NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Chemicals Used as Solvents and in Polymer Manufacture. Lyon (FR): International Agency for Research on Cancer; 2017. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 110.)
4.1. Toxicokinetic data
4.1.1. Absorption
(a) Humans
In workers exposed to 1,2-dichloropropane in air, there was a linear correlation between concentration in the breathing zone and concentration in the urine, indicating systemic absorption via the respiratory tract (Ghittori et al., 1987). No direct data on the absorption of 1,2-dichloropropane in humans exposed by oral or dermal administration were available. However, systemic toxicities after ingestion indicate oral absorption through the gastrointestinal tract (Chiappino & Secchi, 1968; Perbellini et al., 1985, Pozzi et al., 1985).
An estimate of the human blood:air partition coefficient of 10.7 ± 0.5 was obtained in vitro, indicating that under equilibrium conditions, respiratory uptake of 1,2-dichloropropane from inhaled air would be expected to be similar to that for chlorinated compounds such as chloroform and trichloroethylene, all of which have partition coefficients of around 10 (Sato & Nakajima, 1979).
(b) Experimental systems
Hutson et al. (1971) gave male and female rats an oral dose of radiolabelled 1,2-dichloropropane at 4–5 mg/kg bw. After 24 hours, 74–95% of the radiolabel was recovered in the urine or expired air. Similarly, Timchalk et al. (1991) gave male and female rats a single oral dose of radiolabelled 1,2-dichloropropane at 1 or 100 mg/kg bw, and 1 mg/kg bw daily for 8 days. After 48 hours, more than 80% of the radiolabel was recovered in the urine or expired air, with less than 10% in the faeces. These studies indicated near complete systemic absorption of 1,2-dichloropropane via the oral route.
Timchalk et al. (1991) exposed male and female rats to air containing radiolabelled 1,2-dichloropropane at a concentration of 5, 50, or 100 ppm for 6 hours. After 48 hours, 80% or more of the radiolabel was recovered in the urine and expired air, with less than 10% in the faeces, indicating near complete systemic absorption via the inhalation route.
No direct data were available on dermal absorption. However, systemic effects, including death, have been observed after dermal administration of 1,2-dichloropropane in rabbits, indicating systemic absorption through the skin (Smyth et al., 1969).
4.1.2. Distribution
(a) Humans
No data on tissue distribution of 1,2-dichloropropane in humans were available to the Working Group. Meulenberg & Vijverberg (2000) used empirical regression models to predict human tissue:air partition coefficients based on measured saline:air and oil:air partition coefficients. Based on these predictions, tissue:blood partition coefficients in humans were estimated to range from 0.9 (kidney) to 28 (fat), depending on the lipid content of the tissue. These values suggested that 1,2-dichloropropane would be widely distributed to tissues after systemic delivery.
(b) Experimental systems
In rats exposed to 1,2-dichloropropane by inhalation, reported peak blood concentrations were 0.06 (0.06), 0.92 (1.00), and 3.87 (4.55) µg/g in males (females) exposed at 5, 50 and 100 ppm, respectively, indicating systemic delivery of 1,2-dichloropropane in blood via the circulatory system (Timchalk et al., 1991). No sex differences were found; peak concentrations were similar in males and females. No direct data on tissue distribution of 1,2-dichloropropane were available to the Working Group. However, Gargas et al. (1989) reported measured tissue:blood partition coefficients in the range of 0.64 (muscle) to 27 (fat), suggesting that 1,2-dichloropropane is widely distributed to tissues after systemic delivery.
4.1.3. Metabolism
(a) Overview
There are four pathways for the metabolism of 1,2-dichloropropane (summarized in Fig. 4.1). The two best-characterized of these four pathways involve sequential action of cytochrome P450 (CYP) and glutathione S-transferase (GST); the other two pathways are less well characterized with respect to the enzymes involved, but do produce metabolites that have been isolated and identified. Some metabolites have been isolated (indicated in Fig. 4.1 by rectangles around their number designations), while others are presumed to occur based on the known chemistry of similar haloalkanes.
Fig. 4.1
Pathways for the metabolism of 1,2-dichloropropane
1,2-Dichloropropane undergoes sequential GST-mediated conjugation with glutathione (GSH) and then oxidative dehalogenation by cytochrome P450 (CYP) (or vice versa), to generate two GSH conjugates (see Fig. 4.1; metabolites IIa [S-(2-oxopropyl)glutathione] and IIIa [S-(1-carboxyethyl)glutathione]). Guengerich et al. (1991) showed that CYP2E1 is very active in the metabolism of 1,2-dichloropropane and similar halogenated alkanes of low relative molecular mass, including dichloromethane. The two GSH conjugates are processed by the standard reaction pathway in the kidneys (Lash et al., 1988) to form the corresponding mercapturates (Fig. 4.1; metabolites IIb [N-acetyl-S-(2-oxopropyl)-L-cysteine] and IIIb [N-acetyl-S-(1-carboxyethyl)-L-cysteine]). In addition to these two mercapturates, which have been identified in the urine of rats exposed to 1,2-dichloropropane (Bartels & Timchalk, 1990), metabolite IIb (N-acetyl-S-(2-oxopropyl)-L-cysteine) can be reduced to form metabolite Id (N-acetyl-S-(2-hydroxypropyl)-L-cysteine) (also called 2-hydroxypropyl-mercapturic acid), which has also been identified in the urine of rats exposed to 1,2-dichloropropane.
Alternatively, GSH conjugation of 1,2-dichloropropane has also been suggested to form an episulfonium ion (Fig. 4.1; metabolite Ia [GSH-containing episulfonium ion]), which should undergo spontaneous hydrolysis to produce the cysteine conjugate (Fig. 4.1; metabolite Ic [S-(2-hydroxypropyl)-L-cysteine]). This can in turn undergo N-acetylation to form metabolite Id [N-acetyl-S-(2-hydroxypropyl)-L-cysteine]. Metabolite Id has been identified in the urine of rats exposed to 1,2-dichloropropane, but this does not constitute definitive proof for this pathway, since it is also formed through sequential CYP–GST metabolism, as described previously. Based on studies with isotope-labelled 1,2-dichloropropane, Bartels & Timchalk (1990) have determined that formation of the mercapturate Ia through a GST-only pathway is negligible, and that it is most likely that the sequential CYP–GST pathway predominates.
A fourth presumed fate of 1,2-dichloropropane is oxidative dechlorination that leads to formation of lactate, and ultimately release of carbon dioxide. While this pathway is presumed to occur as indicated in Fig. 4.1, with carbon dioxide being detected as derived in part from 1,2-dichloropropane, the mechanism for conversion of 1,2-dichloropropane to lactate has not been determined (while a CYP enzyme is expected to be involved, this has not yet been demonstrated).
The CYP2E1 and GST reactions occur primarily in the liver, which is very efficient at excreting GSH conjugates (Fig. 4.1, metabolites Ia, IIa, and IIIa) into the bile. Because the biliary tract is a significant site of gamma-glutamyltransferase (GGT) and dipeptidase activities, some of the excreted GSH conjugates will be converted to the corresponding cysteine conjugates. These undergo enterohepatic and renal–hepatic circulation, ultimately forming the mercapturates (Fig. 4.1, metabolites Id, IIb, and IIIb). The GSH-conjugation reaction also occurs in the kidney, although the renal activity of CYP2E1 is relatively low, especially in humans. Formation of reactive episulfonium ions (Fig. 4.1, metabolites Ia and Ib) can occur via GSH conjugation, especially at higher concentrations of 1,2-dichloropropane when CYP2E1 is saturated. When this reaction occurs in the liver, excretion of these reactive metabolites into the biliary tract may be partly responsible for toxicity of 1,2-dichloropropane in the liver and/or the biliary tract.
(b) Humans or human-derived tissues
No data on the metabolism of 1,2-dichloropropane in humans were available to the Working Group.
The only published study of the metabolism of 1,2-dichloropropane in human-derived tissues was that of Guengerich et al. (1991), which demonstrated the key role of CYP2E1 in the metabolism of several small halogenated hydrocarbons. 1,2-Dichloropropane was found to be one of the better substrates among the chemicals tested with purified human liver CYP2E1 and human liver microsomes. Thus, while trichloroethane and chlorzoxazone were metabolized by the purified human liver CYP2E1 at rates of 1.6 and 3 nmol of product formed/minute per nmol CYP, respectively, the rate of metabolism of 1,2-dichloropropane was 1.1 nmol of product formed/minute per nmol CYP. This rate compared quite favourably to that of purified CYP2E1 with trichloroethylene, which was only slightly lower at 0.97 nmol of product formed/minute per nmol CYP. Further evidence that the metabolism of 1,2-dichloropropane by human liver microsomes is predominantly mediated by CYP2E1 came from studies of immunoinhibition with specific antibodies to CYP2E1.
(c) Experimental systems
Almost all of the published studies on 1,2-dichloropropane metabolism were either in vivo in rats or in various in-vitro preparations from rat liver tissue. Publications are listed in chronological order.
(i) In vivo
Hutson et al. (1971) exposed rats to 14C-labelled 1,2-dichloropropane by stomach tube and examined products in the urine, faeces, and expired air for 96 hours. A relatively high proportion of the administered dose (approximately 20%) was recovered as carbon dioxide in the expired air during the first 24 hours. Little apparent difference was detected between males and females over the 96-hour collection period.
Jones & Gibson (1980) treated male Sprague-Dawley rats with 1,2-dichloropropane by either single intraperitoneal injection or daily oral dosing for 4 days. N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (Fig. 4.1; metabolite Id) was the major urinary metabolite recovered over 96 hours. Another significant, although relatively minor, metabolite was β-chlorolactate; this finding provides support for carbon dioxide formation via the metabolic route shown in Fig. 4.1.
Timchalk et al. (1991) studied pharmacokinetics and metabolism in male and female Fischer 344 rats given 14C-labelled 1,2-dichloropropane by oral administration or inhalation. By either route, metabolism was rapid, with three urinary mercapturates identified (Fig. 4.1; metabolites Id, IIb, IIIb), and radiolabelled carbon dioxide detected in expired air. As would be expected, the liver contained the highest proportion of radiolabel after oral exposure.
Bartels & Timchalk (1990) treated male and female Fischer 344 rats with radiolabelled 1,2-dichloropropane as a single oral dose at 100 mg/kg bw in corn oil, and measured metabolites in urine. As noted above, these studies were the first to demonstrate the recovery of three different mercapturates in vivo (Fig. 4.1; metabolites Id, IIb, and IIIb). Based on isotope labelling, Bartels & Timchalk (1990) also found no evidence of the pathway involving formation of an episulfonium ion being active.
Timchalk et al. (1991) followed up these studies with a more detailed analysis of the metabolism of 14C-labelled 1,2-dichloropropane by exposing Fischer 344 rats both orally and by inhalation. Distribution of radioactivity in rats exposed to 1,2-dichloropropane at 5, 50, or 100 ppm by inhalation showed the predominance of urine as a route of recovery of metabolites. The concentration of carbon dioxide in expired air increased with 1,2-dichloropropane at 5 to 50 ppm, but decreased at 100 ppm, suggesting saturation of the metabolic pathway through lactate and the citric acid cycle. No sex-specific differences in pharmacokinetics or metabolism by either the oral or inhalation exposure route were observed.
(i) In vitro
The earliest study of the metabolism of 1,2-dichloropropane in vitro used rat liver microsomes (Van Dyke & Wineman, 1971). These authors examined the dechlorination of a series of chloroethanes and propanes. The dechlorination reaction was shown to require NADPH and oxygen, and be inducible by phenobarbital and benzo[a]pyrene, but not by methylcholanthrene. These results implicated the CYP monooxygenase system. However, this study also showed that a factor present in the supernatant was necessary for optimal activity. Among six different chlorinated propanes examined as substrates during the course of a 30-minute incubation, 1,1,2-trichloropropane was by far the best substrate (41% dechlorination). Of the dichlorinated propanes, 1,1-dichloropropane was by far the best substrate (25% dechlorination), whereas 1,2-dichloropropane was only a slightly better substrate than 2,2-dichloropropane (6% versus 2.5% dechlorination).
The dependence on a factor present in the supernatant for an optimal dechlorination reaction rate for 1,2-dichloropropane and the other chloropropanes was subsequently shown to be due to a requirement for GSH. Before isolation of mercapturates as the primary metabolites of 1,2-dichloropropane, Trevisan et al. (1989, 1993) and Imberti et al. (1990) showed an association between toxicity caused by 1,2-dichloropropane in rats and GSH status, and that exposure to 1,2-dichloropropane leads to depletion of GSH. Trevisan et al. (1993) further showed that blockage of oxidative metabolism with carbon monoxide prevented GSH depletion in the rat kidney, demonstrating the importance of the GSH-conjugation reaction in the metabolism of 1,2-dichloropropane.
Tornero-Velez et al. (2004) compared the kinetics of metabolism in rat liver microsomes of various dichlorinated and dibrominated alkanes, with carbon-chain lengths ranging from two to four. In general, metabolism was fastest with higher chain length and the presence of bromine rather than chlorine. 1,2-Dichloropropane exhibited a catalytic efficiency (i.e. Vmax/Km) that was approximately 25% of that of the most efficiently catalysed substrate, which was 1,3-dichloropropane.
Although most studies in mammals have suggested that CYP2E1 is the primary CYP enzyme that metabolizes 1,2-dichloropropane through the oxidative pathway, other CYPs also exhibit activity. For example, Lefever & Wackett (1994) studied the oxidation of several polychlorinated ethanes and 1,2-dichloropropane by cytochrome P450CAM, which is now known as CYP101. Oxidation activity was highest with the more highly chlorinated ethanes (e.g. hexachloroethane and pentachloroethane); 1,2-dichloropropane was oxidized to chloroacetone at a rate that was only 25% of that of these two highly chlorinated ethanes and was only 5% of that of camphor. Nonetheless, these data suggest the possibility that other CYPs besides CYP2E1 may metabolize 1,2-dichloropropane.
4.1.4. Excretion
(a) Humans
Ghittori et al. (1987) measured 1,2-dichloropropane in the urine of men exposed occupationally, indicating that excretion of the parent compound occurs in urine.
(b) Experimental systems
In experimental animals, 1,2-dichloropropane is eliminated primarily as metabolites in urine and expired carbon dioxide, with lesser amounts expired as volatile organic compounds, and excreted in the faeces (Hutson et al., 1971; Timchalk et al., 1991). At 24 hours after oral administration in rats, Hutson et al. (1971) reported that 80–90% of the administered dose was eliminated in the faeces, urine, and expired air, of which urine accounted for 50.2%, carbon dioxide accounted for 19.3%, and expired volatiles accounted for 23.1%. Similarly, in rats exposed orally or by inhalation, Timchalk et al. (1991) reported 37–65% recovery in the urine, or 18–40% recovery in expired air, depending on dose. The amount expired as volatile organic compounds increased with dose or concentration, and in all cases the majority of the expired volatile organic material was found to be unchanged 1,2-dichloropropane (Timchalk et al., 1991). This dose-dependency is consistent with dose-dependent saturation of 1,2-dichloropropane metabolism (Timchalk et al., 1991). Overall, elimination is fairly rapid, with the majority of the administered dose excreted in the first 24 hours after exposure (Hutson et al., 1971; Timchalk et al., 1991).
4.2. Genetic and related effects
4.2.1. Humans
No data were available to the Working Group.
4.2.2. Experimental systems
See Table 4.1
Table 4.1
Studies of genotoxicity with 1,2-dichloropropane.
The genetic toxicology of 1,2-dichloropropane has been reviewed previously by the Working Group (IARC, 1999). There is evidence for induction of base-pair mutation in two studies in Salmonella typhimurium (TA100, TA1535 [De Lorenzo et al., 1977, Principe et al., 1981]), with and without an exogenous metabolic system, but not in a third study (Haworth et al., 1983). Stolzenberg & Hine (1980) tested 1,2-dichloropropane at a lower dose, which may explain the negative results in that study. Results were negative in TA1537, TA1538, TA98, and TA1978 strains (De Lorenzo et al., 1977; Principe et al., 1981; Haworth et al., 1983). Results were also negative in one study in Streptomyces coelicolor (Principe et al., 1981). 1,2-Dichloropropane induced weak mutagenic effects, but no chromosomal effects in Aspergillus nidulans (Principe et al., 1981; Crebelli et al., 1984). It did not induce sex-linked recessive lethal mutation in Drosophila melanogaster (Woodruff et al., 1985). In Chinese hamster ovary cells in culture, 1,2-dichloropropane induced sister-chromatid exchange and chromosomal aberration, both with and without exogenous metabolic activation (Galloway et al., 1987; von der Hude et al., 1987).
The acute toxicity and mutagenicity of halogenated aliphatic compounds was assessed in a test for somatic mutation and recombination in Drosophila melanogaster (wing spot test). Compared with several structurally related compounds, the median lethal concentration (LC50) of 1,2-dichloropropane was high (14.4 µg/L). At ½ LC50, slight but statistically significant positive effects in terms of wing-spot number frequencies were noted (Chroust et al., 2007).
1,2-Dichloropropane was not mutagenic in the dominant-lethal assay in rats in a study by EPA (1989) in which male Sprague-Dawley rats were exposed to drinking-water containing 1,2-dichloropropane at a concentration of 0.024%, 0.10%, or 0.24% (w/v) for 14 weeks. The positive control, cyclophosphamide (100 mg/kg bw, single oral dose), induced a significant dominant lethal effect in the same study (EPA, 1989).
Male B6C3F1 and Gpt Delta C57BL/6J mice were exposed to 1,2-dichloropropane (0, 150, 300, or 600 ppm), dichloromethane (400, 800, or 1600 ppm), or combinations of both solvents (1,2-dichloropropane plus dichloromethane at 150 plus 400 ppm and 300 plus 800 ppm), by inhalation (6 hours per day, 5 days per week, for 6 weeks for each agent, or for 4 weeks for the combination, respectively). Genotoxicity was assessed by Pig-a gene mutation and assays for micronucleus formation in peripheral blood, and by Gpt mutation and comet assays in the liver. Pig-a mutation frequencies and micronucleus incidences were not significantly increased by any exposure. In the liver, DNA damage as measured by the comet assay (tail intensity) was increased in a dose-dependent manner by 1,2-dichloropropane (being significant at 300 ppm), but not by dichloromethane (Suzuki et al., 2014). There was a significant increase in comet tail intensity at a lower dose of 1,2-dichloropropane (150 ppm) after co-exposure with dichloromethane (400 ppm) (Suzuki et al., 2014). Gpt mutations were not induced after exposure to 1,2-dichloropropane at 300 ppm, but were significantly increased after co-exposure to 1,2-dichloropropane (300 ppm) and dichloromethane (800 ppm) (Suzuki et al., 2014). [The Working Group noted that a plausible explanation for this result was that co-exposure to dichloromethane leads to saturation of CYP2E1, leading to greater bioactivation of 1,2-dichloropropane through the GSH pathway.]
4.3. Biochemical and cellular effects
In-vitro experiments using renal cortical slices from the kidneys of male Wistar rats showed that exposure to 1,2-dichloropropane caused loss of organic anion accumulation (a measure of renal function), release into the incubation medium of tubular enzymes, aspartate aminotransferase (AST) and lactate dehydrogenase, depletion of GSH, and increase in concentrations of malondialdehyde (Trevisan et al., 1993). Acivicin and aminooxyacetic acid, inhibitors of GGT and the cysteine conjugate β-lyase, respectively, partially prevented loss of organic anion accumulation (p-aminohippurate) and increases in malondialdehyde induced by exposure to 1,2-dichloropropane, suggesting that toxicity is at least partially related to the cysteine conjugate. Alpha-ketobutyrate, an activator of the cysteine conjugate β-lyase, enhanced the effects of 1,2-dichloropropane, suggesting that the toxicity of 1,2-dichloropropane is partially due to nephrotoxic thioalkanes formed from the cysteine conjugate activated by the β-lyase.
Another study investigated the effect of testosterone on the nephrotoxicity of 1,2-dichloropropane in naïve males, females, and castrated males with testosterone replacement (Odinecs et al., 1995). The nephrotoxicity was evaluated by measuring accumulation of an organic anion (p-aminohippurate) and release of AST into the incubation medium in renal cortical slices prepared from animals with differing hormonal status. 1,2-Dichloropropane decreased accumulation of p-aminohippurate by renal cortical slices and increased release of AST. This effect was the largest in the slices obtained from naïve male rats. Males were more susceptible than females to the decreases in p-aminohippurate accumulation and increases in release of AST caused by exposure to 1,2-dichloropropane. Castration of males had a protective effect against the changes in p-aminohippurate uptake and AST release, but pretreatment with testosterone significantly increased the susceptibility of females for effects on p-aminohippurate accumulation only. This study showed that greater susceptibility to 1,2-dichloropropane-induced nephrotoxicity in males can be explained by CYP activity in the kidney, as treatment with testosterone leads to an increase of CYP activity in the kidneys of female and castrated males.
4.4. Organ toxicity
4.4.1. Liver
(a) Humans
Several studies show evidence for liver toxicity in humans exposed to 1,2-dichloropropane. A case report of a worker using stain-remover containing 1,2-dichloropropane described liver injury (indicated by elevations in AST and alanine aminotransferase (ALT), and reduced prothrombin activity). Hepatic biopsy revealed acute centrolobular necrosis characterized by pyknosis and a few “cellular shadows” (Lucantoni et al., 1992). Three cases of intoxication with 1,2-dichloropropane (one by ingestion, two by inhalation) were reported to present with clinical features of severe liver damage evident from elevation of serum enzymes (Pozzi et al., 1985).
Kumagai et al. (2014) reported indications of liver damage both during and after exposure to 1,2-dichloropropane in 10 printing workers later diagnosed with cholangiocarcinoma. Values for erythrocytes, haemoglobin, haematocrit (erythrocyte volume fraction), total cholesterol, triglycerides, and fasting plasma glucose were within the standard ranges during exposure to 1,2-dichloropropane for almost all patients, but GGT levels exceeded the standard range for six patients. Two of these six patients were diagnosed with cholangiocarcinoma during exposure, and the other four patients were diagnosed 1–9 years after termination of exposure. The remaining four patients had GGT levels that were within the standard range during exposure, but had increased GGT levels thereafter, and were diagnosed with cholangiocarcinoma 4–10 years after termination of exposure. AST and ALT levels were also elevated in exposed workers.
(b) Experimental systems
(i) Rats
In 13-week and 2-year studies in male and female F344 rats exposed to 1,2-dichloropropane by inhalation, absolute and relative liver weights were significantly increased in female rats exposed at 500 ppm and above, and swelling of centrilobular hepatocytes was observed in male and female rats exposed at 2000 ppm (Umeda et al., 2010). Centrilobular hepatic fatty degeneration with atrophy and necrosis of the liver was found in studies of shorter duration in rats (Heppel et al., 1946).
In studies in Sprague-Dawley rats given 1,2-dichloropropane by gavage for up to 13 weeks, morphological changes were reported in the liver, including moderate cytoplasmic condensation, necrosis of centrilobular hepatocytes, and mixed inflammatory cell infiltration (Bruckner et al., 1989). Another 13-week study in male and female F344N rats treated by oral gavage found centrilobular congestion of the liver, hepatic fatty changes, and centrilobular necrosis (NTP, 1986). Daily dosing of rats with 1,2-dichloropropane for 4 weeks resulted in a dose-dependent increase in the incidence of focal liver necrosis and steatosis (Trevisan et al., 1989).
Treatment of rats with buthionine sulfoximine, a glutathione-depleting agent, increased lethality of 1,2-dichloropropane (2 mL/kg bw, by gavage), while administration of N-acetylcysteine, a glutathione precursor, decreased toxicity (Imberti et al., 1990).
(ii) Mice
In a 13-week study in B6D2F1/Crlj mice given 1,2-dichloropropane by inhalation, swelling of centrilobular hepatocytes was found to be significantly increased in both male and female mice exposed at 300 ppm and above (Matsumoto et al., 2013). Other pathological observations included necrosis, fatty change, vacuolic change, and mineralization of centrilobular hepatocytes. Total bilirubin, AST, ALT, and lactate dehydrogenase were increased in male and female mice exposed at 400 ppm. Alkaline phosphatase activity was significantly increased in male mice exposed at 300 ppm and above. A study in C3H mice exposed to 1,2-dichloropropane at 400 ppm for up to 37 days (4–7 hours/day) found moderate to marked congestion and fatty degeneration of the liver, extensive centrilobular coagulation and necrosis of the liver. Some of the observations were made post mortem in mice that died during treatments (Heppel et al., 1948).
Several long-term bioassays in mice exposed to 1,2-dichloropropane by inhalation reported signs of liver histopathology (Heppel et al., 1946; Matsumoto et al., 2013). Dose-dependent increases in the incidences of hepatomegaly and hepatic necrosis (focal, not otherwise specified, and centrilobular combined) were also found in male mice, but not females, given 1,2-dichloropropane by gavage for 2 years, (NTP, 1986).
(iii) Other species
In a study by Heppel and colleagues, rabbits and dogs were exposed to 1,2-dichloropropane via inhalation (Heppel et al., 1946). Few animals were examined in each of these species, usually one per group. Mild steatosis was observed in two rabbits exposed for 1 or 2 weeks. Post-mortem (death due to 1,2-dichloropropane exposure at 1000 ppm for up to 96 days) pathological evaluation of the liver in dogs showed moderate to marked fatty degeneration of the liver. In a follow-up study in dogs treated with 1,2-dichloropropane at lower concentrations (400 ppm, 134 exposures, 4–7 hours per exposure) via inhalation, slight haemosiderosis was observed in the liver of one dog (Heppel et al., 1948).
4.4.2. Kidney
(a) Humans
Several case studies reported that exposure to 1,2-dichloropropane may cause acute renal failure in humans (Pozzi et al., 1985; Lucantoni et al., 1992; Fiaccadori et al., 2003).
(b) Experimental systems
(i) Rats
In male and female F344/DuCrj rats exposed to 1,2-dichloropropane for 13 weeks or 2 years, no exposure-related kidney lesions were reported (Umeda et al., 2010). In rats exposed to 1,2-dichloropropane for between 2 and 140 days, no kidney histological changes were observed (Heppel et al., 1948). No apparent nephrotoxicity was observed in male Sprague-Dawley rats treated with 1,2-dichloropropane by gavage for 1 day, 10 days, or 13 weeks (Bruckner et al., 1989), or in male and female F344 rats treated by gavage for 13 weeks or 2 years (NTP, 1986).
As mentioned above (see Section 4.3), in-vitro studies in which rat renal cortical slices were exposed to 1,2-dichloropropane showed that a depletion in GSH occurs, and that it can be prevented by carbon monoxide. It was also shown that the loss of organic anion accumulation (p-aminohippurate) can be partially inhibited by acivicin and aminooxyacetic acid, which are inhibitors of GGT and β-lyase activities, respectively (Trevisan et al., 1993).
(ii) Mice
Kidney toxicity has been observed in several studies in mice. In B6D2F1/Crlj mice exposed to 1,2-dichloropropane by inhalation for 2 years, basophilic changes in the proximal tubules and mineralization of the cortex were reported in males (Matsumoto et al., 2013). No kidney pathology was found at the 13-week time-point in this study. Two additional studies in mice reported fatty degeneration of the kidney after a single lethal dose, or repeated dosing for 2–4 weeks (Heppel et al., 1946, 1948). In studies in male and female B6C3F1 mice treated by gavage, no exposure-related lesions were reported in the kidney at either 13 weeks or 2 years (NTP, 1986).
(iii) Other species
In a study in guinea-pigs killed 6–8 months after exposure to 1,2-dichloropropane by inhalation for up to 4 months, renal cortical scarring, extensive renal fibrosis and amyloidosis, tubular atrophy and fatty degeneration alternating with dilated and occasionally cystic tubules were reported in some exposed animals (Heppel et al., 1948). A study in dogs exposed to 1,2-dichloropropane for up to 4 months observed scattered granulomatous lesions in the kidney, with no demonstrable acid-fast bacilli (Heppel et al., 1948).
4.4.3. Central nervous system
Depression of the central nervous system was reported in humans exposed to 1,2-dichloropropane at high concentrations (Perbellini et al., 1985; Imberti et al., 1987; Lucantoni et al., 1992). Depression of the central nervous system was observed in adult male Sprague-Dawley rats given 1,2-dichloropropane by gavage for 1 day, 10 days, or 13 weeks (Bruckner et al., 1989).
4.4.4. Haematotoxicity
Haemolytic anaemia has been observed in humans in two case reports of exposure to 1,2-dichloropropane (Pozzi et al., 1985; Lucantoni et al., 1992).
In experimental animals, haemolytic anaemia, accompanied by pathological changes of the spleen, was observed in B6D2F1 mice and F344/DuCrj rats exposed to 1,2-dichloropropane by inhalation for 13 weeks (Umeda et al., 2010; Matsumoto et al., 2013), and in Sprague-Dawley rats exposed by gavage for 13 weeks (Bruckner et al., 1989).
4.4.5. Skin
In a case series of 10 subjects with contact allergic dermatitis, all demonstrated a positive response to 1,2-dichloropropane (Baruffini et al., 1989). In another case report, a woman exposed occupationally to 1,2-dichloropropane reported hand dermatitis that receded after changing work (Grzywa & Rudzki, 1981).
No data on experimental animals were available to the Working Group.
4.4.6. Respiratory system
No data on humans were available to the Working Group.
In mice exposed to 1,2-dichloropropane by inhalation for 13 weeks, treatment-related metaplasia and atrophy of the nasal cavity epithelium, and necrosis of the olfactory epithelium, were reported in males and females (Matsumoto et al., 2013). In rats exposed to 1,2-dichloropropane by inhalation for 13 weeks or 2 years, hyperplasia of the respiratory epithelium, and atrophy of the olfactory epithelium occurred in males and females (Umeda et al., 2010).
4.4.7. Adrenal gland
No data on humans were available to the Working Group.
In a study in rats exposed to 1,2-dichloropropane by inhalation for 13 weeks, the incidence of fatty changes in the adrenal gland was statistically significant in females (Umeda et al., 2010). In a study in dogs exposed by inhalation, marked congestion, atrophy, pigmentation and focal necrosis of the zona reticularis of the adrenal gland was reported in one dog (Heppel et al., 1946).
4.5. Susceptible populations
4.5.1. Polymorphisms
No publications were available that had directly assessed the effects of 1,2-dichloropropane in potentially susceptible populations. However, the dependence of toxicity on the metabolism of 1,2-dichloropropane by CYP2E1 and GST suggests that genetic polymorphisms in these enzymes will modulate individual susceptibility to 1,2-dichloropropane. Specifically, it is expected that higher activities of CYP2E1 and certain GST isoforms would promote greater toxicity after exposure to 1,2-dichloropropane. Regarding the GST-dependent metabolism of 1,2-dichloropropane, the function of specific isoforms has not been determined.
4.5.2. Life stage
No studies providing data related to life-stage susceptibility to the carcinogenic effects of 1,2-dichloropropane were available to the Working Group.
4.6. Mechanistic considerations
Limited information was available on the toxicokinetics of 1,2-dichloropropane. However, the available data suggested that 1,2-dichloropropane behaves similarly to other halogenated alkanes, and is metabolized by CYP and GST-mediated conjugation with GSH. Available toxicokinetic data indicated that metabolism is extensive, with excretion of multiple urinary metabolites indicating that multiple metabolic pathways are active (Timchalk et al., 1991).
The best-studied metabolic pathways involve GSH conjugation in combination with CYP, leading to mercapturates that are excreted in the urine; GSH-conjugation alone, which may lead to formation of reactive metabolites; or CYP alone, which leads to formation of carbon dioxide that is exhaled. CYP2E1 plays a major role in CYP-mediated metabolism (Guengerich et al., 1991), although the evidence suggests that other CYPs can also be involved (Lefever & Wackett, 1994). Under conditions of higher exposure when CYP2E1 is saturated, it is plausible that GSH-only metabolism would predominate, but this has not been demonstrated. Alternatively, saturation of CYP without a shift to GSH-only metabolism would lead to increased excretion of the parent compound, which has been observed in rats (Timchalk et al., 1991). Moreover, a shift to GSH-only metabolism would lead to a change in the proportion of urinary mercapturates, but no such change was observed with increasing dose (Timchalk et al., 1991). Finally, based on isotope-labelling, Bartels & Timchalk (1990) found no evidence for activity of the GSH-only pathway. Overall, the Working Group concluded that, while plausible, there was insufficient direct evidence for the activity of a GSH-only pathway, leading to formation of reactive metabolites.
No data on the genotoxicity of 1,2-dichloropropane or its metabolites in humans were available to the Working Group. In experimental systems in vivo, no dominant-lethal effect was observed in one study (EPA, 1989). In another in-vivo study, no increases in the frequency of Pig-a mutation or micronucleus formation were observed with exposure to 1,2-dichloropropane, but DNA damage as measured by the comet assay was increased in a dose-dependent manner, with increases occurring at lower levels of exposure to 1,2-dichloropropane under conditions of co-exposure to dichloromethane (Suzuki et al., 2014). Genotoxicity with 1,2-dichloropropane has been observed in vitro, including mutation in Salmonella, and sister-chromatid exchanges in Chinese hamster ovary and lung fibroblast V79 cells, and chromosomal aberrations in Chinese hamster ovary cells, where results did not depend on the presence or absence of exogenous metabolic activation (De Lorenzo et al., 1977; Principe et al., 1981; Galloway et al., 1987; von der Hude et al., 1987). While there is some evidence for genotoxicity with 1,2-dichloropropane in vivo and in vitro, the genotoxicity database contains mixed results and is not extensive.
1,2-Dichloropropane causes hepatic and renal toxicity, including fatty degeneration and necrosis, in humans (Perbellini et al., 1985; Pozzi et al., 1985; Lucantoni et al., 1992; Fiaccadori et al., 2003) and in experimental systems (Heppel et al., 1946, 1948; NTP, 1986). Damage is often extensive, and sometimes fatal. Haemolytic anaemia as a result of 1,2-dichloropropane exposure has also been consistently reported in studies in humans and experimental animals (Heppel et al., 1946; Pozzi et al., 1985; Lucantoni et al., 1992; Umeda et al., 2010; Matsumoto et al., 2013). Nasal, but not lung, toxicity has been reported in mice and rats exposed to 1,2-dichloropropane via inhalation, with effects observed including desquamation of the olfactory epithelium (Umeda et al., 2010; Matsumoto et al., 2013).
No direct data on susceptibility were available to the Working Group.
- Mechanistic and Other Relevant Data - Some Chemicals Used as Solvents and in Pol...Mechanistic and Other Relevant Data - Some Chemicals Used as Solvents and in Polymer Manufacture
Your browsing activity is empty.
Activity recording is turned off.
See more...