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Carcinogenicity

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Description of key information

The carcinogenicity of 1,1-dichloroethene was studies by inhalation, dermal as well as oral route. No carcinogenic effects were observed in the studies addressing 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.
Based on the results of a 105-week carcinogenicity study in rats and mice addressing inhalation, 1,1-dichloroethene was determined to show evidence of carcinogenic activity in both species after inhalation exposure.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
26.7 mg/m³
Study duration:
chronic
Species:
mouse

Additional information

The carcinogenicity of 1,1-dichloroethene has been studied in rats and mice by dermal, oral and inhalation exposure.

Dermal

Through dermal exposure, vinylidene chloride increased skin lesions (papillomas) when used as a tumors initiator with phorbol myristate acetate as a promoter, but had no toxic effects when applied repeatedly alone or subcutaneously (Van Duuren et al., 1979).

Oral

No dose-related, significant increases in tumors were observed in animals given 1,1-dichloroethene orally (Maltoni et al., 1977; NTP, 1982; Quast et al., 1983; Rampy et al., 1977; Ponomarkov et al. 1980).

Inhalation

No significant increase in tumors was observed in CD and Sprague-Dawley rats exposed to vinylidene chloride by inhalation for up to 18 months (Hong et al., 1981, Quast et al., 1986; Maltoni et al., 1977-1985; Rampy et al., 1977; Lee et al., 1977). CD-1 mice exposed to 1,1-dichloroethene by inhalation for 6 or 12 months also showed no significant increase in tumors (Lee et al., 1978; Hong et al., 1981). One study showed an increase in kidney adenocarcinomas in male Swiss mice following 12 months of 1,1-dichloroethene exposure by inhalation (Maltoni et al., 1977). In another study using a similar, Swiss-origin mouse strain (CD-1) (Lee et al., 1977), no increase in kidney tumors was observed in male or female mice with substantially greater 1,1-dichloroethene exposure (220 mg/m3, 6 h/day, 5 days per week versus 100 mg/m3, 4 h/day, 4-5 days per week; 52-week duration in both studies). This comparison suggests that an effect of 1,1-dichloroethene on kidney adenocarcinomas, if real, would be species, strain, and even gender specific.

The study by Maltoni et al. suffered from significant shortcomings. In EPA's toxicological review of 1,1 -dichloroethene (2002) it was stated that the study was rejected for the definition of the inhalation reference concentration because the animals were only exposed for 1 year and there was no evaluation of endpoints at the termination of exposure. Thus the true incidence of the effects due to exposure to 1,1 -dichloroethene could not be determined.

On the other hand, it needs to be mentioned that compounds similar in structure to 1,1 -dichloroethene (tetrachlorethene, trichlorethene and 1,2 -dichloroethene) have been found to produce varying amounts of kidney tumours in animal assays (Benson, CICAD 51, 2003). In order to further clarify the uncertainty regarding the carcinogenic potential of 1,1 -dichloroethene, an additional 2 year carcinogenicity studies was carried out. The study examined groups of 50 male and 50 female rats and mice that were exposed by whole-body inhalation to 1,1 -dichloroethene vapor for 6 hours plus T90 (10 minutes) per day, 5 days per week for 105 weeks. Exposure concentrations were determined based on a 2 -week and on a 3 -months repeated dose toxicity study in both species. The rats were exposed to vapor concentrations of 0, 25, 50 or 100 ppm

(corresponding to 0.107, 0.214 or 0.428 mg/L, and 107, 214 or 428 mg/m3, whereas the mice were exposed to concentrations of 0, 6.25, 12.5 or 25 ppm (corresponding to 0.0267, 0.0534 or 0.107 mg/L, and 26.7, 53.4 or 107 mg/m3).

Under the conditions of the test with rats, there was clear evidence of carcinogenic activity in male F344/N rats and some evidence of carcinogenic activity in female F344/N rats following inhalation exposure to 1,1 -dichloroethene. These conclusions are based on the following findings:

- Male rats: dose-related increased incidence of malignant mesothelioma and a chemical-related increased incidence of renal tubule carcinoma and respiratory epithelium adenoma in the nose.

- Female rats: chemical-related increased incidence of C-cell adenoma or carcinoma in the thyroid gland and systemic mononuclear cell leukemia, and a marginal increase in the occurrences of malignant mesothelioma.

Under the conditions of the test with mice, there was clear evidence of carcinogenic activity in male and female mice following inhalation exposure to 1,1 -dichloroethene. These conclusions are based on the following findings:

- Male mice: dose-related increased incidence of renal tubule adenoma and carcinoma and a chemical-related increased incidence of hepatocholangiocarcinoma.

- Female mice: dose-related increased incidence of systemic hemangioma or hemangiosarcoma (combined), chemical-related increased incidence of hepatocholangiocarcinoma and hepatocellular adenoma and carcinoma (combined), and a marginal increase in the occurrences of alveolar/bronchiolar carcinoma in the lungs and carcinoma of the small intestine.

No LOAEC/NOAEC was derived in the report. However, based on the results of the study and under these experimental conditions, the LOAEC following 105-week inhalation (whole body) administration of 1,1 -dichloroethylene (or vinylidene chloride) to mice and rats were estimated to be 6.25 ppm and 25 ppm, respectively.

As a conservative approach, it is proposed to select the LOAEC in mice for risk assessment purposes because this is the lowest one. In addition, other toxicity studies show that mice are more susceptible laboratory animal species than rats.


Justification for selection of carcinogenicity via oral route endpoint:
Oral study with the highest tested dose.

Justification for classification or non-classification

Based on the data from the 105-week carcinogenicity study in mice and rats it is concluded that, under the conditions of the test, there is clear evidence of the carcinogenic activity of 1,1-dichloroethene. As a consequence, classification as a Category 1B carcinogen according to CLP is deemed appropriate.

This self-classification of 1,1 -dichloroethene therefore is more stringent than the harmonized classification (Index No.: 602-025-00-8, REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2008, Consolidated version 01.06.2015), according to which the substance is classified as a category 2 carcinogen.