dermal doses of one of several mineral oil hydraulic fluids (Sunsafe F, Houghto-Safe 5047F, Quintolubric 95830W, Pyroguard A-443 and MIL-H-5606) for 24 hours displayed no signs of neurological toxicity within 14 days postdosing (Kinkead et al. 1985, 1987a, 1988). Other information on neurological effects in animals following dermal exposure to mineral oil hydraulic fluids was not located.

Organophosphate Ester Hydraulic Fluids. A brief overview of organophosphate ester neurotoxicity is presented in Section 2.2.1.4.

During a cleaning operation, 14 men on a U.S. Navy ship were dermally exposed on their hands and arms, and on the clothing to a hydraulic fluid described as a mixture of triphenyl phosphates (Baldridge et al. 1959). The men were directed to bathe and change clothing 24 hours after the operation. Blood samples were drawn for plasma and red blood cell cholinesterase measurement presumably 24 hours after the cleanup event and after an interval of 2 weeks. No significant differences in cholinesterase values were observed between theexposed men and a group of nonexposed men. The men were instructed to report the occurrence of any neuropathic symptoms to the medical department of the ship, but none were reported.

Another group of 14 men was exposed primarily by dermal contact to a triaryl phosphate hydraulic fluid during installation and operation of hydraulic aircraft elevators on a U.S. Navy ship (Baldridge et al. 1959). Neurological examinations, physical examinations, white blood cell counts, and blood cholinesterase measurements made several times during a 3- to 4-month operation period failed to detect differences between the exposed men and a group of eight nonexposed men from the same ship.

No other information was located regarding neurological effects in humans after dermal exposure to hydraulic fluids.

Several organophosphate ester hydraulic fluids produced no clinical signs of neurotoxicity in rats and rabbits during 14-day observation periods after 24-hour periods of occluded dermal exposure. Tested hydraulic fluids included Durad 110 (FMC 1990a), Durad 300 (FMC 1990a), and a cyclotriphosphazene-based hydraulic fluid (Kinkead et al. 1992c; MacEwen and Vemot 1985). These species are not susceptible to organophosphate-induced delayed neuropathy (Abou-Donia and Lapadula 1990).

Delayed neuropathy occurred in a group of 50 cattle after the waste from reclamation of contaminated hydraulic fluid was poured over their backs as a treatment for ringworms (Julian et al. 1976). The animals were observed licking their backs and the backs of others, suggesting that oral as well as dermal exposure occurred. The composition of the waste product was unknown, but the hydraulic fluid was identified as a Fyrquel that may have been contaminated with tri-ortho-cresyl phosphate (TOCP). The first signs of posterior weakness (knuckling at the fetlocks and mild ataxia) were noted 20 days after treatment. Decreased sensory and motor responses in the hind limbs were observed, and histopathological examination of seven cows revealed demyelination and degeneration in the spinal cord and the sciatic nerve.

Severe cholinergic signs (diarrhea, generalized weakness, dyspnea, and decreased blood cholinesterase activity) and subsequent death occurred in two rabbits given daily 4-hour occluded dermal exposures to Cellulube 220 that contained a mixture of tricresyl and trixylenyl phosphate esters (Carpenter et al. 1959). One rabbit died after 6 days of exposure and the other died after 42 days of exposure. Daily exposures of 1 or 2 hours also produced cholinergic signs in groups of two rabbits exposed for ≤44 days. One of the two rabbits exposed daily for 2 hours developed hind limb weakness with an altered gait. Histological examination of brain, spinal cord, and sciatic nerve tissues in exposed rabbits revealed no “remarkable” alterations. Although this study indicates that neurological effects occurred in rabbits with repeated dermal exposure to Cellulube 220, no dosage levels were reported. Neither clinical nor histopathological signs of neurotoxicity were observed in hens treated dermally with two doses of 5,000 mg/kg tributoxyethyl phosphate 21 days apart (Carrington et al. 1989)

A cyclotriphosphazene-based hydraulic fluid produced no deaths, signs of neurotoxicity or histological alterations in the brain or sciatic nerve in rabbits after occluded dermal exposure at 1,000 mg/kg/day, 6 hours/day (≈10% of body surface area), 5 days/week for 21 days (Kinkead et al. 1989c, 1990).

No other information was located regarding neurological effects in animals after intermediate to chronic dermal exposure to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding neurological effects in humans after dermal exposure to polyalphaolefin hydraulic fluids.

Information regarding neurological effects in animals after dermal exposure to polyalphaolefin hydraulic fluids is restricted to a report that lethargy was observed in some rabbits during 24-hour periods of exposure to occluded topically applied (1,700 mg/kg) of polyalphaolefin hydraulic fluids designated as DTNSRDC Nos. N448, N501, N517, N518, N525, and N527 (MacEwen and Vemot 1983).

2.2.3.5. Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after dermal exposure to mineral oil hydraulic fluids or to polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding reproductive effects in humans after dermal exposure to organophosphate ester hydraulic fluids.

Dermal exposure of male rabbits to unspecified doses of Cellulube 220 (14 hours/day, 4-5 days/week for ≤46 days) did not elicit histological alterations in the testes (Carpenter et al. 1959). Dermal exposure of male and female rabbits to cyclotriphosphazene at doses ≤1,000 mg/kg/day for 6 hours/day, 5 days/week, for 21 days did not affect the reproductive organs (Kinkead et al. 1989c, 1990). No other dermal studies examining reproductive effects in animals were located. This NOAEL value for reproductive effects in rabbits acutely exposed to cyclotriphosphazene hydraulic fluid is recorded in Table 2-8.

2.2.3.6. Developmental Effects

No studies were located regarding developmental effects in humans or animals after dermal exposure to mineral oil hydraulic fluids or to polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding developmental effects in humans after derrnal exposure to organophosphate ester hydraulic fluids.

After a single dermal exposure to waste from the reclamation of a Fyrquel hydraulic fluid that may have been contaminated with tri-ortho-cresyl phosphate (TOCP), no apparent signs of neurotoxicity wereobserved in calves of 10 cows that manifested neurotoxicity just after the birth of the calves. The cows were apparently also exposed orally concurrent to the dermal exposure (Julian et al. 1976). No intermediate- or chronic-duration dermal studies examining developmental effects in animals were located.

2.2.3.7. Genotoxic Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after dermal exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after dermal exposure to organophosphate ester hydraulic fluids. Genotoxicity studies for organophosphate ester hydraulic fluids are discussed in Section 2.5.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding genotoxic effects in humans or animals after dermal exposure to polyalphaolefin hydraulic fluids.

2.2.3.8. Cancer

Mineral Oil Hydraulic Fluids. A significant elevated odds ratio was found between stomach cancer and occupational exposure to hydraulic fluids in a case-control study examining associations between subjectively reported occupational exposure to petroleum-derived liquids and cancer in particular organs (Siemiatycki et al. 1987a). The reference group consisted of 2,514 cancer patients who did not have stomach cancer. The main group of patients (n=155) exposed to hydraulic fluids consisted of automotive mechanics exposed to transmission and brake fluids. While inhalation exposure was possible, dermal contact was the expected predominant exposure route. Although the association between exposure to hydraulic fluids and stomach cancer was statistically significant, the biological relevance is uncertain due to several limitations of the study including sample size, possible misclassification errors in subjective exposure assessment, and confounding exposure to other compounds. The importance of exposure to other chemicals as a limitation was emphasized by the authors’ report that the association between stomach cancer and exposure to hydraulic fluids was no longer significant when adjustments were made for exposure to gasoline. No other information on cancer in humans exposed dermally to mineral oil hydraulic fluids was located.

No studies were located regarding cancer in animals after dermal exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding cancer in humans or animals after dermal exposure to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding cancer in humans or animals after dermal exposure to polyalphaolefin hydraulic fluids.

2.3.1.1. Inhalation Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding absorption in humans or animals after inhalation exposure to mineral oil hydraulic fluids.

Indirect evidence suggests that pulmonary absorption of hydrocarbons in mineral oil hydraulic fluids may occur. Mice, rats, and rabbits exposed to fogs (particle size ranged from 0.34 to 1.45 μm) of 63 mg/L of a diesel-engine lubricating oil for ≤343 days displayed (as indicated by histological analysis) oil in alveolar macrophages, mediastinal lymph nodes, lymphatic channels of the lungs, and in the pleura (Lushbaugh et al. 1950). A chemical analysis of lung and liver tissue found oil at respective concentrations of 0.13% and 0.03% (w/w) in exposed mice, but no oil in the same tissues from controls. These results are consistent with the hypothesis that mineral oil aerosols are not quickly absorbed by alveolar pneumocytes, and macrophages subsequently mediate clearance.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding absorption in humans after inhalation exposure to organophosphate ester hydraulic fluids.

No data were located regarding absorption in animals after inhalation exposure to organophosphate ester hydraulic fluids or specific organophosphate esters, except for the observation that parent material was not detected by gas chromatography in the blood or urine of male rats exposed to 5,120 mg/m³ of an aerosol of a cyclotriphosphazene (99.9%) hydraulic fluid for 4 hours, thereby suggesting that the extent of absorption was limited (Kinkead and Bashe 1987). Blood samples were collected at 0,24, and 48 hours after exposure was terminated. Urine was collected for 24 hours after exposure.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding absorption in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids or their major components. Based on physicochemical similarities with mineral oils (i.e., long-chain aliphatic hydrocarbons are predominant components), inhaled aerosols of polyalphaolefin hydraulic fluids may enter the body by macrophagemediated clearance (see discussion above for mineral oil hydraulic fluids).

2.3.1.2. Oral Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding absorption in humans or animals after oral exposure to mineral oil hydraulic fluids.

Food-grade or medicinal mineral oil, a mixture of aliphatic hydrocarbons that also may be found in mineral oil hydraulic fluids, is known to be absorbed only to a limited extent by the human gastrointestinal tract and has a laxative effect (Anonymous 1967; Brunton 1985), thus suggesting that mineral oil hydraulic fluids may behave likewise.

Experiments with rats given oral doses of tritiated food-grade mineral oil provide supporting evidence that the absorption of hydrocarbons in mineral oils is limited. Five hours after dosing with 0.66 mL/kg of tritiated mineral oil (“liquid petrolatum U.S.P.“), ≈75% of the administered radioactivity remained in the alimentary tract, and only 3% of the administered radioactivity was accounted for by radioactivity in other parts of the rat carcass (Ebert et al. 1966). About 80% of the administered radioactivity was recovered in feces during the first 2 days after treatment, and over 90% of the radioactivity in the feces was in the form of mineral oil. These data are consistent with the hypothesis that ingested mineral oil was poorly absorbed. Neither biliary excretion nor enterohepatic circulation of mineral oils was measured in this study, and thus, any quantitative estimates of the extent of absorption based on these data should be viewed as tentative.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding absorption in humans or animals after oral exposure to organophosphate ester hydraulic fluids.

Studies of excretion in animals following oral administration of TOCP and tri-para-cresyl phosphate suggest that organophosphate esters found in hydraulic fluids may be extensively absorbed by the gastrointestinal tract (Abou-Donia et al. 1990a, 1990b; Kurebayashi et al. 1985; Suwita and Abou-Donia 1990).

One day after oral administration of single 7.8-mg/kg doses of [methyl-¹⁴C]tri-para-cresyl phosphate (in DMSO) to male rats, radioactivity in urine, feces, expired air (as CO₂), and bile represented approximately 34%, 42%, 14%, and 28% of the administered dose, respectively (Kurebayashi et al. 1985). Measurements for expired air and excreted bile were carried out on five rats with cannulated bile ducts; fecal and urinary excretion were measured in another group of three rats without cannulated bile ducts. Assuming that radioactivity in urine, expired air, and bile represent absorbed compound, these results suggest that at least 76% of the tri-para-cresyl phosphate dose was absorbed. In rats given larger single doses of [¹⁴C]tri-para-cresyl phosphate (89.6 mg/kg), radioactivity in urine, feces, and expired air accounted for approximately 8%, 65%, and 3% of the dose, respectively, 1 day after dosing, and for 12%, 77%, and 6% of the dose, respectively, after 7 days. Enterohepatic circulation was not examined in the high-dose rats, but GC-MS analysis of the feces indicated that most of the radioactivity in the feces from the high-dose rats was unchanged tri-para-cresyl phosphate. This observation is consistent with the hypothesis that a significant portion of the high dose was not absorbed.

Male rats given single gavage doses of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]tri-ortho-cresyl phosphate in corn oil excreted approximately 50% and 25% of administered radioactivity in urine and feces, respectively, 24 hours after dosing (Abou-Donia et al. 1990a). Five days after dosing, cumulative radioactivity in urine and feces accounted for approximately 60% and 35%, respectively. Although biliary excretion and enterohepatic circulation were not examined in this study, the appearance of a large proportion of the administered radioactivity in the urine is indicative of extensive gastrointestinal absorption. Peak concentrations of radioactivity were observed between 2 and 48 hours after dosing (most tissues attained peak levels at 6 hours) in a number of nongastrointestinal tissues (Abou-Donia et al. 1990a); this implies that the TOCP was absorbed in less than 6 hours. The extent of absorption could not be estimated in companion excretion studies with chickens given single gavage doses of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]TOCP in corn oil, because chickens void urine and feces together and the authors did not attempt to separate them (Abou-Donia et al. 1990b; Suwita and Abou-Donia 1990). However, the hen studies provided qualitative evidence that TOCP was readily absorbed since radioactivity was detected within 12 hours of dosing in nongastrointestinal tissues including plasma, liver, kidney, and gall bladder.

Results from animal studies with other organophosphate esters also indicate ready gastrointestinal absorption. Rats given single oral doses of 14 mg/kg [1-butyl-¹⁴C]tributyl phosphate excreted approximately 50%, 10%, and 6% of applied radioactivity in urine, expired CO₂ and feces, respectively (Suzuki et al. 1984a). Metabolites of isopropylated phenyl phosphates were detected in the bile of rabbits within 6-24 hours of gavage administration of 2 g/kg Reolube HYD46, a hydraulic fluid containing isopropylated phenyl phosphates (Yang et al. 1990). Evidence for extensive absorption of tributyl phosphate was shown by the recovery of 66 to 80% of the radioactivity from [¹⁴C]tributyl phosphate in urine for single oral doses up to 350 mg/kg in rats (Gatz 1992a, 1992b, 1994).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding absorption in humans or animals after oral exposure to polyalphaolefin hydraulic fluids.

As mentioned previously, ingested food-grade mineral oil is absorbed only to a limited extent in humans and animals (Brunton 1985; Ebert et al. 1966). The physicochemical similarities between polyalphaolefins and mineral oils suggest that the extent of gastrointestinal absorption of polyalphaolefin hydraulic fluids also may be limited.

2.3.1.3. Dermal Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding absorption in humans or animals after dermal exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Limited studies indicate that organophosphate esters found in hydraulic fluids are absorbed by human skin. Radioactivity was detected in the blood and urine of two human subjects 1 hour after dermal exposure of both palms to 0.11 or 0.22 g of tri-ortho-cresyl phosphate labeled with radioactive phosphorus (Hodge and Sterner 1943). In vitro studies with human cadaver abdominal skin separating neat hydraulic fluids from an ethanol/water solution (70:30) found mean steady-state absorption rates of 0.9 and 0.54 μg/cm²/hour for triphenyl phosphate (TPP) and 2-isopropylphenyl diphenyl phosphate (2-IDPP), respectively, from the hydraulic fluid additive Reofos 50 (Ciba-Geigy 1985). The Reofos 50 sample reportedly contained 261.5 mg/mL TPP and 341.43 mg/mL 2-IDPP. Using the hydraulic fluid, Reolube HYD46 (which contained 30.5 mg/mL TPP and 218.1 mg/mL 2-IDPP), steady-state absorption rates of 0.67 and 3.32 μg/cm2kour were measured for TPP and 2-IDPP, respectively. The applicability of these in vitro absorption rates to in vivo exposures is uncertain due to several limitations of the study, including the use of skin from only one individual, the use of 70% ethanol in the receptor chamber, and the absence of reference standards in the study.

Single dermal doses of 50 mg/kg tri-ortho-cresyl-[uniformly labeled ¹⁴C-phenyl]phosphate (TOCP) were applied to preclipped, unprotected, 10-cm² areas of skin in male cats (Nomeir and Abou-Donia 1986). Three treated cats were sacrificed 0.5, 1,2,5, and 10 days after treatment. Radioactivity in urine and feces collected over the 10-day period accounted for 28% and 19% of the applied dose, respectively, but no radioactivity was detected in expired air. Radioactivity in analyzed tissues reached maximal levels at 24 hours (accounting for 8.7% of the applied dose). These data are inadequate for quantitative measurements of the extent of dermal absorption of TOCP, because a significant fraction of the applied radioactivity was not accounted for in the analysis, and some of the TOCP may have been ingested by the cats during grooming.

Radioactivity was detected in the blood and urine of a single female dog, 1 hour after dermal application of a 2.094-g dose of TOCP labeled with radioactive phosphorus to a 300-cm² area of clipped and depilated abdominal skin (Hodge and Sterner 1943). Gas chromatographic analysis of blood detected no parent material in male rats at 4,24, or 48 hours after a 24-hour, occluded exposure to a hydraulic fluid containing 99.9% cyclotriphosphazene, but the presence of metabolites in the blood was not investigated (Kinkead and Bashe 1987).

In Yucatan minipigs dermally exposed for 6 hours to 350 mg/kg, [¹⁴C]tributyl phosphate was only poorly absorbed (less than 5% of the applied dose). Absorption in rats treated under similar conditions was much higher (54-58%) (Gatz 1992a, 1992b).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding absorption in humans or animals after dermal exposure to polyalphaolefin hydraulic fluids.

2.3.1.4. Other Routes of Exposure

Mineral Oil Hydraulic Fluids. Absorption of a mineral oil in an emulsion was apparently very slow in female rats injected subcutaneously with 0.1 mL and in squirrel monkeys injected intramuscularly with 0.3 mL (Bollinger 1970). The emulsion contained 1 volume mannide monoleate, 9 volumes mineral oil, and 9 volumes water; [¹⁴C] labeled hexadecane, a major component of the mineral oil, was added to the emulsion as a radiotracer. At 1 week and 10 months after treatment, radioactivity remaining at the sites of injection accounted for 85-99% and 25-33%, respectively, of the administered radioactivity.

Organophosphate Ester Hydraulic Fluids. Absorption rates of TOCP were measured in chickens after subcutaneous injection by measuring the apparent disappearance of TOCP from the site of injection with ³¹P NMR spectroscopy (Carrington et al. 1988). Five chickens were injected with single, 1,187-mg/kg, neurotoxic doses in the back of the neck. Diminishment of the ³¹P-TOCP signal at the site of injection showed a biphasic pattern; calculated half-lives for the first and second phases were 3.22 hours and 15.3 days. The authors interpreted the first phase to be indicative of spreading of the material under the skin and the second phase to be indicative of absorption. They concluded that absorption of the subcutaneously injected material was slow.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding absorption of polyalphaolefin hydraulic fluids in humans or animals after exposure by routes other than inhalation, oral, or dermal.

2.3.2.1. Inhalation Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding distribution in humans or animals after inhalation exposure to mineral oil hydraulic fluids.

Numerous case reports of lipoid pneumonia in humans exposed through intranasal application of liquid petrolatum in medicinal nose drops (Cannon 1940; Lushbaugh et al. 1950) suggest that accumulation of oil in the lungs may be a concern with prolonged or high-level exposure to aerosols of mineral oils in hydraulic fluids. An examination of mice exposed to fogs of a lubricating oil for ≤343 days chemically detected oil in lung (0.13% [w/w]) and liver (0.03% [w/w]) tissue and histologically detected oil in alveolar macrophages, mediastinal lymph nodes, and lymphatic channels of the lung (Lushbaugh 1950). Further information regarding the distribution of inhaled mineral oil was not located.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding distribution in humans or animals after inhalation exposure to organophosphate hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding distribution in humans or animals after inhalation exposure to polyalphaolefin hydraulic fluids.

Oil accumulationin the lungs after long-term or high-level exposure to aerosols of polyalphaolefin may be a concern, based on observations of lipoid pneumonia in humans after prolonged intranasal application of mineral oil mists (Lushbaugh 1950) and the physical and chemical similarities between mineral oil and polyalphaolefins (i.e., both are composed predominately of aliphatic hydrocarbons).

2.3.2.2. Oral Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding distribution in humans or animals after oral exposure to mineral oil hydraulic fluids.

Limited evidence suggests that oil accumulation in the lungs may occur due to aspiration of ingested mineral oil hydraulic fluids. Although the danger of aspiring mineral oil into the lungs is not as great as other petroleum-based hydrocarbon mixtures with higher volatility and lower viscosity such as kerosene (Gerarde 1963; Klein and Simon 1986), oil accumulation in the lungs and lipoid pneumonia were observed in a child who ingested approximately 5-10 mL of a mineral oil automobile transmission fluid (Perrot and Palmer 1992).

Mineral oil may accumulate to some degree in liver and fatty tissues after absorption of ingested mineral oil hydraulic fluids, as indicated by experiments with rats given single, 0.66-mL oral doses of tritiated mineral oil (Ebert et al. 1966). Twenty-four hours after administration, the concentrations of tritiated mineral oil in liver and fat were approximately seven-fold greater than those in kidney and brain; other tissues were not examined.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding distribution in humans or animals after oral exposure to organophosphate ester hydraulic fluids.

A triaryl phosphate ester, tributoxyethyl phosphate, was detected at a mean concentration of 11.3 ng/g in 41 of 115 human adipose tissue samples taken from cadavers from Kingston and Ottawa, Canada (LeBel and Williams 1986). Because triaryl phosphate esters have been found in Canadian drinking water and fish, the presumed route of exposure of these individuals was oral. This study provides limited evidence that organophosphate esters found in hydraulic fluids may accumulate in human fatty tissue.

Studies with rats and chickens given oral doses of TOCP and tri-para-cresyl phosphate provide more definitive evidence that, following absorption, organophosphate esters in hydraulic fluids (or their metabolites) may be widely distributed among tissues with a preferential distribution to fatty tissues, the liver, and the kidneys (Abou-Donia et al. 1990a, 1990b; Kurebayashi et al. 1985; Somkuti and Abou-Donia 1990; Suwita and Abou-Donia 1990).

Less than 1% of total radioactivity was found in tissues 6-48 hours after oral administration of [¹⁴C]tributyl phosphate. The majority of label was found in urine (70%) and feces (18%) after both single and multiple doses of 10 and 350 mg/kg/day (Gatz 1992b). Approximately 5% of the label was recovered as CO₂ in expired air.

Twenty-four hours following oral administration of 89.6 mg/kg of [methyl-¹⁴C]tri-para-cresyl phosphate to male rats, radioactivity was detected in all tissues examined (Kurebayashi et al. 1985). Aside from the stomach and intestines, the highest concentrations (in units of ug-equivalents per gram of tissue) were found in fatty tissue (20), liver (11), and kidney (4). Radioactivity was detected at lower concentrations (>0.2 and <2 μg-equivalents per gram of tissue) in the following tissues listed in order of decreasing concentration: lungs, spleen, thymus, blood, testicles, heart, muscle, and brain. In male rats given single oral doses of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]TOCP, peak concentrations of radioactivity were observed between 2 and 48 hours after dosing (most tissues attained peak levels at 6 hours) in the following nongastrointestinal tissues, listed in order of decreasing concentration: urinary bladder, adipose tissue, liver, kidney, plasma, lungs, red blood cells, sciatic nerve, heart, spleen, testes, brain, spinal cord, and muscle (Abou-Donia et al. 1990a). The high concentration of radioactivity in the urinary bladder suggests that urinary excretion was significant (see Section 2.3.4). Similar evidence for widespread distribution of TOCP with preferential distribution to fat, liver, and kidneys was found in experiments in which male rats were given 10 daily doses of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]TOCP (Somkuti and Abou-Donia 1990) and chickens were given single oral doses of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]TOCP (Abou-Donia et al. 1990b).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding distribution in humans or animals after oral exposure to polyalphaolefin hydraulic fluids.

Based on physical and chemical similarities between mineral oil and polyalphaolefins, oil accumulation in the lung (and subsequent lipoid pneumonia) may occur following the ingestion of polyalphaolefin hydraulic fluids due to aspiration, and that distribution of polyalphaolefins to the liver and fatty tissues may occur to some degree (see-discussion for distribution of mineral oil hydraulic fluids).

2.3.2.3. Dermal Exposure

No studies were located regarding distribution in humans or animals after dermal exposure to mineral oil or polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding distribution in humans after dermal exposure to organophosphate ester hydraulic fluids.

A study with a dog exposed to an occluded dermal dose of TOCP labeled with radioactive phosphorus provides limited evidence that organophosphate esters in hydraulic fluids may be widely distributed after dermal absorption (Hodge and Sterner 1943). Similar widespread distribution of radioactivity among tissues was observed in male cats after dermal exposure to [uniformly labeled ¹⁴C-phenyl]TOCP (Nomeir and Abou-Donia 1986). Tissues and fluids with the highest concentrations of radioactivity in these studies included the bile, gall bladder, urinary bladder, liver, kidney, and fat, thus suggesting that TOCP and metabolites are somewhat preferentially distributed to these tissues.

Twenty-four hours after application of 2.094 g TOCP labeled with radioactive phosphorus to a 15×20 cm area of clipped and depilated abdominal skin, radioactivity was detected in the following tissues in a dog, listed in order of decreasing concentration (counts per gram of tissue): skin and facia at site of application, liver, omental fat, blood, kidney, lung, muscle (triceps femoris), spinal cord, heart, spleen = brain = sciatic nerve, and bone (femur) (Hodge and Sterner 1943).

In male cats, peak concentrations of radioactivity in most tissues and fluids were observed 24 hours after application of 50 mg/kg [uniformly labeled ¹⁴C-phenyl]TOCP to unprotected areas of skin on the back of the neck (Nomeir and Abou-Donia 1986). Peak concentrations of radioactivity (reported in parentheses in units of μg TOCP equivalent per gram) were highest for collected bile (317), followed by gall bladder (39.7), urinary bladder (39.1), kidneys (25.3), liver (16.3), cecum (14.5), fat (12.0), plasma (12.1), and lungs (12.1). Radioactivity was also detected in the following cat tissues (listed in order of decreasing concentration) but at peak concentrations <10 ug TOCP equivalents per gram: large intestine, sciatic nerve, red blood cells, pancreas, small intestine, heart, stomach, muscle, spleen, brain, and spinal cord. The observation of radioactivity in the stomach suggests that cats in his study ingested TOCP during grooming.

2.3.4.1. Inhalation Exposure

No studies were located regarding elimination and excretion in humans or animals after inhalation exposure to mineral oil hydraulic fluids, organophosphate ester hydraulic fluids, or to polyalphaolefin hydraulic fluids.

2.3.4.2. Oral Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding excretion in humans or animals after oral exposure to mineral oil hydraulic fluids.

Experiments with rats given oral or intraperitoneal doses of tritiated mineral oil (Liquid Petrolatum USP) indicate that orally administered hydrocarbons in mineral oil are predominately excreted rapidly, unchanged, and unabsorbed in the feces and that absorbed mineral oil is slowly excreted in the feces (presumably via biliary excretion) (Ebert et al. 1966).

Approximately 80% of administered radioactivity was excreted in the feces of rats within 2 days of oral administration of single 0.66 mL/kg doses of tritiated mineral oil (Ebert et al. 1966). Of administered radioactivity, 7-8% was excreted in the urine, but was in chemical forms other than mineral oil. The fecal radioactivity was predominately (90%) in the form of mineral oil. Pretreatment of the rats with 0.66 ml/kg/day nonradioactive mineral oil for 31 days did not substantially alter the excretion patterns.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding excretion in humans after oral exposure to organophosphate ester hydraulic fluids.

Studies with rats treated orally with triaryl or trialkyl phosphate esters (which may be found in organophosphate ester hydraulic fluids) indicate that these compounds and their metabolites are readily excreted in the urine, bile, feces and, to a limited extent, in expired air (Kurebayashi et al. 198.5; Somkuti and Abou-Donia 1990a; Suzuki et al. 1984a; Yang et al. 1990). Urinary excretion of metabolites appears to be the predominant elimination route in rats for tri-ortho-cresyl phosphate and tri-para-cresyl phosphate, but biliary excretion of parent material and metabolites is also important (Kurebayashi et al. 1985; NTP 1988). Fecal excretion may gain relative importance as an excretory route for tri-para-cresyl phosphate as doses approach levels of ≈100 mg/kg (Kurebayashi et al. 1985; NTP 1988). Fecal excretion of tri-m-cresyl phosphate appears to be predominant in rats even at a dose level of 200 mg/kg (NTP 1988).

In rats gavaged with 7.8 mg/kg [methyl-¹⁴C]tri-para-cresyl phosphate, most administered radioactivity was excreted in the urine (41%) and feces (44%) within 7 days of administration (Kurebayashi et al. 1985). Biliary excretion was estimated using a separate group of rats with cannulated bile ducts to account for −28% of administered dose. CO, in expired air accounted for 18% of administered radioactivity, but this diminished to 3% when the rats were pretreated with the antibiotic, neomycin (thereby indicating that some of the compound was metabolized by the gut microflora). Fecal excretion was relatively more important than urinary excretion after administration of a higher dose, 89.6 mg/kg tri-para-cresyl phosphate (77% versus 12% of administered radioactivity, respectively). Unchanged tri-para-cresyl phosphate was reported to be the main fecal “metabolite,” thereby indicating that absorption may have been incomplete at the higher dose. Half-lives of radioactivity in tissues were reported to range from 14 hours for blood to 26 hours for lungs and brain.

In rats given 10 daily 50-mg/kg doses of [phenyl-¹⁴C]TOCP, 63.1% and 36.1% of administered radioactivity was excreted in the urine and feces, respectively, within 4 days of the last administration (Somkuti and Abou-Donia 1990a). Most of the radioactivity in urine was in metabolites found in an acid hydrolysate fraction, emphasizing the importance of Phase II metabolism in the disposition of TOCP (see Section 2.3.3). Major metabolites in feces included (in order of decreasing abundance) o-cresol, unchanged TOCP, “unknowns,” and o-hydroxybenzoic acid. The authors reported that TOCP concentrations in brain, liver, kidney, testis, and plasma decreased exponentially within 4 days of the last dosing; estimated half-lives ranged from approximately 12 hours (0.49 days) in brain tissue to 24 hours (0.98 days) in the liver. The authors did not calculate half-lives for total radioactivity in tissues or plasma, but in a related study, the same group of investigators reported that the approximate half-life of radioactivity in tissues in general was 1 day in rats treated with single doses of 50 mg/kg [phenyl-¹⁴C]TOCP (Abou-Donia et al. 1990a).

Patterns of excretion in rats differed among [¹⁴C]labeled tricresyl phosphate isomers administered by gavage at dosage levels ranging from 0.5 to 200 mg/kg (NTP 1988). Radioactivity from tri-ortho-cresyl phosphate was excreted within 24 hours predominately in urine at all dosage levels (270% of applied doses). Radioactivity from tri-m-cresyl phosphate was excreted predominately in feces at all dosage levels. In contrast, urinary excretion of radioactivity from tri-para-cresyl was the predominant excretory route at low doses (0.5 or 2 mg/kg), while fecal excretion was the primary route at higher doses (20 or 200 mg/kg).

Male rats given single, oral doses of 14 mg/kg [l-¹⁴C]tributyl phosphate excreted 50% of the label in urine, 10% in exhaled air as CO₂and 6% in the feces within 1 day (Suzuki et al. 1984a). Within 5 days, cumulative radioactivity in urine, exhaled CO₂and feces accounted for approximately 68%, 10%, and 10% of the administered radioactivity, respectively.

Studies with chickens treated with single oral doses of 50 mg/kg [phenyl-¹⁴C]TOCP provide general corroborative data for the ready excretion of TOCP and metabolites (Abou-Donia et al. 1990b; Suwita and Abou-Donia 1990). However, the relative importance of urinary and fecal excretion cannot be ascertained from these studies, because feces and urine were not separated. Approximately 47% of administered radioactivity was found in excreta by 12 hours after administration; radioactivity in excreta collected for 5 days accounted for 99% of administered radioactivity (Abou-Donia et al. 1990b). Plasma half-lives of TOCP and saligenin cyclic-ortho-tolyl phosphate, the putative neurotoxic agent in TOCP, were reported to be 53 and 46 hours, respectively, and were compared with respective values of 46 and 19 hours for plasma half-lives in rats treated with single doses of [phenyl-¹⁴C]TOCP at the same dosage level (Abou-Donia 1990a). The authors suggested that the clearance of TOCP and its metabolites in plasma and tissues is slower in the hen (which is sensitive to TOCP-induced delayed neuropathy) than in the rat (which is less sensitive) and that this apparent difference may contribute to the difference in responses between these species (Abou-Donia 1990a, 1990b; Suwita and Abou-Donia 1990).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding excretion in humans or animals after oral exposure to polyalphaolefin hydraulic fluids or major components. The physicochemical similarities between polyalphaolefins and mineral oils suggest that hydrocarbons in ingested polyalphaolefins may be excreted similarly to hydrocarbons in ingested mineral oil.

2.3.4.3. Dermal Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding excretion in humans or animals after dermal exposure to mineral oil hydraulic fluids or to their major components. -.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding excretion in humans after derrnal exposure to organophosphate ester hydraulic fluids. However, a human study using the tricresyl phosphate isomer tri-o&o-cresyl phosphate (TOCP) was located.

Urinary excretion of radioactivity was measured in human volunteers during and after a 3.5-hour period of dermal exposure to 0.11 or 0.22 g ³²P-labeled TOCP (Hodge and Sterner 1943). The specific activity of the test substance was not reported. Radioactivity in urine was measured with a Geiger-Muller counter, but the limits of detection were not reported. Maximum estimated excretion rates, 10 and 43 ug TOCP/hour for the respective dosage levels, were measured within 24 hours of initiation of exposure. Radioactivity was not detected 48 or 72 hours after dosing ceased. Cumulative radioactivity detected in urine accounted for 0.13% and 0.36% of the dermally applied radioactivity.

Cyclotriphosphazene was not detected by gas chromatography in urine collected for 24 hours after occluded dermal exposure of rats to a hydraulic fluid containing 99.9% cyclotriphosphazene (Kinkead and Bashe 1987).

Urinary excretion of radioactivity has been observed in cats (Nomeir and Abou-Donia 1986) and a dog (Hodge and Sterner 1943) after dermal exposure to radiolabeled TOCP, thereby suggesting that this route of excretion is important following dermal exposure. In cats, cumulative excretion of radioactivity, within 10 days of dermal exposure to [phenyl-¹⁴C]TOCP, reached 28% and 20% of the administered dose (50 mg/kg) via the urinary and fecal routes, respectively (Nomeir and Abou-Donia 1986). The importance of biliary excretion was demonstrated in cats by the observation that the peak concentration of radioactivity in bile was much higher than peak concentrations for any other analyzed tissue or body fluid (see Section 2.3.2.3.). Interpretation of the cat data should be addressed with caution, because a portion of the dose was probably ingested during grooming. Peak rates of urinary excretion of radioactivity (equivalent to 202 pg TOCP/hour) were measured for a dog, 12 hours after initiation of a 25.5-hour exposure of a 15x20 cm area of skin to 2.094 g TOCP labeled with radioactive phosphorus (Hodge and Sterner 1943). Radioactivity in urine collected during exposure (the dog was sacrificed immediately following exposure) accounted for 0.14% of the applied dose. Fecal or biliary excretion was not examined.

Urinary excretion of radioactivity after a dermal dose of [¹⁴C]tributyl phosphate was 29944% of the applied dose in rats (Gatz 1992b). A large proportion of the dose (24-43%) was recovered in the sitewash at the end of the exposure.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding excretion in humans or animals after dermal exposure to polyalphaolefin hydraulic fluids or major components.

2.3.4.4. Other Routes of Exposure

Mineral Oil Hydraulic Fluids. No studies were located regarding excretion in humans after exposure by other routes to mineral oil hydraulic fluids.

Within 8 days of an intraperitoneal dose of 0.66 mL/kg tritiated mineral oil to rats, 11% of administered radioactivity was excreted in the feces, predominately in the form of mineral oil (95%) (Ebert et al. 1966). Urine during the same time frame after intraperitoneal administration contained about 8% of the administered radioactivity, but in chemical forms other than mineral oil. The detection of radioactivity in the feces after intraperitoneal administration suggests that significant biliary excretion of absorbed mineral oil can occur.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding excretion in humans after exposure by other routes to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding excretion in humans or animals after exposure by other routes to polyalphaolefin hydraulic fluids.

Inhalation MRLs

No inhalation MRLs were derived.

Available data are restricted to acute lethality studies in rats exposed to four water-in-oil emulsion hydraulic fluids or a mineral oil hydraulic fluid for 4-6 hours. No deaths or body weight alterations occurred at exposure concentrations ranging from 180 to 210 mg/m³ for the water-in-oil fluids and 1,130 mg/m³ for the mineral oil fluid. The data are inadequate for acute inhalation MRL derivation. No data regarding intermediate or chronic inhalation exposure to mineral oil hydraulic fluids were located.

Oral MRLs

No oral MRLs were derived.

The available data did not adequately identify target organs or effects. In acute lethality studies in rats gavaged with 5,000 mg/kg doses of the water-in-oil emulsion hydraulic fluids or mineral oil hydraulic fluids, no deaths or body weight changes occurred. One of these fluids was tested for neurotoxicity in chickens without effects.

Inhalation MRLs

No inhalation MRLs were derived.

No NOAELs or LOAELs were identified for toxic effects in humans after inhalation exposure to organophosphate ester hydraulic fluids. Reliable NOAELs and LOAELs for acute inhalation exposure are restricted to 4-hour NOAELs for systemic effects in rats exposed to Fyrquel220 or Durad MP280 and 4-hour LOAELs for mild lethargy in rats exposed to Durad MP280 and Fyrquel 220 (Gaworski et al. 1986). The study identifying these NOAEL and LOAEL values did not measure cholinesterase inhibition, did not allow sufficient follow-up time for the development of delayed neurotoxic effects, and used a species that is relatively insensitive to OPIDN. An acute inhalation MRL was not derived for organophosphate ester hydraulic fluids as a class due to the inadequacy of the available data to assess the neurotoxicity of Fyrquel 220 and Durad MP280 and the lack of any acute inhalation data for other organophosphate ester hydraulic fluids.

There are insufficient data to derive hydraulic fluid-specific acute-duration inhalation MRLs. No systemic effects were observed in rats exposed to 6,350 mg/m³ of Durad MP280 for 4 hours (Gaworski et al. 1986). Mild lethargy was observed 1-3 hours post-exposure to 6,190 and 6,350 mg/m³. Longer-term inhalation exposure to Durad MP280 resulted in testicular atrophy in rats (MacEwen and Vemot 1983). Reproductive end points have not been examined following acute inhalation exposure. In rats exposed to Fyrquel 220, no systemic effects were observed following exposure to 6,3 10 mg/m³ and mild lethargy was observed at ≥5,790 mg/m³ (Gaworski et al. 1986; Kinkead et al. 1992a). The short duration of the study (single 4-hour exposure), the lack of testing in a species sensitive to the neurotoxic effects, and the lack of reproductive testing (especially for Durad MP280) precludes deriving acute-duration inhalation MRLs for Durad MP280 and Fyrquel 220.

Reliable intermediate-duration inhalation NOAELs and LOAELs were located for systemic effects in rats and rabbits exposed to several organophosphate ester hydraulic fluids (Durad MP280, Fyrquel 220, Skydrol 500B-4, or Cellulube 220) and cyclotriphosphazene. Neurological effects were observed in rats, rabbits, dogs, hamsters, monkeys, and hens exposed to Durad MP280, Fyrquel 220, Skydrol 500B-4, Cellulube 220, or triaryl phosphate. In addition, reproductive effects (histological alteration of reproductive organs) were observed in rats, rabbits, and hamsters exposed to cyclotriphosphazene, Durad MP280, or Fyrquel 220. Based on the lowest LOAEL, the most sensitive end point appears to be the neurological effects. The NOAELs for neurological effects ranged from 4.4 to 260 mg/m³ and the range of serious LOAELs was 23 to 2,000 mg/m³. Not all of the organophosphate ester hydraulic fluids tested had the same targets. For example, head droop and generalized weakness or lethargy were observed in rabbits exposed to 2,000 mg/m³ (lowest concentration tested) of Cellulube 220 4 hours/day, 4-5 days/week for 11 or 22 days (Carpenter et al. 1959) and 101 mg/m³ of Durad MP280 continuously for 90 days (MacEwen and Vemot 1983). No neurological effects were observed in rabbits continuously exposed to 100 mg/m³ of Fyrquel 220 for 90 days (MacEwen and Vemot 1983). Testicular atrophy was observed in rats continuously exposed to 101 mg/m³ Durad MP280, but not in rats continuously exposed to Fyrquel 220 for 90 days (MacEwen and Vemot 1983), rats exposed for 13 weeks (6 hours/day, 5 days/week) to Skydrol 500B-4 (Healy et al. 1992; Monsanto 1987a, 1987b, 1989), or rats exposed to 990 mg/m³of cyclotriphosphazene for 21 days (6 hours/day, 5 days/week) (Kinkead et al. 1989b, 1990). No intermediate inhalation MRL was derived for organophosphate ester hydraulic fluids as a class because of the uncertainty that derivation of a MRL based on data for a single fluid with the lowest identified threshold would be representative for other fluids in the class.

The available inhalation data for Durad MP280, Fyrquel 220, Cellulube 220, Skydrol 500B-4, and cyclotriphosphazene (reviewed in the next paragraph) are inadequate to derive intermediate-duration MRLs for these individual fluids, principally because the studies were conducted in species (rats or rabbits) that are generally considered to be insensitive to the delayed neurotoxicity of acute exposure to organophosphate esters. Cats, dogs, or nonhuman primates more accurately model the human expression of OPIDN than rats and rabbits, and studies in these species would provide a better basis for MRL derivation.

Following a 90-day continuous exposure to 101 mg/m³ of Durad MP280, leukocytosis, kyphosis, and testicular atrophy were observed in rats and 100% mortality, cachexia, head droop, anorexia, and lethargy were observed in rabbits. No effects were observed in either species at 10.3 mg/m³ Durad MP280 (MacEwen and Vemot 1983). Continuous exposure to 100 mg/m³ of Fyrquel220 for 90 days resulted in kyphosis in rats (MacEwen and Vemot 1983); the NOAEL for this effect was 10.1 mg/m³. No adverse effects were observed in rabbits exposed to 100 mg/m³ Fyrquel 220 continuously for 90 days (MacEwen and Vemot 1983). At the lowest tested concentration of Cellulube 220 (2,000 mg/m³, 4 hours/day, 4-5 days/week for 11 or 22 days), severe dyspnea, head droop, and generalized weakness were observed in rabbits (Carpenter et al. 1959). No adverse effects were observed in rats exposed to 990 mg/m³ of cyclotriphosphazene (6 hour/day, 5 days/week) for 21 days (Kinkead et al. 1989b, 1990). Exposure of rats to Skydrol500B-4 for 13 weeks (6 hours/day, 5 days/week) resulted in nasal discharge at 100 mg/m³, decreased erythrocyte, hemoglobin, and hematocrit levels at 300 mg/m³, and decrease in plasma cholinesterase activity at 300 mg/m³ (Healy et al. 1992; Monsanto 1987a, 1987b, 1989). Mild hepatocellular vacuolization and excessive salivation, a sign of cholinergic neurotoxicity, were also observed in these studies at 300 mg/m³. The lowest LOAEL is 5.3 mg/m³ Skydrol 500B-4 for nasal effects. No chronic exposure data were located.

Oral MRLS

No oral MRLs were derived.

No data are available regarding systemic or neurological effects in humans after oral exposure to organophosphate ester hydraulic fluids. The acute oral data base consists of a number of studies examining limited end points. Effects associated with cholinesterase inhibition (e.g., diarrhea) and OPIDN have been observed. Extensive testing of organophosphate ester hydraulic fluids in chickens (this species is generally thought of as one of the most sensitive to the neurotoxicity of organophosphorus compounds and a valid model species for identifying neurotoxic potential in humans) has demonstrated that there is a wide diversity in the ability of organophosphate ester hydraulic fluids to produce neurological effects. Some fluids produced no signs of neurological effects in chickens after administration of substantial doses (e.g., Pydraul29ELT, Pydraul50E, and Pydraul90E), other fluids produced only subtle neurological effects (e.g., Skydrol500B-4, Skydrol LD-4, and Reofos 65), and a few produced frank neurological effects (OPIDN) at comparatively low doses (e.g., Cellulube 220 and Fyrquel 150). A comparison of the relative toxicity of the different organophosphate ester hydraulic fluids is difficult because many of the studies only tested one dose level or a NOAEL was not identified. For hydraulic fluids causing cholinesterase inhibition effects, the LOAELs ranged from 120 mg/kg/day in rabbits for Cellulube 220 (Carpenter et al. 1959) to 5,750 mg/kg in rats exposed to Fyrquel 220 (Gaworski et al. 1986; Kinkead et al. 1992a). NOAELs for this effect were not reported. Inhibition of brain neurotoxic esterase and butyrylcholinesterase were observed in chickens exposed to approximately 2,600 mg/kg Skydrol500B-4 (Monsanto 1987d) or Skydrol LD-4 (Monsanto 1987c) and 114 mg/kg Fyrquel EHC (Stauffer Chemical Co. 1981). The range of LOAELs for OPIDN was 60 mg/kg/day for chickens exposed to Cellulube 220 for 5 days (Carpenter et al. 1959) to 11,350 mg/kg in chickens exposed once to Fyrquel EHC (Stauffer Chemical Co. 1980).

Derivation of an acute-duration oral MRL for organophosphate ester hydraulic fluids as a class based on the lowest identified reliable LOAEL for neurological effects in chickens (60 mg/kg/day Cellulube 220 for leg and wing weakness) (Carpenter et al. 1959) is not recommended for two reasons. First, the LOAEL is a serious LOAEL (no NOAEL was identified in the study) and MRLs are not derived from serious LOAELs. Second, the wide diversity in the apparent neurotoxicities among members of the class indicates that derivation of an MRL based on data for a single fluid may not be representative for the class. Acute-duration oral MRLs for individual organophosphate ester hydraulic fluids have not been proposed. In addition, although chickens have been identified as a good species for qualitatively identifying the neurotoxicity of organophosphate esters, the extrapolation of chicken doses to human doses is uncertain.

Reliable NOAELs and LOAELs for intermediate oral exposure are restricted to a 90-day NOAEL of 50 mg/kg/day for systemic toxicity in rats (a species that is not sensitive to the neuropathic effects of organophosphate esters) exposed to Pydraul 90E for 90 days and NOAELs and LOAELs for delayed neuropathy in chickens exposed to Durad 110. In chickens exposed to Durad 110 for 28 days, a NOAEL of 444 mg/kg/day and LOAEL of 1,333 mg/kg/day were identified (FMC 1986); when the duration was increased to 90 days, the NOAEL was 20 mg/kg/day and the LOAEL was 90 mg/kg/day (FMC 1986). These data are inadequate for derivation of an intermediate oral MRL for organophosphate ester hydraulic fluids. As discussed under the acute-duration oral MRL section, there is uncertainty regarding extrapolation of chicken doses to human doses.

No data were located regarding chronic oral exposure to organophosphate ester hydraulic fluids

Toxicity data are available for several organophosphate ester components of hydraulic fluids, in particular tricresyl phosphate (NTP 1994). However, these components are always present in products as mixtures with other chemicals. Since insufficient information exists to assess the effect on toxicity of interactions among these mixtures, MRLs for the components were not derived.

Inhalation MRLs

No inhalation MRLs were derived.

No data were located regarding toxic effects in humans following inhalation exposure to polyalphaolefin hydraulic fluids. Three of nine tested polyalphaolefin hydraulic fluids were lethal in rats at 4-hour aerosol concentrations ranging from <5,330 to <10,720 mg/m³. LC₅₀ values for the three lethal fluids in females ranged from 1,390 to 1,670 mg/m³. Deaths were associated with respiratory irritation. The data are inadequate for acute inhalation MRL derivation. No intermediate or chronic inhalation MRLs for polyalphaolefin hydraulic fluids were derived due to the lack of data.

Oral MRLS

No oral MRLs were derived.

No data were located regarding toxic effects in humans following oral exposure to polyalphaolefin hydraulic fluids. No deaths or body weight changes occurred in rats in a series of acute lethality studies with nine polyalphaolefin hydraulic fluids at doses ranging from 4,250 to 5,000 mg/kg. One of these fluids was also tested for neurotoxicity in chickens, and did not produce effects at 4,250 mg/kg. The available data have not identified a target organ or effect for these fluids. The data are inadequate for MRL derivation. No intermediate or chronic oral MRLs for polyalphaolefin hydraulic fluids were derived due to the lack of data.

Respiratory Effects

Mineral Oil Hydraulic Fluids. There is a paucity of data on respiratory effects following inhalation, oral, ordermal exposure to mineral oil hydraulic fluids. The only available information for humans comes from a case report of a child ingesting a lethal dose of an automotive transmission fluid, which was most likely amineral oil hydraulic fluid. Lipoid pneumonia with marked fibrosis was observed (Perrot and Palmer 1992). It is likely that some of the fluid was aspirated and that the oil caused irritation of the lung tissue. Lipoidpneumonia is frequently reported among people who chronically use medicated oils via intranasa sprays or nose drops (Cannon 1940; Lushbaugh 1950). It is unlikely that individuals living at or near hazardous waste sites contaminated with mineral oil hydraulic fluids would ingest (and subsequently aspirate) or inhale sufficient mineral oil to produce lipoid pneumonia. In the only animal study available, histopathological examination of the lungs from rats exposed to ≤ 1.0 mg/m³ of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, showed no treatment-related lesions (Kinkead et al. 1991).

Organophosphate Ester Hydraulic Fluids. No studies were located regarding respiratory effects in humans after inhalation, oral, or dermal exposure to organophosphate ester hydraulic fluids. The most commonly reported respiratory effects in animals are dyspnea and rapid respirations. These effects have been observed in rabbits exposed to 2,000 mg/m³ of airborne Cellulube 220 (Carpenter et al. 1959); in cows and goats exposed to oral doses of 5,000 and 7,700 mg/kg of Cellulube 220, respectively, (Dollahite and Pierce 1969); in cows eating grass contaminated with Fyrquel 150 (Beck et al. 1977); in cows orally exposed to 500 mg/kg (Beck et al. 1977); and in rabbits dermally exposed to Cellulube 220 (Carpenter et al. 1959). It is likely that the respiratory effects observed shortly after exposure were the result of acetylcholinesterase inhibition (see section on neurological effects for more information on cholinesterase inhibition) rather than a direct effect on the respiratory tract. Other respiratory effects include nasal discharge in rats exposed to Skydrol 500B-4 for an intermediate duration (Healy et al. 1992; Monsanto 1987a, 1987b, 1989) and rats orally exposed to Durad 110 for an acute duration (FMC 1990a); bronchopneumonia in rabbits acutely exposed to orally administered Cellulube 220 (Carpenter et al. 1959); and emphysema and intralobular fibrosis in cows eating grass contaminated with Fyrquel 150 (Beck et al. 1977). It is not known whether the respiratory effects observed following oral exposure to organophosphate ester hydraulic fluids were due to aspiration of the hydraulic fluid. Following acute and intermediate inhalation exposure to a number of organophosphate ester hydraulic fluids, including Fyrquel 220, Durad MP280, and cyclotriphosphazene, no evidence of gross and/or histological damage was observed in rats, rabbits, hamsters, dogs, monkeys, and hens (Carpenter et al. 1959; Gaworski et al. 1986; Kinkead et al. 1989a, 1990; MacEwen and Vemot 1983; Siegel et al. 1965). Based on the observations of dyspnea in cows, goats, and rabbits exposed to hydraulic fluids, it is likely that sufficient exposure to organophosphate ester hydraulic fluids that contain acetylcholinesterase inhibitors would result in dyspnea in humans.

Polyalphaolefin Hydraulic Fluids. No information was located on the toxicity of polyalphaolefin hydraulic fluids to the respiratory tract of humans following inhalation, oral, or dermal exposure. Animal data suggest that certain airborne polyalphaolefin hydraulic fluids may be respiratory tract irritants. Bloody nasal discharge, rapid and shallow breathing, lung congestion, and perivascular and peribronchial edema have been observed in rats acutely exposed to polyalphaolefin hydraulic fluids (Kinkead et al. 1987b, 1992b; MacEwen and Vemot 1983). No information was located on respiratory effects in animals orally or dermally exposed to polyalphaolefin hydraulic fluids.

Cardiovascular Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding cardiovascular effects in humans after inhalation, oral, or dermal exposure to mineral oil hydraulic fluids. In the only animal study available, histopathological examination of the hearts from rats exposed to ≤1.0 mg/m³ of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, showed no treatment-related lesions (Kinkead et al. 1991).

Organophosphate Ester Hydraulic Fluids. No studies regarding cardiovascular effects in humans after inhalation, oral, or dermal exposure to organophosphate ester hydraulic fluids or cyclotriphosphazene were located. Animal data suggest that the cardiovascular system would not be a direct target of organophosphate ester hydraulic fluid toxicity. No gross and/or histological damage was observed in animals intermediately exposed to airborne Fyrquel 220, Durad MP280 (Gaworski et al. 1986; MacEwen and Vemot 1983), Skydrol 500B-4 (Healy et al. 1992; Monsanto 1976a, 1987b, 1989), cyclotriphosphazene (Kinkead et al. 1989a, 1990), or triaryl phosphate hydraulic fluids (Carpenter et al. 1959; Siegel et al. 1965); acute oral doses of triaryl phosphate hydraulic fluids (Carpenter et al. 1959; Kinkead et al. 1989b) or intermediate oral doses of Pydraul 90E (Monsanto 1979); or to intermediate dermal applications of Fyrquel 220 (MacEwen and Vemot 1983), cyclotriphosphazene (Kinkead et al. 1989a, 1990), or Cellulube 220 (Carpenter et al. 1959). Although no direct histological effects on the cardiovascular system have been observed in studies with organophosphate ester hydraulic fluids, organophosphate esters that inhibit acetylcholinesterase can overstimulate muscarinic receptors in the heart resulting in bradycardia or complete heart block (arrest) (Murphy 1986). Tachycardia can also result due to stimulation of sympathetic ganglia to overcome bradycardia due to muscarinic overstimulation (Murphy 1986).

Polyalphaolefin Hydraulic Fluids. No studies were located regarding cardiovascular effects in humans after inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids or in animals after inhalation or dermal exposure. The only information available on the cardiovascular effects of polyalphaolefin hydraulic fluids is a histopathology finding that oral exposure to MIL-H-83282 and MIL-H-83282LT for 4 weeks at ≤1,000 mg/kg/day in the rat had no effect on the heart (Mattie et al. 1993).

Gastrointestinal Effects

Mineral Oil Hydraulic Fluids. The only information available on gastrointestinal effects in humans or animals exposed to mineral oil hydraulic fluids is from a case report of a child ingesting a lethal dose of automotive transmission fluid, which was probably a mineral oil hydraulic fluid. Subserosal hemorrhages were observed in the small and large intestine and omentum (Perrot and Palmer 1992). Focal gastritis with edema was also noted in rats receiving 1,000 mg/kg/day of MIL-H-5606 (Mattie et al. 1993). Mineral oils (petroleum-derived aliphatic hydrocarbons) are known to have laxative effects, to interfere with absorption of essential fat-soluble substances, and to cause foreign body reactions in the intestinal mucosa (Brunton 1985). These data, however, are not adequate to determine the likelihood of individuals living at or near hazardous waste sites having gastrointestinal effects from exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Gastric upset and diarrhea have been reported in humans following oral exposure to organophosphate ester hydraulic fluid components (Goldstein et al. 1988; Srivastava 1990). In animals, the most widely reported gastrointestinal effect is diarrhea. Diarrhea (or soft feces) has been observed following oral exposure of rats to Durad MP280 (Gaworski et al. 1986), rabbits to Cellulube 220 (Carpenter et al. 1959; Dollahite and Pierce 1969), hens to Skydrol 500B-4 (Monsanto 1987d) or Skydrol LD-4 (Monsanto 1987c), and cows to Cellulube 220 (Dollahite and Pierce 1969) or Fyrquel 150 (Beck et al. 1977). Diarrhea (or soft feces) has also been observed in rabbits dermally exposed to Fyrquel 220 (Gaworski et al. 1986; MacEwen and Vemot 1983) or Cellulube 220 (Carpenter et al. 1959). The studies that reported diarrhea did not conduct histological examinations of the gastrointestinal tract. However, it is possible that the diarrhea was the result of acetylcholinesterase inhibition (see discussion on neurological effects) rather than direct damage to the gastrointestinal tract. In other studies, gastrointestinal effects have not been observed in rats, rabbits, and hamsters exposed to Fyrquel 220 or Durad MP280 (MacEwen and Vemot 1983) Skydrol 500B-4 (Healy et al. 1992; Monsanto 1987a, 1987b, 1989), cyclotriphosphazene (Kinkead et al. 1989a, 1990), or Cellulube 220 (Carpenter et al. 1959). Because the gastrointestinal effects are possibly the result of acetylcholinesterase inhibition rather than direct damage, it is likely that there will not be route-specific differences. Based on the results of the animal studies, it is likely that humans exposed to sufficient organophosphate ester hydraulic fluids to inhibit acetylcholinesterase will exhibit gastrointestinal effects.

Polyalphaolefin Hydraulic Fluids. No studies were located regarding gastrointestinal effects in humans or animals after inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids.

Hematological Effects

Mineral Oil Hydraulic Fluids. No information on hematological effects in humans after inhalation, oral, or dermal exposure to mineral oil hydraulic fluids is available. In another animal study, a statistically significant reduction of 16% was reported in the percentage of lymphocytes in whole blood in rats receiving 1,000 mg/kg/day MIL-H-5606 by gavage for 26 days (Mattie et al. 1993).

Organophosphate Ester Hydraulic Fluids. There is limited information on hematological effects following exposure to organophosphate ester hydraulic fluids. In workers dermally exposed to triaryl phosphate hydraulic fluids for an intermediate duration, no changes in the levels of leukocytes were observed (Baldridge et al. 1959). This study is limited because leukocyte levels were the only hematological parameter monitored. No other human studies examining hematological parameters were located. Significant decreases in erythrocyte, hemoglobin, and hematocrit levels were observed in rats exposed to 300 mg/m³ of Skydrol 500B-4 (Healy et al. 1992; Monsanto 1987a, 1987b, 1989) and leukocytosis was observed in male rats exposed to 101 mg/m³ Durad MP280 (MacEwen and Vemot 1983); both of these studies were for intermediate durations. A number of intermediate-duration animal studies examined hematological parameters, but no significant effects were found. Hematological examinations were made after inhalation exposure to Durad MP280, Fyrquel 220, and cyclotriphosphazene (Gaworski et al. 1986; Kinkead et al. 1989a, 1990; MacEwen and Vemot 1983); oral exposure to Pydraul90E (Monsanto 1979); and dermal exposure to cyclotriphosphazene (Kinkead et al. 1989c, 1990) and Fyrquel 220 (MacEwen and Vemot 1983). Studies of oral exposures to MIL-H-83306 also have shown decreased hematocrits, erythrocyte numbers, and hemoglobin at levels of 250 mg/kg and 500 mg/kg, respectively (Mattie et al. 1993). A chronic-duration study of oral exposure to tricresyl phosphate for 2 years in rats and mice showed no alteration in hematological parameters (NTP 1994).

Polyalphaolefin Hydraulic Fluids. Studies examining hematological effects in humans or animals following inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids are limited to a 4-week study in rats orally exposed to 1,000 mg/kg/day of MIL-H-83282 or MIL-H-83282LT (Mattie’et al. 1993). No effect was seen with MIL-H-83282 but reductions in total and mean cell hemoglobin as well as anemia were seen in rats exposed to MIL-H-83282LT.

Musculoskeletal Effects

Mineral Oil Hydraulic Fluids. No studies were located regarding musculoskeletal effects in humans or animals after inhalation, oral, or dermal exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No human studies examining musculoskeletal effects following inhalation, oral, or dermal exposure to organophosphate ester hydraulic fluids were located. No musculoskeletal abnormalities were observed in rabbits and hens orally exposed to Cellulube 220 for an acute duration (Carpenter et al. 1959). In rats, kyphosis was observed following intermediate-duration exposure to ≈ 100 mg/m³ of Durad MP280 or Fyrquel 220 (MacEwen and Vemot 1983). It is not known if this deformity of the spine characterized by extension flexion is the result of damage to musculoskeletal system or a neurological effect. No histological damage to the skeletal muscle was observed following intermediateduration inhalation exposure of rats or dermal exposure of rabbits to cyclotriphosphazene (Kinkead et al. 1989a, 1989~ 1990) or rabbits to Cellulube 220 (Carpenter et al. 1959). There is insufficient information to determine the likelihood of humans having musculoskeletal effects following exposure to organophosphate ester hydraulic fluids.

Polyalphaolefin Hydraulic Fluids. There is limited information on the potential of polyalphaolefin hydraulic fluids to induce musculoskeletal effects. Kyphosis, a deformity of the spine characterized by extension flexion was observed in rats exposed to 880-5,030 mg/m³ (concentration eliciting response not reported) of a polyalphaolefin hydraulic fluid designated at B85-174 for 4 hours (Kinkead et al. 1987b). It is not known if this effect is related to damage to the musculoskeletal system or to neurological damage. This is the only study that examined musculoskeletal effects. Thus, the likelihood of musculoskeletal effects occurring in humans exposed to polyalphaolefin hydraulic fluids cannot be determined.

Hepatic Effects

Mineral Oil Hydraulic Fluids. No studies regarding hepatic effects in humans following inhalation, oral, or dermal exposure to mineral oil hydraulic fluids were located. In an animal study, histopathological examination of the livers from rats exposed by inhalation to ≤ 1.0 mg/m³ of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, showed no treatment-related lesions (Kinkead et al. 1991). Animal data for oral exposure are limited to one study where rats were exposed to MLH-5606 at 1,000 mg/kg/day for 26 days (Mattie et al. 1993). Increases in liver weight and peroxisomal betaoxidation activity were observed.

Organophosphate Ester Hydraulic Fluids. No human exposure studies examining hepatic end points were located. Several hepatic effects have been observed in animals after exposure to organophosphate ester hydraulic fluids. Mild hepatocellular vacuolation and increased liver weight were found in rats exposed to 300 mg/m³ Skydrol500B-4 (Healy et al. 1992; Monsanto 1987a, 1987b, 1989). Increased smooth endoplasmic reticulum was seen with increased liver weight after oral exposure in rats to MIL-H-83306 at 500 mg/kg/day for 26 days (Mattie et al. 1993). Evidence of adverse histological alterations and/or changes in serum enzymes indicative of liver damage was not observed in other inhalation studies (Carpenter et al. 1959; Healy et al. 1992; Kinkead et al. 1989a, 1990, 1992a; Monsanto 1987a, 1987b, 1989; Siegel et al. 1965), in oral exposure studies (Carpenter et al. 1959; Monsanto 1979), or in dermal exposure studies (Carpenter et al. 1959; Kinkead et al. 1989c, 1990; MacEwen and Vemot 1983). Increased fatty accumulation and decreased hepatocyte vacuolization, along with increased absolute and relative liver weights were observed in rats orally exposed to dibutylated phenyl phosphate for 91 days at 250 mg/kg/day (Healy et al. 1991). Minimal to mild papillary hyperplasia of the gallbladder mucosa was observed in mice orally exposed to tricresyl phosphate at 110-230 mg/kg/day for 13 weeks (NTP 1994). In 2-year feeding studies, clear cell foci, fatty change, and ceroid pigmentation were observed in mice but not in rats (NTP 1994).

Polyalphaolefin Hydraulic Fluids. The only information available on hepatic effects of polyalphaolefin hydraulic fluids in humans or animals is a report of increased peroxisomal beta-oxidation and serum alkaline phosphatase after oral exposure in rats to 1,000 mg/kg/day MIL-H-83282 for 26 days (Mattie et al. 1993). Increased peroxisomal beta-oxidation but no increase in serum alkaline phosphatase was observed in rats similarly treated with MIL-H-83282LT.

Renal Effects

Mineral Oil Hydraulic Fluids. The only information regarding renal effects in humans or animals following inhalation, oral, or dermal exposure to mineral oil hydraulic fluids are two animal studies. Histopathological examination of the kidneys from rats exposed to ≤1.0 mg/m³ of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, showed no treatment-related lesions (Kinkead et al. 1991). Persistent diuresis, and increased protein and protein/creatinine ratios in the urine were reported in rats orally exposed to 1,000 mg/kg/day MIL-H-5606 for 26 days (Mattie et al. 1993). Hyaline droplets were also observed in the proximal tubule on histopathological examination.

Organophosphate Ester Hydraulic Fluids. No human studies examining renal end points were located. No renal effects were observed in rats exposed by inhalation to ≈6,300 mg/m³ of Durad MP280 or Fyrquel 220 for 4 hours (Gaworski et al. 1986; Kinkead et al. 1992a) or in rabbits exposed orally to 120 mg/kg/day Cellulube 220 for ≤14 days (Carpenter et al. 1959). A minimal to mild accumulation of hyaline droplets was found in the kidneys of male and female rats exposed to ≥240 mg/m³ of cyclotriphosphazene for 90 days (Kinkead et al. 1989a, 1990). Orally exposed mice showed renal tubule degeneration at 430-730 mg/kg/day tricresyl phosphate over 13 weeks (NTP 1994). Urinary bladder hyperplasia was observed after oral exposure in rats to tributyl phosphate at 55-350 mg/kg (Healy et al. 1991; Laham et al. 1985). In rabbits exposed dermally to ≥2,882 mg/kg/day of Fyrquel 220 for an intermediate duration, significant increases in serum urea nitrogen and creatinine levels were observed (MacEwen and Vernot 1983); this study did not report the results of histological examination of the kidneys. Interpretation of this study is complicated by the fact that one of the rabbits was infected with Pasturella. Other intermediate-duration inhalation studies have found no gross or histological damage in the kidneys of rats, rabbits, hamsters, dogs, monkeys, and hens exposed to Durad MP280 (Gaworski et al. 1986; MacEwen and Vernot 1983) Fyrquel 220 (Gaworski et al. 1986; MacEwen and Vernot 1983), Skydrol 500B-4 (Healy et al. 1992; Monsanto 1987a, 1987b, 1989), Cellulube 220 (Carpenter et al. 1959), and a triaryl phosphate hydraulic fluid (Siegel et al. 1965). In addition, no evidence of renal damage was observed following intermediate-duration exposure of rats to oral doses of Pydraul 90E (Monsanto 1979), rabbits to topical cyclotriphosphazene (Kinkead et al. 1989c, 1990), or rabbits to topical Cellulube 220 (Carpenter et al. 1959).

Polyalphpolejin Hydraulic Fluids. The only information on renal effects in humans or animals following inhalation, oral, or dermal exposure to polyalphaolefm hydraulic fluids is a report of increased urinary protein to creatinine ratio of rats orally exposed to MIL-H-83282 at 1,000 mg/kg/day for 4 weeks. Diuresis was noted in rats similarly exposed to MIL-H-83282LT (Mattie et al. 1993).

Endocrine Effects

Mineral Oil Hydraulic Fluids. No information on endocrine effects in humans or animals following inhalation, oral of dermal exposure to mineral oil hydraulic fluids was located.

Organophosphate Ester Hydraulic Fluids. No information on endocrine effects in humans following inhalation, oral, or dermal exposure to organophosphate ester hydraulic fluids was located.

There are some equivocal data suggesting that the adrenal gland is a target for organophosphate ester hydraulic fluid toxicity. Nodular hyperplasia was observed in the adrenal cortex of one of two dogs examined following 20 subcutaneous injections of an unspecified amount of Cellulube 220 (Carpenter et al. 1959). No adrenal effects were observed in rats continuously exposed to 100 mg/m³ Fyrquel 220 or 101 mg/m³ Durad MP280 for 90 days (MacEwen and Vemot 1983); rats exposed to 300 mg/m³ Skydrol 500B-4,6 hours/day, 5 days/week for 13 weeks (Healy et al. 1992; Monsanto 1987a, 1987b, 1989); or rabbits inhaling 2,000 mg/m³ Cellulube 220,4 hours/day, 4-5 days/week for 11 or 22 days (Carpenter et al. 1959). Rabbits receiving repeated dermal exposure (6 hours/day, 5 days/week for 21 days) to 1,000 mg/kg cyclotriphosphazene (Kinkead et al. 1989c, 1990) did not have adrenal effects. In a reproductive toxicity study (Chapin et al. 1988) in which male and female mice were exposed to 62.5 mg/kg of a mixture of tricresyl phosphates containing <0.1% pure TOCP, hypertrophy of the zona fasciculata cells and brown degeneration of cells in the juxtamedullary zone were observed in the adrenal gland. Tricresyl phosphate, a widely used fire-retardant additive for hydraulic fluids, produced minimal to moderate cytoplasmic vacuolization of the adrenal cortex of rats and mice exposed orally for subchronic and chronic durations (NTP 1994). Both tricresyl phosphate and butyl triphenyl phosphate treatment resulted in bilaterally enlarged adrenal glands and lipidosis and vacuolization of the adrenal cortex in rats orally exposed to 400 mg/kg/day for 20-60 days (Latendresse et al. 1994a).

Polyalphaolefin Hydraulic Fluids. No information on endocrine effects in humans or animals following inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids was located.

Dermal Effects

Mineral Oil Hydraulic Fluids. No human studies examining dermal end points were located. In animals, no information on dermal effects following inhalation or oral exposure were located. A number of mineral oil hydraulic fluids have been tested for acute dermal toxicity in rabbits. Signs of skin irritation have been observed following application of a naphthenic petroleum-based hydraulic fluid designated as MIL-H-5606 (Kinkead et al. 1985). No signs of skin irritation were observed following exposure to Sunsafe‘F, Houghto- Safe 5047F, Quintolubric 9583OW, or Pyroguard A-443 (Kinkead et al. 1987a, 1988).

Organophosphate Ester Hydraulic Fluids. No studies regarding dermal effects in humans after inhalation or oral exposure were located. Erythema was observed in humans repeatedly exposed to dermal patches of Skydrol 500B-4 for an intermediate duration (Monsanto 1980). Skin scabbing was seen after oral exposure to Sanitizer 154 at 300 mg/kg (IRDC 1981).

Signs of skin irritation were observed in one acute dermal exposure study. A single application of 0.5 mL of Durad 550B resulted in mild erythema and skin thickening in rabbits (FMC 1992a). No signs of skin irritation or evidence of histological damage were observed in rabbits exposed once to Durad 220B, Durad 110, Durad 300, Durad MP280, Durad 125, Fyrquel 220, or cyclotriphosphazene (FMC 1990a, 1991b; Gaworski et al. 1986; Kinkead et al. 1992a, 1992c, 1992d, 1992e; MacEwen and Vet-not 1985) or after intermediate-duration dermal exposure of rabbits to Fyrquel 220, cyclotriphosphazene, or Cellulube 220 (Carpenter et al. 1959; Kinkead et al. 1989c, 1990; MacEwen and Vet-not 1983). No evidence of skin damage was located in hens ingesting Cellulube 220 for 5 days (Carpenter et al. 1959), or following intermediate-duration inhalation exposure of rats, rabbits, or hamsters to Fyrquel 220 or Durad MP280 (MacEwen and Vemot 1983), rabbits to Cellulube 220 (Carpenter et al. 1959), or rats to cyclotriphosphazene (Kinkead et al. 1989a, 1990).

Polyalphaolejin Hydraulic Fluids. No studies regarding dermal effects in humans following inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids were located. Mild skin irritation was observed following a single application of a polyalphaolefin hydraulic fluids designated as DTNSRDC N501 and N5 17. No signs of skin irritation were observed following single applications of polyalphaolefin hydraulic fluids designated as DTNSRDC N448, N518, N525, N527 (MacEwen and Vemot 1983), B85-174 (Kinkead et al. 1987b), or meeting military specifications of MIL-H-83282 (Kinkead et al. 1985) or MIL-H-83282LT (Kinkead et al. 1992b).

Based on these data, it is not likely that acute exposure of humans to environmental levels of polyalphaolefin hydraulic fluids will result in dermal irritation. There is insufficient information to determine if long-term exposure to polyalphaolefin hydraulic fluids will result in dermal irritation in humans.

Ocular Effects

Mineral Oil Hydraulic Fluids. No human studies examining ocular end points were located. In animals, no information on ocular effects following inhalation or dermal exposure were located. Mild eye irritation was observed in rabbits following a single application of 0.1 mL of Sunsafe F, Houghto-Safe 5047F, Quintolubric 9583OW, or Pyroguard A-443 (Kinkead et al. 1987a, 1988). No signs of irritation were observed following application of MIL-H-5606 (Kinkead et al. 1985).

Organophosphate Ester Hydraulic Fluids. No studies regarding ocular effects in humans after inhalation or oral exposure were located.

Eye irritation was not observed in animal studies following a single application of 0.1 mL of Fyrquel 220 (Gaworski et al. 1986; Kinkead et al. 1992e), Durad MP280 (Gaworski et al. 1986; Kinkead et al. 1992d), or cyclotriphosphazene (Kinkead et al. 1992c; MacEwen and Vernot 1985). No evidence of eye damage was observed in hens ingesting Cellulube 220 for 5 days (Carpenter et al. 1959), or following intermediateduration exposure of rats, rabbits, or hamsters to aerosols of Fyrquel220 or Durad MP280 (MacEwen and Vet-not 1983), rabbits to Cellulube 220 (Carpenter et al. 1959), or rats to cyclotriphosphazene (Kinkead et al. 1989a, 1990).

Polyalphaolefin Hydraulic Fluids. No studies regarding ocular effects in humans following inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids were located. Evidence of eye irritation was observed in rats following a single ocular application or acute exposure to airborne polyalphaolefin hydraulic fluids with a designation of MIL-H-83282LT (Kinkead et al. 1992b). No signs of eye irritation were observed following single ocular applications of polyalphaolefin hydraulic fluids designated as DTNSRDC N448, N501, N517, N518, N525, N528 (MacEwen and Vemot 1983), B85-174 (Kinkead et al. 1987b), or meeting military specifications of MIL-H-83282 (Kinkead et al. 1985) or MIL-H-83282LT (Kinkead et al. 1992b).

Based on these data, it is not likely that acute exposure of humans to environmental levels of polyalphaolefin hydraulic fluids will result in ocular irritation. There is insufficient information to determine if long-term exposure to polyalphaolefin hydraulic fluids will result in ocular irritation in humans.

Body Weight Effects

Mineral Oil Hydraulic Fluids. There is limited information on body weight effects following exposure to mineral oil hydraulic fluids. No studies were located regarding body weight effects in humans following inhalation, oral, or dermal exposure to mineral oil hydraulic fluids. In rats, no changes in body weight gain were observed following acute inhalation, oral, or dermal exposure to Sunsafe F, Quintolubric 9583OW, Houghto-Safe 5047F, or Pyroguard A-443 (Kinkead et al. 1989b, 1988) and a mineral oil hydraulic fluid meeting military specifications of MIL-H-5606 (Kinkead et al. 1985). Body weights of rats exposed to ≤1.0 mg/m³ of the water-in-oil emulsion hydraulic fluid Houghto-Safe 5047F for 90 days, 23 hours/day, were similar to those of controls (Kinkead et al. 1991). No longer-term studies were located. Based on this limited information, it is not likely that effects on body weight will be observed in humans acutely exposed to environmental levels of mineral oil hydraulic fluids. The likelihood of changes in body weight occurring following longer-term exposure to mineral oil hydraulic fluids is not known.

Organophosphate Ester Hydraulic Fluids. No studies were located regarding body weight effects in humans following inhalation, oral, or dermal exposure to organophosphate ester hydraulic fluids.

Most animal studies found no significant alterations in body weight gain following inhalation, oral, or dermal exposure to a number of organophosphate ester hydraulic fluids. Several studies demonstrated weight loss following acute or intermediate oral exposure to high doses. The identified LOAEL values were 250 mg/kg/day in rats exposed to dibutyl phenyl phosphate for an intermediate duration (Healy et al. 1991), 5,775 mg/kg/day in rats acutely exposed to Durad MP280 (Gaworski et al. 1986) or 10,000 mg/kg and 15,000 mg/kg/day in hens acutely exposed to Reofos 65 or Fyrquel EHC for acute exposures, respectively, (Mortensen and Ladefoged 1992), and 1,333 mg/kg/day in hens exposed to Durad 110 for an intermediate duration (FMC 1986). No changes in body weight gain were observed in rats, rabbits, hamsters, hens, monkeys, or dogs exposed to Fyrquel 220, Skydrol 500B-4, cyclotriphosphazene, a triaryl phosphate hydraulic fluid, Durad MP280 (<5,775 mg/kg/day oral), Durad 550B, Durad 100, Durad 300, Durad 110, Durad 220B, Pydraul 50E, or Pydraul 90E (Ciba-Giegy 1973; FMC 1986, 1990a, 1992a; Gaworski et al. 1986; Healy et al. 1992; Kinkead et al. 1989a, 1989c, 1990, 1992a, 1992c; MacEwen and Vernot 1983, 1985; Monsanto 1979, 1987a, 1987b, 1989; Siegel et al. 1965) via inhalation, oral, or dermal exposure. High oral doses of organophosphate esters have caused body weight changes. In a dose-finding study using 5 pregnant rats per group, a 12% decrease in maternal weight gain was noted after 11 days at 200 mg/kg/day tributyl phosphate (Noda et al. 1994) but in a larger study with 20 animals per group, only minor body weight reductions were observed at 500 mg/kg/day. Several intermediate-duration studies showed reduction in body weight gain in rats or mice. Thirteen-week feeding exposures to tricresyl phosphate in rats at 430 mg/kg/daywere associated with an 11% reduction in body weight in both males and females (NTP 1994). Exposure to 750 mg/kg/day caused a 33% decrease in body weight in male rats. Treatment by gavage for 13 weeks, 5 days a week did not affect female body weight at ≤800 mg/kg/day; male body weight was decreased 13% at this dose (NTP 1994). Body weight effects were also reported in mice in this study, decreases greater than 10% were seen in female mice at 530 mg/kg/day and above and in males at 900 mg/kg/day exposed to tricresyl phosphate by feed Gavage doses greater than 400 mg/kg/day also caused decreased body weight (NTP 1994). Dibutyl phenyl phosphate exposure for 91 days at 250 mg/kg/day in female rats was observed to cause a 15% body weight reduction (Healy et al. 1991). Butylated triphenyl phosphate exposure at 1,000 mg/kg/day for 106 days caused an 11-17% decrease in body weight in Fischer 344 rats (Latendresse et al. 1994b). Similar results have been reported with exposure to tributyl phosphate in rats: a 15% decrease at 300 mg/kg/day for 18 weeks (Laham et al. 1985) and an 11% decrease at 250 mg/kg/day for 9 weeks (Oishi et al. 1982). Based on these animal data, it is not likely that human exposure to organophosphate ester hydraulic fluids at concentrations expected to be found at or near hazardous waste sites will result in changes in body weight.

Polyalphaolefin Hydraulic Fluids. No information on body weight effects in humans after inhalation, oral, or dermal exposure to polyalphaolefin hydraulic fluids was located. In acute rabbit inhalation, oral, or dermal exposure studies, no changes in growth were observed following exposure to polyalphaolefm hydraulic fluids designated as DTNSRDC N448, N501, N5 17, N518, N525, or N528 (MacEwen and Vemot 1983) B85-174 (Kinkead et al. 1987b), or polyalphaolefin hydraulic fluids meeting military specifications of MIL-H-83282 (Kinkead et al. 1985) or MIL-H-83282LT (Kinkead et al. 1992b). These acute exposure animal studies suggest that short term human exposure to polyalphaolefin hydraulic fluids will not result in alterations of body weight gain. There is insufficient information to determine longer-term human risks.

Acute-Duration Exposure

Mineral Oil Hydraulic Fluids. There is limited information on the acute toxicity of mineral oil hydraulic fluids to humans. A single case report of a child accidentally ingesting automotive transmission fluid reported respiratory and gastrointestinal effects (Perrot and Palmer 1992).

There is also limited animal data. A series of acute inhalation, oral, and dermal lethality studies monitored death and body weight gain in rats exposed to Sunsafe F, Quintolubric 9583OW, Houghto-Safe 5047F, or Pyroguard A-443 mineral oil hydraulic fluids (Kinkead et al. 1988, 1989a) or mineral oil hydraulic fluids meeting military specifications of MIL-H-5606 (Kinkead et al. 1985). The dermal and ocular irritancy of these fluids has also been tested (Kinkead et al. 1985, 1988, 1989a). These lethality studies are not adequate for the derivation of acute inhalation or oral MRLs. No acute-duration studies performing complete histopathological examinations or repeated exposure studies that identify target organs were located. These studies would be useful in determining the health risks of individuals acutely exposed to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Human studies of exposure to organophosphates are primarily those of acute, accidental poisonings with tricresyl phosphate (Goldstein et al. 1988; Senayanake and Jeyaratnam 1981; Srivastava et al. 1990).

In rats, studies of the acute toxicity of inhaled Durad MP280 and Fyrquel 220 (Gaworski et al. 1986), examined respiratory, hepatic, and renal end points and found no effects. In rabbits, acute inhalation exposure to Cellulube 220 caused respiratory and gastrointestinal problems (Carpenter et al. 1959). Mice and rabbits exhibited acute neurotoxicity with exposure to triphenyl phosphate and Cellulube 220 (Carpenter et al. 1959; Sutton et al. 1960). Acute-duration oral exposure studies were located for rats, mice, guinea pigs, rabbits, hens, goats, and cows exposed to Durad 220B (FMC 1990a), Durad 550B (FMC 1992a), Durad 110 (FMC 1990a), Durad 300 (FMC 1990a), Cellulube 220 (Dollahite and Pierce 1969; Carpenter et al. 1959), Reofos 65 (Mortensen and Ladefoged 1992), Pydraul 50E (Ciba-Geigy 1973), Fyrquel EHC (Mortensen and Ladefoged 1992), Fyrquel 220 (FMC 1977a), Skydrol 500B-4 (Monsanto 1987d), Skydrol LD-4 (Monsanto 1987c), Fyrquel 150 (Beck et al. 1977), ethylhexyldiphenyl phosphate (Noda et al. 1984), butylated triphenyl phosphate (Latendresse et al. 1994), dibutylphenyl phosphate (Carrington et al. 1989), isopropyltriphenyl phosphate (Sprague et al. 1984), Santicizer 141048 (Robinson et al. 1986), tributoxyethyl phosphate (Carrington et al. 1989), triphenyl phosphate (Sutton et al. 1960), and tributyl phosphate (Healy et al. 1995; Johannsen et al. 1977).

Neurotoxic end points, especially acetylcholinesterase and related enzymes, were the most heavily studied, but other studies have expanded the toxicity literature to include developmental, immunological, and systemic effects. The acute dermal toxicity of Fyrquel 220 and Durad MP280 (Gaworski et al. 1986; Kinkead et al. 1992a, 1992d, 1992e), Durad 220B, Durad 110, and Durad 300 (FMC 1990a), Durad 125 (FMC 1991b), cyclotriphosphazene (Kinkead et al. 1992c; MacEwen and Vemot 1985), and Durad 550B (FMC 1992c) has been tested in rats and rabbits. These studies were designed to examine dermal and/or ocular irritancy or to assess neurotoxicity. Because the inhalation and oral exposure studies examined a limited number of end points, MRLs could not be derived. EPA has been negotiating an Enforceable Consent Agreement with the manufacturers of aryl phosphates and in reviewing the needs for testing, acute testing is not identified (EPA 1994).

Polyalphaolefin Hydraulic Fluids. No acute exposure human studies were located.

There is limited information on the acute toxicity of polyalphaolefin hydraulic fluids to animals. Several single 4-hour exposure studies identified the respiratory tract as a target of toxicity following exposure to polyalphaolefin hydraulic fluids designated as B85-174 (Kinkead et al. 1987b), MIL-H-83282LT (Kinkead et al. 1992b), or DTNSRDC N501 (MacEwen and Vemot 1983). Acute inhalation, oral, and dermal lethality studies on polyalphaolefin hydraulic fluids designated as DTNSRDC N448, N501, N5 17, N5 18, N525, or N527 (MacEwen and Vemot 1983) or a polyalphaolefin hydraulic fluid meeting military specifications of MIL-H-83282 (Kinkead et al. 1985) provide evidence that polyalphaolefin hydraulic fluids were not very lethal and did not affect body weight gain. Dermal and ocular irritancy were also assessed using polyalphaolefin hydraulic fluids designated as DTNSRDC N448, N501, N5 17, N5 18, N525, or N527 (MacEwen and Vemot 1983), MIL-H-83282LT (Kinkead et al. 1992b), B85-174 (Kinkead et al. 1987b), or meeting military specifications of MIL-H-83282 (Kinkead et al. 1985). The DTNSRDC N501 was a mild skin irritant and MIL-H-83282LT was a eye irritant. Based on these animal data, the targets of toxicity of polyalphaolefin hydraulic fluids cannot be identified. Repeated exposure and studies conducting complete histological examinations would be useful in assessing the risk of individuals exposed to polyalphaolefin hydraulic fluids for acute durations.

Intermediate-Duration Exposure

Mineral Oil Hydraulic Fluids. No intermediate exposure human studies were located.

Two studies on intermediate-duration exposure to mineral oil hydraulic fluids are available: a single oral exposure rat study to MIL-H-5606 (Mattie et al. 1993), and an inhalation-exposure study in rats to Houghto-Safe 5047F (Kinkead et el. 1991). Because no other intermediate-duration studies were located, no inhalation or oral intermediate MRLs were derived. Inhalation, oral, and dermal systemic toxicity studies examining a number of end points would be useful in identifying the targets of toxicity of mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Four human exposure studies were located. In one study, no change in hematological parameters was observed in workers dermally exposed to organophosphate ester hydraulic fluids for an intermediate duration (Baldridge et al. 1959). The application of patches containing Skydrol500B-4 resulted in erythema in individuals exposed for an intermediate duration (Monsanto 1980). A woman developed an allergic reaction to triphenyl phosphate found in the frames of her glasses (Carlson et al. 1986) and a man also became hypersensitive to organophosphates found in a glue he was using (Camaras and Serra-Baldrich 1992).

The toxicity of inhaled triaryl phosphates (triaryl phosphate-mixture), Fyrquel 220, Durad MP280, and cyclotriphosphazene has been well studied in rats, rabbits, and hamsters. These studies suggest that Fyrquel 220 (Gaworski et al. 1986; MacEwen and Vemot 1983), Durad MP280 (Gaworski et al. 1986; MacEwen and Vemot 1983), cyclotriphosphazene (Kinkead et al. 1989a, 1990), and Cellulube 220 (Carpenter et al. 1959; Siegel et al. 1965) are not potent systemic toxicants. No further inhalation exposure studies are needed for these organophosphate ester hydraulic fluids. Although there is a reasonable body of data for intermediate oral exposure to organophosphate esters, EPA and the aryl phosphate industry are planning additional testing (EPA 1994). The National Toxicology study, published in 1994, has helped to define oral, systemic end points for exposure to tricresyl phosphate. Adrenal, liver and body weight changes are reported in rats and mice. Endocrine effects are further delineated for rats exposed to TCP and butylated triphenyl phosphate (Latendresse et al. 1994a, 1994b; Oishi et al. 1982). Following exposure to low doses of Pydraul 90E, no evidence of systemic toxicity was observed in rats (Monsanto 1979) and no changes in body weight gain were observed in hens exposed to Durad 110 (FMC 1986). As a broad range of systemic end points become defined, it would be useful to have additional testing of systemic effects. A number of studies on organophosphorus ester hydraulic fluids suggest that neurological effects may be the most sensitive end point of toxicity. Because of limitations in the neurotoxicity database, inhalation and oral intermediate-duration MRLs were not derived. Information is available on the intermediate-duration dermal toxicity in rabbits of cyclotriphosphazene (Kinkead et al. 1989c, 1990), Fyrquel220 (MacEwen and Vemot 1983), and Cellulube 220 (Carpenter et al. 1959). No further systemic toxicity studies on the dermal toxicity of cyclotriphosphazene and Fyrquel 220 are needed. (Cellulube 220 is no longer in production.) Studies on other organophosphate ester hydraulic fluid components might be useful for assessing the potential for human toxicity following intermediate-duration exposure.

Polyalphaolefin Hydraulic Fluids. No intermediate exposure human studies were located.

Information on polyalphaolefin hydraulic fluids is limited to a single study in rats orally exposed to MIL-H83282 and MIL-H-83282LT (Mattie et al. 1993). Intermediate-duration inhalation or oral MRLs could not be derived based on a single study. Significant toxicity was not observed. Systemic toxicity studies in which animals were exposed via inhalation and dermal routes would be useful in identifying the end points of toxicity for humans living at or near hazardous waste sites and exposed for intermediate-durations.

Chronic-Duration Exposure and Cancer

Mineral Oil Hydraulic Fluids. No human or animal studies involving inhalation, oral, or dermal chronicduration exposure were located. Because no chronic-duration studies were located, no inhalation or oral chronic MRLs were derived. Inhalation, oral, and dermal systemic toxicity studies examining a number of end points would be useful in identifying the targets of toxicity of mineral oil hydraulic fluids.

One human carcinogenicity exposure study was located. This study did not find convincing associations between exposure to hydraulic fluid and the incidence of cancer at a specific site (Siemiatycki et al. 1987a). As discussed in Section 2.2.1.8, there are a number of limitations to this study. An animal carcinogenicity study or well-controlled cohort retrospective or prospective study would be useful for determining the carcinogenic potential of mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No chronic exposure human studies were located.

Chronic animal studies of organophosphates are few in number, but those that do exist provide a useful base from which to draw toxicological insight. In rats and mice exposed orally to tricresyl phosphate for 2 years, endocrine effects were found in a dose-response pattern and hepatic effects were found. Ovarian interstitial hyperplasia was also observed but was not dose related. No chronic-duration MRLs could be derived because of the limited number of studies. Tricresyl phosphate, a component of certain hydraulic fluids, produced no evidence of carcinogenic activity in assays with rats and mice (NTP 1994). However, another component, tributyl phosphate, was associated with an increased incidence of bladder tumors in rats and mice (FMC 1994a, 1994b).

Polyalphaolefin Hydraulic Fluids. Because no chronic-duration human or animal inhalation, oral, or dermal exposure studies using polyalphaolefin hydraulic fluids were located, chronic-duration inhalation or oral MRLs could not be derived. Systemic toxicity studies in which animals were exposed via inhalation, oral, and dermal routes would be useful in identifying the end points of toxicity for humans living at or near hazardous waste sites and exposed for chronic durations. Further carcinogenicity studies on individual organophosphate ester components of hydraulic fluids may be useful.

No information on the carcinogenic potential of polyalphaolefin hydraulic fluids was located. Studies designed to assess carcinogenicity in animals exposed via inhalation, oral, and dermal routes or a well controlled cohort retrospective or prospective study would be useful for determining the carcinogenic potential of polyalphaolefin hydraulic fluids.

Genotoxicity

Mineral Oil Hydraulic Fluids and Polyalphaolefin Hydraulic Fluids. No studies were located regarding genotoxicity after inhalation, oral, or dermal exposure to mineral oil hydraulic fluids or polyalphaolefin. hydraulic fluids. No studies were located regarding genotoxicity of mineral oil hydraulic fluids or polyalphaolefin hydraulic fluids in in vitro assays. Studies that address the genotoxicity of members of these classes of hydraulic fluids would be helpful.

Organophosphate Ester Hydraulic Fluids.In vivo genotoxicity assays have been conducted for two organophosphate ester hydraulic fluids. Results have generally been negative. The in vivo genotoxicity of Reofos 50 and Reolube HYD46 has been tested in Chinese hamsters (Ciba-Geigy 1983b, 1984a, 1984b). Durad 550B (FMC 1992b), Reofos 95 (Ciba-Geigy 1978a), Reolube HYD46 (Ciba-Geigy 1983a, 1984a), Reofos 50 (Ciba-Geigy 1978b, 1984b), Skydrol500B-4 (Monsanto 1988a), and Skydrol LD-4 (Monsanto 1988b) have been tested for in vitro genotoxicity using gene mutation, DNA damage, and/or chromosomal aberrations. In EPA’s Notice of Proposed Test Rule for aryl phosphates there is no mention of genotoxic testing (EPA 1992), nor is there an identified need for genotoxic testing in the 1994 EPA Testing Consent Order (EPA 1994).

Reproductive Toxicity

Mineral Oil Hydraulic Fluids and Polyalphaolefin Hydraulic Fluids. No studies were located regarding reproductive toxicity after exposure by any route to mineral oil or polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Rats and mice were tested with oral exposure to certain components of organophosphate ester hydraulic fluids, generally for subchronic periods, and effects were reported for both males and females. Females showed ovarian interstitial hypertrophy, increased ovarian weights, and decreased fertility after exposure to tricresyl phosphate (Latendresse et al. 1994a, 1994b; NTP 1994). Males exhibited abnormal sperm, necrosis of seminiferous tubules, and reduced testes weights after exposure to tricresyl phosphate (Carlton et al. 1987; Latendresse et al. 1994a, 1994b; NTP 1994). Reproductive toxicity is an area of concern, and further reproductive toxicity testing on individual components of organophosphate ester hydraulic fluids would be useful.

Developmental Toxicity

Mineral Oil Hydraulic Fluids and Polyalphaolefin Hydraulic Fluids. The developmental toxicity data base is generally inadequate. No studies were located regarding developmental toxicity after exposure by any route to mineral oil hydraulic fluids or polyalphaolefin hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No studies concerning developmental effects of organophosphate ester hydraulic fluids in humans were located; among the limited number of studies that report organophosphate ester developmental toxicity are reports of reduced litter size, pup survivability and pup weights in rats with tricresyl phosphate and dibutyl phenyl phosphate (Carlton et al. 1987; Healy et al. 1991). Teratogenicity was not observed. The database also has two observations of developmental effects in cows that were probably environmentally exposed to organophosphate ester hydraulic fluids (Beck et al. 1977; Julian et al. 1976). Further developmental toxicity testing may be warranted.

Immunotoxicity

Mineral Oil Hydraulic Fluids. No information was located regarding immunological effects in humans after inhalation, oral, or dermal exposure to mineral oil hydraulic fluids. Data from animal testing of limited immunological end points suggest that the immunological system may not be a sensitive target for certain mineral oil hydraulic fluids. In guinea pig skin sensitization assays, four of five tested mineral oil hydraulic fluids were inactive as skin sensitization agents, and the remaining fluid only showed weak activity (Kinkead et al. 1985, 1987a, 1988). Testing of other mineral oil hydraulic fluids using an immunological test battery in animals by several routes of exposure would help to determine if the immunologic system is a target of mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. No dermal sensitization reactions were observed in a study of human subjects exposed dermally to Skydrol 500B-4 (Monsanto 1980) or in a study of guinea pigs exposed to a cyclotriphosphazene-based hydraulic fluid (Kinkead et al. 1992c; MacEwen and Vemot 1985). Two case reports indicate dermal sensitization from eyeglass frames and glue (Carlsen et al. 1986; Camarasa and Serra-Baldrich 1992). No histological alterations were observed in the thymus of rats exposed to aerosols of cyclotriphosphazene for 21 days (Kinkead et al. 1989a, 1990). Thymus weight decreases (both absolute and relative to body weight) were observed, without histological alterations, in rabbits exposed dermally to cyclotriphosphazene (Kinkead et al. 1989c, 1990). Additional testing of other organophosphate ester hydraulic fluids would provide support for the hypothesis suggested by the limited available data that skin sensitization may not be a concern with dermal exposure to organophosphate ester hydraulic fluids. Testing of other organophosphate ester hydraulic fluids for additional immunological end points in animals would help to determine if the immunologic system is a target of these materials.

Polyalphaolefin Hydraulic Fluids. No data were located regarding immunological effects in humans after exposure to polyalphaolefin hydraulic fluids. Results from guinea pig skin sensitization assays indicated that two of nine tested polyalphaolefin hydraulic fluids were skin sensitizers (Kinkead et al. 1985, 1992b; MacEwen and Vemot 1983). Data from oral administration is limited to histological examination of immunological tissues where no effect was found (Mattie et al. 1993). Examination of additional immunological end points in animals after oral, inhalation, and dermal exposure to polyalphaolefin hydraulic fluids would help to determine the likelihood of immunologic effects occurring in humans exposed to environmental media contaminated with these materials.

Neurotoxicity

Mineral Oil Hydraulic Fluids. Reports of neurological effects in humans or animals are restricted to a single case report of neuropathy in a man who was heavily exposed to mineral oil hydraulic fluids by occupational dermal contact (Jarvholm et al. 1986) and a report of subtle electromyographical effects in four of eight examined men who were less heavily exposed by occupational dermal contact (Jkvholm et al. 1986). However, an association between human exposure to mineral oil hydraulic fluids and neurological effects is uncertain, due to the lack of corroborative case reports and epidemiological data and the lack of studies demonstrating neurological effects in animals after exposure to mineral oil hydraulic fluids. The presence of organophosphate ester additives in many mineral oil hydraulic fluids raises some concern regarding neurotoxicity, but levels of these additives are normally low. Acute inhalation, oral or dermal testing of additional fluids for organophosphate-induced delayed neuropathy (OPJDN) in sensitive species (e.g., cats or chickens) may provide useful information to ascertain the neurological hazard presented by mineral oil hydraulic fluids. No information was located regarding neurological effects in humans or animals after intermediate to chronic exposure to mineral oil hydraulic fluids.

Organophosphate Ester Hydraulic Fluids. Neurotoxicity is a concern from acute dermal, inhalation, or oral exposure to organophosphate ester hydraulic fluids because of the well-established susceptibility of humans to the cholinergic and delayed neuropathic properties of certain organophosphate este compounds such as TOCP. Sufficient acute oral testing of organophosphate hydraulic fluids in chickens has been conducted to conclude that there is a wide range in the ability of organophosphate ester fluids to produce adverse neurological effects. Certain fluids (e.g., Durad 220B and Durad 125), however, have not been tested for neurotoxicity in sensitive animal species. Acute testing of these additional organophosphate hydraulic fluids for neurotoxicity in chickens will provide useful information regarding their potential to produce acute neurological effects. Dermal or inhalation testing in cats (another sensitive species to OPIDN) may provide additional information regarding the hazard from these expected routes of certain occupational exposures. It is unknown if long-term, low-dose exposures to organophosphate ester hydraulic fluids will produce neurological effects. Experiments with hens, however, suggested that with longer exposure periods, lower doses of Durad 110 produced increased incidences of ataxia and nerve damage. A LOAEL of 1,333 mg/kg/day was observed with a 2%day oral exposure, compared with a LOAEL of 90 mg/kg/day with 90 days of exposure (FMC 1986). Additional animal experiments with other organophosphate ester hydraulic fluids are needed to assess the neurological hazard presented by intermediate to chronic exposure.

Polyalphaolefin Hydraulic Fluids. Several polyalphaolefin hydraulic fluids have been tested for clinical signs of OPIDN in chickens after acute gavage exposure, but adverse effects were not seen (Kinkead et al. 1985, 1992b). As with mineral oil hydraulic fluids, the possible presence of organophosphate ester additives in these fluids may raise some concern regarding neurotoxicity, but levels would normally be expected to be low. Acute oral or dermal testing of additional fluids for OPIDN in sensitive species may be useful to further ascertain the neurological hazard presented by polyalphaolefin hydraulic fluids. No information was located regarding neurological effects in humans or animals after intermediate to chronic exposure to polyalphaolefin hydraulic fluids.

Epidemiological and Human Dosimetry Studies

Mineral Oil Hydraulic Fluids. Two human studies involving exposure to mineral oil hydraulic fluids were located. One was a case report of a child who accidentally ingested a lethal dose of automotive transmission fluid (Perrot and Palmer 1992). The other is an occupational exposure in which workers were dermally exposed to mineral oil hydraulic fluids (Jarvholm et al. 1986). Both of these studies are limited because only a small number of end points were examined and there is no accurate reporting of dose levels. Because mineral oil hydraulic fluids are widely used, the potential for human exposure is great. The identified human studies and the animal studies did not identify the primary target of toxicity for mineral oil hydraulic fluids. Epidemiology studies of workers (including auto mechanics exposed to transmission fluids) exposed to mineral oil hydraulic fluids would be useful in identifying targets of toxicity.

Organophosphate Ester Hydraulic Fluids. Two human exposure studies were identified. In these studies, individuals were dermally exposed to organophosphate ester hydraulic fluids for an intermediate duration (Baldridge et al. 1959; Monsanto 1980). In the Baldridge et al. (1959) study, no hematological or neurological effects were observed. The Monsanto (1980) study was designed to assess dermal irritation and sensitization. Organophosphate ester hydraulic fluids are fire-resistant hydraulic fluids used in the hydraulic systems of aircraft; thus, there is a potential for occupational exposure. The animal data suggest that the most sensitive target of toxicity is the neurological system. Studies designed to monitor acetylcholinesterase inhibition, particularly in the workplace, would be useful in establishing dose-response relationships.

Polyalphaolefin Hydraulic Fluids. No human studies for polyalphaolefin hydraulic fluids were located. Polyalphaolefin hydraulic fluids are used in U.S. military aircraft hydraulic systems; thus, there is a potential for occupational exposure. Animal studies were insufficient for determining the primary targets of toxicity. Epidemiology studies examining a number of end points would be useful for identifying targets of toxicity.

Biomarkers of Exposure and Effect

Methods for Reducing Toxic Effects

Mineral Oil Hydraulic Fluids. Aside from the possibility of the development of pneumonitis.following the aspiration of ingested mineral oil hydraulic fluid, little is known regarding the toxicity of these materials. Additional animal studies to identify the possible toxic effects of exposure to these materials may provide information relevant to the investigation of methods for reducing the toxic effects.

Organophosphate Ester Hydraulic Fluids. There are no established methods for reducing absorption of organophosphate esters. Studies in animals designed to identify agents that could inhibit or delay the absorption of organophosphate esters may provide valuable information for the preventive treatment of acute neurotoxic effects produced by some organophosphate ester hydraulic fluids. The mechanism of the acute cholinergic toxicity of organophosphorus esters is well known, as are methods to interfere with it. Identification of chemicals that reactivate “irreversibly” inhibited acetylcholinesterase would be valuable in the treatment of acute poisoning by organophosphorus esters. In contrast, the mechanism of OPIDN is poorly understood. Additional studies on the mechanism of OPIDN may provide information relevant to the identification of chemicals that interfere with a requisite step in its development.

Polyalphaolefin Hydraulic Fluids. Aside from the acute lethality of inhalation exposure to certain polyalphaolefin hydraulic fluids, little is known regarding the toxic effects produced by these materials. Additional animal studies to identify the possible toxic effects of exposure to these materials may provide information relevant to the investigation of methods for reducing the toxic effects.