Alkanes, C10-13, chloro

Carcinogenicity

Description of key information

In 2-yr carcinogenicity studies, to GLP, the C12 chlorinated paraffin (60% chlorination) produced toxicologically significant, dose-related increases in the incidence of several tumour types in both rats and mice following gavage administration. Dose-related increased incidence of adenomas and carcinomas of the liver and thyroid were observed in mice. There was an indication of similar effects in the rat study. These findings reflect, in the case of the liver, chronic tissue damage caused by peroxisome proliferation and for the thyroid, long-term hormonal stimulation. From consideration of the probable underlying mechanisms involved, it is likely that these carcinogenicity observations are not relevant to human health. Male rats also showed an increased incidence of kidney tubular cell adenomas. This was not seen in female rats or in mice of either sex. Although hyaline droplets were not directly observed, the pattern of results in male rats is consistent with tumour formation following kidney damage caused by hyaline droplet formation, which is a male rat-specific phenomenon. This is suggestive that the benign tumours observed in the kidney of males rats are not likely to be relevant for human health. Therefore, given that SCCPs are not genotoxic, it is considered that there would be no risk of kidney tumour development associated with exposures lower than those required to produce chronic toxicity in this target organ. A NOAEL for kidney toxicity in male rats has been previously identified at 100 mg/kg bw/day. This value will be used in the risk characterisation.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Justification for classification or non-classification

Under the EU CLP and DSD regulations, SCCPs would not be classified for human carcinogenicity based on the information described above.

Additional information

No relevant carcinogenicity information is available in humans exposed to SCCPs, and no dermal or inhalation animal studies are available.

In a well-conducted carcinogenicity study, to GLP, groups of 50 male and 50 female B6C3F1 mice were given 0, 125 or 250 mg/kg bw/day of a C12 chlorinated paraffin (60% chlorination), in corn oil by gavage, 5 days/week, for 103 weeks. A comprehensive range of tissues were examined microscopically (including those of the reproductive system). Among treated animals, there were increased incidences of hepatocellular tumours (adenomas/carcinomas) in both sexes and of thyroid follicular cell adenomas/carcinomas in females at 125 mg/kg bw/day and above. Alveolar/bronchiolar carcinomas in the lungs of males occurred with a positive trend, and the incidence was significant in the high-dose group. However, occurrences of alveolar/bronchiolar adenomas and carcinomas (combined) were not greater than in vehicle controls and no similar effect was seen in females, therefore this is not considered to be treatment-related. Harderian gland adenomas in low-dose females occurred more often than in the vehicle controls, but a lack of dose-response suggested that this effect may be spurious, and these findings are not considered to be of significance for human health. In conclusion, it appears that a C12 chlorinated paraffin (60% chlorinated) is carcinogenic in B6C3F1 mice, and that the liver and thyroid are the main target organs. Overall, a LOAEL of 125 mg/kg bw/day (the lowest tested dose) can be identified for carcinogenic effects in both sexes (NTP, 1986). [See opinion of Specialised Experts below.]

In a well-designed study, to GLP, with generally low survival rates towards the end of the treatment period, groups of 50 male and 50 female F344/N rats were given 0, 312 or 625 mg/kg bw/day of a C12 chlorinated paraffin (60% chlorination), in corn oil by gavage, 5 days/week, for 104 weeks. A comprehensive range of tissues were examined microscopically (including those of the reproductive system). There were increased incidences of hepatocellular tumours (mostly neoplastic nodules but including carcinomas) in both sexes, of thyroid follicular cell adenomas/carcinomas in females, and of kidney tubular cell adenomas/carcinomas in males (0/50, 9/50, 3/49 in control-, low- and high-dose animals, respectively; the historical incidence is around 0.4%), which reached statisitical significance in the low-dose male rats only. Mononuclear cell leukemia was increased in males (with a clear positive trend), whereas in females a significant increase compared to controls was seen only in the low-dose group. In conclusion, the evidence indicates that a C12 chlorinated paraffin (60% chlorinated) is carcinogenic to F344/N rats, and that the liver, thyroid and kidney are the main target organs. Overall, a LOAEL of 312 mg/kg bw/day (the lowest tested dose) can be identified for carcinogenic effects in both sexes (NTP, 1986). [See opinion of Specialised experts below.]

Discussion at Technical Meetings and by the Specialised Experts, as cited in the final RAR (EU, 2000)

The carcinogenicity of SCCPs was discussed at Technical Meetings on October 1st-3rd 1996 and February 19th-21st 1997. Member States agreed that the substance was not genotoxic but could not agree further on the significance of the tumours seen nor on their relevance to man.

The Commission Group of Specialised Experts in the fields of Carcinogenicity, Mutagenicity and Reprotoxicity met on 4 -6th June 1997. The Specialised Experts considered the NTP cancer bioassays to be of poor quality and that no significance should be attributed to the slight excess of tumours seen in the lung, pancreas, stomach or Haderian gland, or increase of leukemia(s). The Specialised Experts agreed that of the tumours observed, only those in the liver, thyroid and kidney could be considered significant. Mechanisms for two of these had been suggested - peroxisome proliferation for the liver tumours and hormonal imbalance for the thyroid. These mechanisms were accepted by the Specialised Experts. [From consideration of the probable underlying mecahnisms involved [see IUCLID Chapter 7.5] it is likely that these carcinogenicity observations are not relevant to human health.] However, the Specialised Experts considered that no plausible mechanism was suggested for the kidney tumour seen in male rats. It had been noted that α2u globulin might be responsible, but studies had failed to show significant levels of the protein. Other evidence had shown that there was chronic nephropathy which might be a contributing factor in the tumour development. The Specialised Experts considered that as there was still insufficient evidence to conclude a male rat specific event, the consequences for humans could not be ruled out.

Therefore, given that SCCPs are not genotoxic, it is considered that there would be no risk of kidney tumour development associated with exposures lower than those required to produce chronic toxicity in this target organ. A NOAEL for kidney toxicity in male rats has been previously identified at 100 mg/kg bw/day (see IUCLID Chapter 7.5). This value will be used in the risk characterisation.

Carcinogenicity: via oral route (target organ): digestive: liver; glandular: thyroids; urogenital: kidneys