Registration Dossier

Administrative data

Description of key information

In a 6 months inhalation study with rats, an inhalation NOAEC of 50 ppm (130 mg/m3) was established. Exposure to higher concentrations was associated with increased liver weights along with histopathological changes. Comparable studies with other species showed a NOAEC for rabbits of 100 ppm (260 mg/m3, effects on liver) and a NOAEL at the highest level tested, 200 ppm (520 mg/m3), for dogs and guinea pigs.
Exposure of rats and mice to 50 ppm (130 mg/m3) for longer periods (10-12 months) is associated with decreased body weight, increased mortality, increased weights of some organs and liver effects.
Oral administration of 30 mg vinyl chloride/kg/day in soya oil for 13 weeks or 0.13 mg/kg/day for 149 weeks as PVC powder enriched with vinyl chloride produced no adverse effects in rats. Lifetime oral exposure to vinyl chloride in PVC powder at doses equal to or greater than 1.3 mg/kg/day is toxic to the liver. However, as this route of administration is considered to be not the most appropriate means of conducting an oral toxicity study, the NOAEL for repeated dose toxicity by oral route is considered to be 30 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
30 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
130 mg/m³

Additional information

Due to gaseous nature of vinyl chloride, inhalation is considered to be the most relevant exposure route.

Several repeated toxicity inhalation studies for vinyl chloride were available for assessment. In a 6 months inhalation study with rats, an inhalation NOAEC of 50 ppm (corresponding to 130 mg/m3) was established by Torkelson et al. (1961), based on the slight increase in the average liver weights at 100 ppm (260 mg/m3). Exposure to 500 ppm (1300 mg/m3) was associated with increased liver weights and with increased lobular granular degeneration in the livers, and interstitial and tubular changes observed in kidneys. Comparable studies with other species showed a NOAEC for rabbits of 100 ppm (260 mg/m3, effects on liver) and a NOAEC at the highest level tested, 200 ppm (520 mg/m3), for dogs and guinea pigs (all Torkelson et al, 1961).

Exposure of rats and mice to 50 ppm (130 mg/m3) for longer periods (10-12 months) was found to be associated with decreased body weight, increased mortality, increased weights of some organs and liver effects (amongst others, morphological effects, ultrastructural changes, proliferation of cells and DNA synthesis) (Lee et al., 1977; Sokal et al., 1980). A LOAEC of 50 ppm (130 mg/m3) was established by Lee et al. (1977) in a 12 months study with rats, based on increased mortality, and by Sokal et al. (1980) in a 10 months study with rats, based primarily on the changes in liver. These effects are likely related to the carcinogenicity of vinyl chloride.

Oral administration of 30 mg vinyl chloride/kg/day as a solution in soya been oil for 13 weeks (Feron et al., 1975) resulted in an effect level of 100 mg/kg bw/day based on decreased leukocytes and blood sugar. Exposure to 0.13 mg/kg/day vinyl chloride in polyvinyl chloride for 149 weeks produced no adverse effects in rats (Til et al., 1991). Lifetime oral exposure to vinyl chloride in PVC powder at doses equal to or greater than 1.3 mg/kg/day is toxic to the liver (Til et al., 1991 and Feron et al., 1981). The critical non-neoplastic effect was determined to be statistically significantly increased incidences of morphological liver effects in male and female rats. The NOAEL for non-neoplastic liver effects, established in the study of Til et al., was 0.13 mg/kg/day. An increase in the incidence of female rats with many hepatic cysts was also observed at the highest dose (1.3 mg/kg/day).

Because administration of vinyl chloride-enriched PVC, used in the studies of Til et al., 1991 and Feron et al., 1981, is considered to be not the most appropriate means of conducting an oral toxicity study, the study of Feron et al., 1975, was selected as a key study for repeated dose toxicity - oral route.

Past occupational exposure to several hundred ppm of vinyl chloride for periods ranging from one month to 3 years has been associated with development of “vinyl chloride disease”. Vinyl chloride disease is characterized by acroosteolysis, a condition characterized by lytic lesions of bones (primarily of fingers), scleroderma of the connective tissue in the fingers with dermal thickening, and a Raynaud-like condition with reversible arteriole constriction causing numbness, pallor and cyanosis of the fingers. The attribution of acroosteolysis to vinyl chloride exposure is based almost entirely on case reports and has been estimated to affect <3% of workers involved in the polymerization of vinyl chloride.

Long-term occupational exposure of workers to vinyl chloride prior to 1973 has been associated with cancer in humans.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The LOAEC of 50 ppm (130 mg/m3= 0.13 mg/l) (6 hours/day) is below the classification and labelling cut-off of 0.25 mg/l (6 hours/day), applicable to subchronic (90 days) exposure. According to EU Directive 67/548/EEC available chronic toxicity studies should be evaluated case by case: as the major liver effects observed at 50 ppm are likely related to the carcinogenicity of vinyl chloride (carcinogenic effects in these studies are also observed in the liver), for which the substance is classified (as Cat. 1; R45 according to EU Directive 67/548/EEC; and as Cat. 1A (H350) under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008), supplementary classification for repeated dose toxicity is not considered as needed.

Oral administration of 30 mg vinyl chloride/kg/day in soya been oil for 13 weeks (Feron et al., 1975) or 0.13 mg/kg/day in PVC powder for 149 weeks produced no adverse effects in rats (Til et al., 1991). In the 13 weeks study a LOEL of 100 mg/kg bw/day was established based on decreased leukocytes and blood sugar. These effects do no trigger classification. Lifetime oral exposure (in this case 149 weeks) to doses equal to or greater than 1.3 mg/kg/day is toxic to the liver: inducing liver cell changes, hepatocellular carcinoma and angiosarcoma. This level is below the cut-off values for classification. However, as these effects are directly related to the endpoint carcinogenicity, for which vinyl chloride is classified, classification for repeated dose toxicity is not considered as needed.