Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
15.9 mg/kg bw/day
Additional information

Information from animal testing

Oral exposure to chloroform resulted in minor effects on fertility in mice exposed via oral gavage. Albino Swiss mice were exposed to chloroform in corn oil via oral gavage for 31 weeks (Chapin et al. 1997). Food and water consumption were not affected by the treatment. There were no treatment-related changes in any endpoint related to reproductive function. Dam body weights, number of litters, number of pups per litter were all unchanged. In males of the F1 generation, there was a 7 % increase in relative epididymis weight in the treated groups. Sperm mobility, density and percent of abnormal sperm were not affected by the treatment. Epididymal lesions rated as "minimal" were identified in 6/20 treated mice in the high dose group; two additional mice in this group had lesions classified as "mild". The lesions consisted of vacuolar degeneration of the ductal epithelium in the cauda epididymis. Based on the findings, the NOAEL of the study was 15.9 mg/kg body weight/day.

Human information

There is no direct evidence of effects on human fertility caused by chloroform exposure. An analysis of the effect of laboratory vs. non-laboratory work on the incidence of spontaneous abortions (lost of the embryo before gestational week 20) was performed on Swedish women born after 1945, who had worked for at least one year between 1990 and 1994 and given birth to at least one child during the period of 1990 to April 1995 (Wennborg et al. 2000). To this end, a cohort of 1052 women was identified and questionnaires were sent to these women. The final analysis was performed on 622 women (856 pregnancies) who had responded to the questionnaire. The study found a slightly increased risk for spontaneous abortions among women working in laboratories with chloroform. The study did include other exposure variables for which no increased risk was found (such as contact with radioactive material, viruses, bacteria). However, the authors of the study did not perform measurements of chloroform concentrations at the work places of women and numerous uncertainties regarding the link between chloroform exposure and increased rate of abortion in women remain.


Short description of key information:
Chloroform was found to induce minor adverse effects on the epididymis weight when administered orally to Swiss mice (Chapin et al 1997). Based on the findings, the NOAEL of the study for the reproduction functions was 15.9 mg/kg body weight/day.

Effects on developmental toxicity

Description of key information
Inhalation exposure to chloroform can lead to retardation of the development of conceptuses in Wistar rats (Baeder and Hofmann 1991). The NOAEC for maternal and developmental effects in the study was 15 mg/m3. The oral exposure to chloroform can induce minor malformations of the reproductive organs in the F1 generation of Swiss mice. The NOAEL for developmental toxicity following oral exposure was 15.9 mg/kg/day (Chapin et al. 1997). Chloroform was not teratogenic in the studies on developmental toxicity performed for the inhalation and oral routes.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
15.9 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
14.7 mg/m³
Additional information

Information from animal testing

Pregnant Wistar rats were exposed to chloroform vapours for 7 hours per day for 10 days (day 7 to 16 after mating) and all animals were killed on Day 21 of gestation in order to examine dams and foetuses (Baeder and Hofmann 1990). Concentrations of 50 mg/m3 and above led to slight retardation in the conceptuses and a decrease in the body weight of dams. Intrauterine embryonic death seemed to occur at concentrations of 147 mg/m3 and greater. This was confirmed in a previous test using higher vapour concentrations (Baeder and Hofmann 1988). All observed effects were judged as foetotoxic. No indication of a teratogenic effect of chloroform was found in the foetuses examined. It was concluded that a concentration of 15 mg/m3 is tolerated by both pregnant rats and conceptuses. The study by Chapin et al. (1997) investigated the developmental toxicity of chloroform to Swiss CD-1 mice by administering chloroform in corn oil via oral gavage. The conclusion was that chloroform had no adverse effect on mouse development at doses that were hepatotoxic and the developmental NOAEL in the test was 15.9 mg/kg body weight/day based on increased relative epididymis weight of animals of the F1-generation of the high dose group (41.9 mg/kg/day). A number of studies on developmental toxicity and teratogenicity are available, which were rated as not reliable (Thompson et al. 1974, Murray et al. 1979, Balster and Borzelleca 1982 and Ruddick et al. 1983). These studies provide weight of evidence that chloroform is foetotoxic and that oral or inhalation exposure of dams during gestation causes adverse effects in the foetuses including decreases in foetal weight and crown-rump length and delayed ossification of the sternebrae and skull bones. Some of the studies reported also the occurrence of abnormalities such as cleft palate. A study on neurobehavioural teratogenicity of chloroform in mice concluded that the substance was not teratogenic at the tested oral dose of 31.1 mg/kg/day administered to dams (Balster and Borzelleca 1982). In sum, the available data indicate that chloroform acts in a foetotoxic manner causing decreases in foetal weight and crown-rump length, delayed ossification and abnormalities such as cleft palate. A teratogenic mode of action of chloroform is unlikely.

Human information

A population-based case-control analysis of the association of chloroform and other trihalomethanes in drinking water with low birth weight, prematurity and intrauterine growth retardation was performed. The analysis used Iowa birth certificates data from January 1, 1989, to June 30, 1990. The study was restricted to singleton live infants born to non-Hispanic white women 19 years of age or older who were residents of Iowa towns with 1000-5000 inhabitants that derived 100 % of their public drinking water from a single source. Exposure was classified using data from a 1987 municipal drinking water survey measuring chloroform in a unified manner. Three exposure categories were used: undetectable chloroform, 1-9 microgram/litre of chloroform, > 10 microgram/litre of chloroform. 159 infants exhibiting birth weights below 2500 g were compared to 795 randomly selected control infants, 342 infants exhibiting prematurity were compared to 1710 randomly selected control infants, and 187 infants with growth retardation were compared to 935 randomly selected control infants. Comparisons showed that there was an increased risk of intrauterine growth retardation associated with higher concentrations of waterborne chloroform and dichlorobromomethane. The elevated risk associated with chloroform remained even when the analysis was restricted to chlorinated water sources, indicating that chloroform has an association over and above that attributable to chlorination alone.

Justification for classification or non-classification

Based on the data available for fertility, the effects of chloroform are not sufficiently severe to justify a classification. In agreement with the decision of the TC C&L during the revision of the classification for chloroform, the proposed GHS classification for developmental toxicity of chloroform is Category 2, "suspected human reproductive toxicant", with the hazard statement: suspected of damaging the fertility or the unborn child.