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Key value for chemical safety assessment

Effects on fertility

Description of key information

In a three generation oral study in rats (Nitschke et al. 1983), the NOAEL for reproductive effects was

200 mg/L (i.e. the highest dose tested), corresponding to an average exposure of 30 mg/kg/d. At 100 mg/L adverse effects on the liver were already observed.

Data on sperm parameters, oestrus cycle, weight of reproductive organs and hystopathology are available from 90-day study

and 2-year study after inhalations exposure of rats and mice (NTP, 2015).

Additional information

A weight of evidence approach was used to assess the toxicity of 1,1-dichloroethene to reproduction. In a three generation study (Nitschke et al., 1983) Sprague-Dawley rats were exposed for 100 days to drinking-water containing nominal vinylidene chloride concentrations of 0, 50, 100 and 200 mg/L. There were no biologically significant changes in fertility index, average number of pups per litter, average body weight of pups, or pup survival at any exposure although slight hepatocellular fatty changes and an accentuated hepatic lobular pattern were observed in the dams at 100 and 200 mg/L for the F1 generation and from 50 to 200 mg/L for the F2 generation. Thus, the NOAEL for the developmental toxicity was 200 mg/L (equivalent to about 30 mg/kg body weight/day). This study is complemented by the data (organ weights, histopathology, oestrus cycle and sperm parameters) from 90-day and 2 year inhalation experiments in rats and mice (NTP, 2013). These studies showed that at doses inducing systemic toxicity no major effects on the reproductive organs, the sperm parameters or the oestrus cycle were observed. Limited effects were observed for the total sperm/cauda epididymis in mice and for the sperm motility, spermatid/testis and total spermatid/testis values in rats (high dose only), but considering the nature of these effects, the fact that these effects were not supported by other findings and the fact that they were observed at doses inducing systemic toxicity, they were not considered convincing indications of a reprotoxic potential of 1,1-dichloroethylene.

Overall, the toxicity to reproduction of 1,1-dichloroethylene appears to be at best limited at concentrations inducing systemic toxicity, and unlikely at concentrations below the NOAEL for systemic toxicity (9 mg/kg/day, Quast et al. 1983).

Finally, and according to the specific rules for adaptation provided in column 2 of point 8.7 and 8.73 of Annex IX and Annex X to Regulation (EC) No 1907/2006, an EORGTS study including all the cohorts, does not need to be conducted as the substance is known to be a genotoxic carcinogen.

In the case of 1,1-dichloroethylene, the carcinogenicity of the substance was studied after inhalation, dermal as well as oral exposure. The substance did increase papillomas when used as a tumor initiator with phorbol myristate through dermal exposure, but when administered alone or subcutaneously, no carcinogenic effects were observed. No carcinogenicity was observed after oral exposure in rats and in mice. Based on the results of a 105-week carcinogenicity study in rats and mice exposed by inhalation, 1,1-dichloroethene showed evidence of carcinogenic activity. It can be concluded that 1,1-dichloroethene shows carcinogenic properties in rodents after inhalation exposure.

On the other hand, based on a positive in vivo Comet assay in male rats by inhalation, 1,1-dichloroethylene was identified as genotoxic to somatic cells.

Therefore it can be concluded, based on the available information, that the substance is a genotoxic carcinogen and that an extended one-generation reproductive toxicity – with F2 generation and both developmental neuro- and immunotoxicity (Cohorts 1A, 1B with extension, 2A, 2B, and 3) does not need to be performed.


Effects on developmental toxicity

Description of key information

Rats exposed by inhalation to 1,1 -dichloroethene at 80 mg/m3, 7 h/day from gestation days 6 -15 showed reduced weight gain, reduced food consumption and increased liver associated with fetal skeletal alterations (wavy ribs and delayed ossification). The NOAEC was 80 mg/m3 and the LOAEC was 320 mg/m3. Concomitant with the findings in the offspring, maternal toxicity was obse Rats exposed by inhalation to 1,1 -dichloroethene at 80 mg/m3, 7 h/day from gestation days 6 -15 showed reduced weight gain, reduced food consumption and increased liver associated with fetal skeletal alterations (wavy ribs and delayed ossification). The NOAEC was 80 mg/m3 and the LOAEC was 320 mg/m3. Concomitant with the findings in the offspring, maternal toxicity was observed.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
40 mg/kg bw/day
Effect on developmental toxicity: via inhalation route
Dose descriptor:
LOAEC
320 mg/m³
Additional information

Developmental toxicity studies were performed on rabbits and mice exposed by inhalation and on rats exposed orally or by inhalation.

In rabbits and rats exposed by inhalation, signs of embryotoxicity/foetotoxicity were observed: minor skeletal alterations (wavy ribs and delayed ossification) in rats at 320 and 640 mg/m3 and in rabbits at 800 mg/m3 and an increase in resorptions in rabbits at 800 mg/m3. These effects on pups were observed concomitantly to decreases in body weight gain and increases in liver weight and/or liver weight relative to body weight of dams (Murray et al., 1979). Thus, the effects on foetuses were considered to be related to maternal toxicity. When orally exposed to 200 mg/mL, female rats and their foetuses showed no signs of toxicity. Dawson et al. observed increased cardiac malformations in Sprague-Dawley foetuses after oral exposure to 1,1 -dichloroethene for approximately 2 months before and during pregnancy (Dawson et al., 1993). However, there was no demonstrated exposure-response relationship and no such malformations were observed in any other study. According to the CICAD 51 (Benson, WHO, 2003), the biological significance of these cardiac structural variations is unclear and there is no indication that the structural variations have functional consequences in animals. The reliability of the Dawson et al. data was also questioned by a review by Hardin et al (2005) who reported improper use of control data. Also EPA did not conclude that the observed cardiac changes were caused by exposure to 1,1-dchloroethane (EPA toxicological review of 1,1 –dichloroethene, 2002). Therefore the data by Dawson et al. was identified as unreliable and not to be taken into consideration.

Toxicity to reproduction: other studies

Description of key information

The behavioral development of rats exposed to vinylidene chloride in utero was assessed using pregnant CD rats exposed to vinylidene chloride by inhalation 22 -23 h/day from day 8 to day 20 of gestation (Short et al., 1977). Despite a reduction in the total weight gain of dams and the body weight of day old pups in both vinylidene chloride exposed groups (LOAEC = 224 mg/m3), no significant effects on neural development were noticed in the pups. The NOAEC for developmental neurotoxicity in this study is 1132 mg/m3.

Justification for classification or non-classification

An extensive data set is available for the assessment of the developmental and reproductive toxicity of 1,1-dichloroethene. The available data does not show convincing indications that 1,1-dichloroethene has a specific reprotoxic potential; the few minor or inconsistent effects which were detected are considered to be due to the concomitant systemic or maternal toxicity.

Therefore, no classification of 1,1-dichloroethene for reproductive and developmental toxicity is deemed necessary.