1.1.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 542-75-6
• Chem. Abstr. Name: 1,3-Dichloro-1-propene
• IUPAC Systematic Name: 1,3-Dichloropropene

1.1.2. Structural and molecular formulae and relative molecular mass

1.1.3. Chemical and physical properties of the pure substance

• (a) Description: Liquid with chloroform-like odour (Budavari, 1996)
• (b) Boiling-point: 104°C (cis), 112°C (trans) (Verschueren, 1996)
• (c) Solubility: Insoluble in water; soluble in acetone and toluene (Lewis, 1993)
• (d) Vapour pressure: 5720 Pa at 25°C (cis), 4522 Pa at 25°C (trans); relative vapour density (air = 1), 3.83 (Verschueren, 1996)
• (e) Flash-point: 35°C, open cup (Lewis, 1993)
• (f) Conversion factor: mg/m³ = 4.54 × ppm

1.3.1. Occupational exposure

According to the 1981–83 National Occupational Exposure Survey (NOES, 1997), approximately 2200 workers in the United States were potentially exposed to 1,3-dichloropropene (see General Remarks). Occupational exposures may occur in its manufacture and use in organic synthesis and as a soil fumigant.

1.3.2. Environmental occurrence

1,3-Dichloropropene is released into the air and in wastewater during its production and use as a soil fumigant and chemical intermediate. 1,3-Dichloropropene may also leach into groundwater. Considerable variation in the amounts of 1,3-dichloropropene lost by volatilization and degradation can be expected depending on the method of application, soil type, moisture and temperature. It has been detected in low levels in ambient air and drinking-water (United States National Library of Medicine, 1997).

3.1.1. Mouse

Mouse: Groups of 50 male and 50 female B6C3F₁ mice, 5–6 weeks of age, were exposed to technical-grade 1,3-dichloropropene (cis-isomer, 49.5%; trans-isomer, 42.6%; 0.7% 1,2-dichloropropane with epoxidized soya bean as a stabilizer) by inhalation at concentrations of 0, 5, 20 or 60 ppm [0, 23, 91 or 272 mg/m³] for 6 h per day on five days per week for 24 months. Ten mice of each sex per group were killed at six and 12 months. At the end of the study, necropsy and histopathological examination of all organs were performed. No sign of toxicity was recorded. Approximately 90% of male and 80–96% of female mice survived until the end of the study. Exposure-related histopathological alterations were observed in nasal tissues of male and female mice exposed to 60 ppm for 24 months, but not for six or 12 months. The alterations were characterized by hypertrophy and hyperplasia of the respiratory epithelium and degeneration of the olfactory epithelium. Hyperplastic changes also occurred in the epithelium of the urinary bladder. In male mice, there was a significant increase in the incidence of bronchioalveolar adenomas at the highest dose: 9/50 in controls compared with 6/50, 13/50 and 22/50 in the groups exposed to 5, 20 and 60 ppm, respectively (Lomax et al., 1989).

3.1.2. Rat

Groups of 50 male and 50 female Fischer 344 rats, 6–8 weeks of age were exposed to 1,3-dichloropropene (as described above). Hyperplastic and degenerative changes occurred to the nasal cavities as well as hyperplastic changes in the urinary bladder. No increase in tumour incidence was observed (Lomax et al., 1989).

4.1.1. Humans

Isomers of N-acetyl-S-(3-chloroprop-2-enyl)-l-cysteine have been detected in urine samples of 1,3-dichloropropene applicators (Osterloh et al., 1984; Van Welie et al., 1989).

4.1.2. Experimental systems

In rats, 1,3-dichloropropene is absorbed rapidly, after either inhalation or oral administration, and is eliminated principally by metabolism (glutathione conjugation) within 24–48 h. The major urinary metabolite of cis-1,3-dichloropropene in rats is the mercapturic acid N-acetyl-S-(cis-3-chloroprop-2-enyl)-l-cysteine. Glutathione conjugation in vitro in rat liver cytosol of the cis-isomer occurs four to five times faster than that of the trans-isomer. 1,3-Dichloropropene is an alkylating agent and the trans-isomer is less reactive than the cis-isomer (IARC, 1986).

At higher inhalation exposure levels in rats, absorption mechanisms become saturated as a result of compromised respiration, while saturation of metabolism also occurs, presumably as result of limitations on glutathione S-transferase activity. Plasma elimination of 1,3-dichloropropene is biphasic, the half-life of the slower phase being roughly 25 to 45 min (Stott & Kastl, 1986). The plasma elimination half-life of the glutathione conjugate of 1,3-dichloropropene is about 17 h, irrespective of the inhalation exposure concentration (Fisher & Kilgore, 1989).

Both cis- and trans-isomers of 1,3-dichloropropene are conjugated with glutathione and excreted as mercapturic acids (55% cis-1,3-dichloropropene and 45% trans-1,3-dichloropropene in 24 h) in Wistar rats after intraperitoneal administration (Onkenhout al., 1986).

1,3-Dichloropropene was given in doses of 0, 25, 50 and 75 mg/kg bw intraperitoneally to male Fischer 344 rats. Excretion of the metabolite N-acetyl-S-(cis-3-chloroprop-2-enyl)-l-cysteine increased in a dose-dependent manner from 0 to 50 mg/kg 1,3-dichloropropene, but no further increase was seen at the 75-mg/kg dose, suggesting that, at higher doses, the metabolism pathway may be saturated or impaired (Osterloh & Xiwen, 1990).

Metabolic activation of 1,3-dichloropropene, as suggested by the use of specific inhibitors of metabolism in the Salmonella typhimurium gene mutation assay, proceeds via an hydrolytic-oxidative pathway; the first step of which is hydrolysis to chloroallyl alcohol, which is then oxidized to chloroacrolein (Neudecker & Henschler, 1986).

4.1.3. Comparison of human and rodent data

The principal metabolic pathway to mercapturic acids is presumably similar in humans and rodents. Because no data on kinetics or metabolic activation in humans are available, no quantitative comparison can be made.

4.2.1. Humans

A 27-year-old previously healthy male worker who accidentally drank a solution containing 1,3-dichloropropene (mixture of cis- and trans-isomers) developed gastrointestinal distress, adult respiratory distress syndrome, haematological and hepatorenal functional impairment, and died 40 h after ingestion (Hernandez et al., 1994).

4.2.2. Experimental systems

Male and female Fischer 344 rats and B6C3F₁ mice were exposed to 0, 10, 30, 90 or 150 ppm [0, 45, 136, 409 or 681 mg/m³] technical grade 1,3-dichloropropene (cis, 48.6%; trans, 42.3%) vapours for 6 h per day on five days per week for 13 weeks (Stott et al., 1988). At the end of the exposure, slight degeneration of the nasal olfactory epithelium and mild hyperplasia of the nasal respiratory epithelium were observed in rats exposed to 150 ppm 1,3-dichloropropene. All male and female Fischer 344 rats exposed to 90 or 150 ppm and two of the 10 rats exposed to 30 ppm 1,3-dichloropropene exhibited minimally detectable hyperplasia of the respiratory epithelium. Exposure to 90 or 150 ppm 1,3-dichloropropene also produced diffuse, moderate hyperplasia of the olfactory epithelium in female B6C3F₁ mice.

Male and female Fischer 344 rats and B6C3F₁ mice were exposed by inhalation to 0, 5, 20 or 60 ppm [0, 23, 91 or 272 mg/m³] 1,3-dichloropropene (cis, 49.5%; trans, 42.6%) for 6 h per day on five days per week for up to two years. Significant morphological alterations in the nasal tissues of rats exposed to 60 ppm and mice exposed to 20 or 60 ppm 1,3-dichloropropene were found at the end of the study (Lomax et al., 1989).

Treatment with buthionine sulfoximine (0.2 M in 0.58% NaCl, 4 mL/kg bw) (to inhibit glutathione synthesis) 4 h before dosing with 1,3-dichloropropene or with diethyl maleate (3.1 M in corn oil, 0.4 mL/kg bw) (to deplete glutathione) or corn oil itself 1 h before dosing with 1,3-dichloropropene at 50 and 75 mg/kg bw resulted in elevations of N-acetylglucosaminidase excretion. In contrast, treatment with aminooxyacetic acid (0.125 M in 0.85% NaCl, 4 mL/kg bw) (which inhibits β-lyase activity) 1 h before 1,3-dichloropropene injection prevented the 1,3-dichloropropene-induced release of N-acetylglucosaminidase from the renal tubule. These results suggest that the nephrotoxic effects of 1,3-dichloropropene may be mediated through the mercapturic acid metabolites in the kidney, rather than glutathione depletion (Osterloh & Xiwen, 1990).

1,3-Dichloropropene was administered to male and female Fischer 344 rats and B6C3F₁ mice for 13 weeks (0, 5, 15, 50 or 100 mg/kg bw per day to rats or 0, 15, 50, 100 or 175 mg/kg bw per day to mice) in the diet by mixing a microencapsulated formulation of 1,3-dichloropropene into animal feed (microencapsulated in a 80/20% starch/sucrose matrix; 1,3-dichloropropene consisted of 50.7% cis-, 45.1% trans-isomers). There was a decrease in the body weights of male and female rats ingesting more than 5 and 15 mg/kg bw per day, respectively, and a decrease in body weights of mice in all treatment groups relative to controls. A low degree of basal cell hyperplasia in the non-glandular portion of the stomach of male and female rats exposed to more than 15 mg/kg bw per day was also observed, but the severity of the damage was somewhat diminished after a four-week recovery period during which the rats were not exposed to 1,3-dichloropropene. The authors established a no-observed-adverse-effect level for rats as 5 mg/kg bw per day, and a no-observed-adverse-effect levels in mice as 15 mg/kg bw per day (Haut et al., 1996).

4.3.1. Humans

In a study of 64 men employed in the production of chlorinated compounds [time-weighted average exposures, < 1 ppm [4.5 mg/m³] 1,3-dichloropropene, 3.1 mg/m³ allyl chloride and 3.8 mg/m³ epichlorohydrin], sperm counts and percentages of normal sperm were similar in the study group and among 63 controls. The volunteer participation rate for the study group was 64% (IARC, 1986).

4.3.2. Experimental systems

Pregnant Fischer 344 rats and New Zealand White rabbits were exposed by inhalation to 0, 20, 60 or 120 ppm [0, 91, 272 or 545 mg/m³ air] 1,3-dichloropropene (47.7% cis, 42.4% trans) for 6 h per day during gestation days 6–15 (rats) or 6–18 (rabbits). Dose-dependent decreases in maternal weight gain and food consumption were observed in rats at all doses of 1,3-dichloropropene, and in rabbits at 60 and 120 ppm. In spite of maternal toxicity, no evidence of teratogenetic or embryotoxic response was observed in rats or rabbits at any of the doses tested (Hanley et al., 1987).

Breslin et al. (1989) conducted a two-generation reproduction study in Fischer 344 rats with 1,3-dichloropropene (92% technical product). Male and female Fischer 344 rats were exposed by inhalation to 0, 10, 30 or 90 ppm [0, 45, 136 or 409 mg/m³] 1,3-dichloropropene for 6 h per day on five days per week for two generations. The parental F₀ and F₁ generations were each bred twice. Parental effects (decreased body weights, histopathological effects on nasal mucosa) occurred only at the highest concentration of 1,3-dichloropropene. No adverse effect on reproductive parameters or neonatal growth or survival was found in either of the F₁ or F₂ litters, even at the 90 ppm dose.

Male and female Wistar rats were exposed by inhalation to concentrations of 0, 10, 30 or 90 ppm (v/v) of a mixture of vapours containing 28.1% cis-1,3-dichloropropene, 25.6% trans-1,3-dichloropropene, 25.6% 1,2-dichloropropane, 20.7% other chemicals (D-D) for 6 h per day on five days per week for 10 weeks. Treated males were paired with untreated virgin females, and treated females were paired with untreated males. Exposure to the vapours produced no adverse effect on the libido, fertility or morphology of the reproductive tracts of rats of either sex (Linnett et al., 1988).

Relative testicular weights of Fischer 344 male rats exposed by inhalation to 90 and 150 ppm [409 and 681 mg/m³] 1,3-dichloropropene (cis, 48.6%; trans, 42.3%) for 6 h per day on five days per week for 13 weeks were increased and thymus weights of female rats exposed to 150 ppm 1,3-dichloropropene were decreased relative to controls (Stott et al., 1988). Changes in testicular or thymic weights at the lower doses of 10 and 30 ppm were not observed.

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems (see Table 1 for references)

Table 1

Genetic and related effects of 1,3-dichloropropene.

1,3-Dichloropropene was mutagenic in Salmonella typhimurium, with or without metabolic activation. In one study, the cis-isomer was reported not to be mutagenic to Salmonella typhimurium TA100 without metabolic activation, and to become active only after exposure to oxygen and consequent generation of autooxidation products. Glutathione was shown to efficiently inhibit the mutagenicity in Salmonella of cis- and trans-1,3-dichloropropene both with and without metabolic activation. There was no difference in the Salmonella mutagenicity between cis- and trans-1,3-dichloropropene.

In one study, a mixture of cis- and trans-1,3-dichloropropene gave positive results for induction of mutations in Drosophila melanogaster.

A mixture of cis- and trans-1,3-dichloropropene caused sister chromatid exchanges in human lymphocytes in vitro as well as in other cultured mammalian cells. It also induced unscheduled DNA synthesis and DNA strand breaks. However, it was negative for induction of chromosomal aberrations in Chinese hamster ovary CHO cells.

A mixture of cis- and trans-1,3-dichloropropene has given contradictory results in the mouse micronucleus assay. In the most recent study, it was positive in female (but not in male) NMRI mice. On the other hand, it did not induce micronuclei in the bone marrow, spleen or liver of partially hepatectomized rats, nor did it cause unscheduled DNA synthesis in rat hepatocytes in vivo.