1,2-dichloropropane

Endpoint summary

Additional information

In vitro Studies

 

The mutagenic potential of 1,2-dichloropropane has been evaluated in a large number of microbial tests in bacteria and fungi, both in the absence and in the presence of exogenous metabolic activation (summarized by IARC, 1999). Overall, results from these tests are mixed, with both positive and negative studies.

 

However, in a GLP-compliant study with liquid pre-incubation conducted by the US National Toxicology Program, no mutagenic activity or cytotoxicity was detected when DCP (up to 2000 μg/plate) was incubated with four strains of Salmonella typhimurium(TA 98, TA 1537, TA 100, TA 1535) in the absence or presence of S9 fraction from Arochlor 1254-induced rats (NTP, 1986). A satisfactory response was obtained with the positive control substances, benzo(a)pyrene and MNNG. DCP was also not cytotoxic or mutagenic in these same tester strains when evaluated in the absence or presence of S9 using a plate incorporation methodology (up to 3150 μg/plate, in the absence or presence of glutathione supplementation; Oesch, 1979). Exposure to DCP vapour (atmosphere generated by evaporation of 0.3 - 10 ml of test substance in a 20 l desiccator) also failed to produce a response in the organisms in the presence or absence of S9 and glutathione supplementation (Oesch, 1979), whereas dichloroethane (3 ml) was positive in TA100 and TA1535 under these same conditions.

 

Overall, DCP has returned consistently negative results in Salmonella typhimurium tester strains TA1537 and TA98 at up to 5800 μg/ml in the absence or presence of S9, whereas TA100 and TA1535 have returned mixed results under similar conditions.

 

When tested in mammalian cells in vitro, no increase in mutations was detected at the thymidine kinase locus in L5178Y cells after incubation with up to 1000 nl/ml 1,2-dichloropropane in the absence of rat S9 (cytotoxic at >800 nl/ml), while assays in the presence of S9 provided evidence of mutagenicity at or around the threshold for cytotoxicity (80 nl/ml) (Myhr and Caspary, 1991). In an assessment of clastogenic potential, the number of chromosomal aberrations present in CHO cells exhibited a dose-related response (reported as a 5- or >16-fold increase) after incubation with 1370 or 1580 μg/ml DCP in the absence of S9, and an approximate 4-fold increase in the number of aberrant cells exposed to 660 or 950 μg/ml in the presence of S9 (NTP, 1986). In another series of in vitro experiments, CHO cells exhibited a dose-related increase in sister chromatid exchanges after exposure to PDC in vitro, with an approximate doubling in response after incubation with 376 or 1127 μg/ml DCP, both in the presence and absence of Arochlor 1254-induced rat S9 (NTP, 1986).

 

In vivo Studies

 

Results from a recent GLP compliant OECD 474 guideline mouse micronucleus study demonstrated no evidence of cytogenetic damage in bone marrow from CD-1 mice given up to 600 mg/kg bw by gavage (corn oil vehicle) on 2 consecutive days (Spencer et al., 2003). Systemic toxicity (2°C drop in body temperature) was noted in high dose animals, while results from the range-finder investigation indicated that higher treatment levels (1000 mg/kg bw and above) were lethal. A satisfactory response was obtained with the positive control substance (cyclophosphamide). Based on toxicokinetic data demonstrating DCP is distributed evenly across all tissues, including bone, exposure of the bone marrow can be assumed for this study. The results demonstrate no potential for DCP to damage genetic material present in immature red blood cells.

 

Similarly, negative results were also reported from a modern, guideline rat dominant lethal assay (Hanley et al., 1989) performed to GLP. Male SD rats (n = 30/group) received DCP in drinking water at doses equivalent to 0, 28, 91 or 162 mg/kg bw/day for at least 13 wk. The high dose was a saturated solution of DCP in water. They were then mated with untreated females for two successive one-week periods. A positive control group (cyclophosphamide, 100 mg/kg bw, 48 hr prior to mating) was included in the study. Mating and fertility indices were comparable between the control and PDC-treated groups (96-100%), but decreased significantly in the positive controls. Slight variations in number of corpora lutea, number of implantations, pre-implantation losses and resorption rates were noted in the first or second week of mating in the low and high dose groups (mid-dose group not different from control), but the magnitude of the change was within the normal control ranges. In contrast, the positive control group showed a 2-fold increase in pre-implantation loss and a 10-fold increase in resorption rate. Overall it was concluded that DCP had no capacity to induce heritable mutations in male SD rats following at least 13-week oral treatment with up to 162 mg/kg bw/day.

 

Limited information, from a non-standard test method of unknown reliability, indicates that the number of polyploid mononuclear and binuclear hepatocytes was increased in rats following 3 days inhalation exposure to 2200 mg/m³ DCP (Belyaeva et al., 1977).

 

Short description of key information:
Results from in vitro genotoxicity tests (bacterial, fungal, mammalian systems; with and without metabolic activation) are mixed, with both positive and negative studies, indicating that PDC hasin vitromutagenic potential. However, results from two modern guidelinein vivotests demonstrate that PDC was not active in a mouse micronucleus test or a rat dominant lethal assay. These findings indicate that PDC is not an in vivo somatic or germ cell genotoxicant, despite widespread distribution throughout the body. In addition, results from adequate carcinogenicity assays in rats and mice provide supplementary information on the mutagenic potential of 1,2-dichloropropane in vivo. The findings (limited to liver tumours in mice and no convincing evidence of carcinogenicity in the rat) indicate that the compound is not a genotoxic carcinogen.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Although DCP is both negative and positive in vitro, well-conducted studies in vivo show DCP to be non mutagenic.