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Carcinogenicity

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Description of key information

The two year chronic dermal studies conducted in rats and mice have shown structurally similar amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) to be carcinogenic in mice based on the induction of liver and kidney tumours but no evidence of carcinogenic effects were observed in rats. Structurally similar lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1) has also shown evidence of liver carcinogenicity in mice but not in rats. In contrast, oleic acid diethanolamine condensate (ODEA, CAS No. 93-83-4) showed no evidence of carcinogenic effects in two year chronic dermal studies in rats and mice. The authors clearly stated that, in amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and lauric acid diethanolamine condensate (LDEA, CAS No.120-40-1), the presence of DEA as a contaminant was considered to be responsible for the observed carcinogenic effects in mice. This suggestion is further strengthened by more recent research which suggests that DEA is a non-genotoxic carcinogen with a mode of action involving choline depletion, which is a rodent specific mechanism unlikely to be relevant to humans. Therefore, in light of all the available information, amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl is not expected to be a carcinogen to humans. 

Key value for chemical safety assessment

Justification for classification or non-classification

The available data suggests that amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl is not carcinogenic to humans. Although rodent carcinogenicity studies conducted on structurally similar amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) and lauric acid diethanolamine (LDEA, CAS No.120-40-1) provided evidence ofcarcinogenicity in mice, this was linked to the presence of free DEA in the test substance. DEA has been shown to be a non-genotoxic carcinogen in mice, with a proposed mode of action which is not relevant for man. This evaluation is supported by a recent decision of a scientific board of the National Toxicology Program (NTP) after a public hearing at which it was decided that DEA should not be listed as a carcinogen under the RoC (Report on Carcinogens) process. Therefore, based on the overall weight of evidence, amides, C12-18 (even numbered) and C18-unsatd., N-hydroxyethyl, does not require classification for carcinogenicity according to EC (67/548/EEC) and CLP (EC 1272/2008) criteria.

Additional information

Dermal

A two year dermal study was conducted in F344/N rats to evaluate the carcinogenic potential of structurally similar amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl). Doses of 0, 50, or 100 mg/kg bw of amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) (0, 85, or 170 mg/mL in ethanol) were administered to 50 male and female test animals in each group. Five exposures per week were given for 104 weeks. The animals were observed twice daily, body weights and clinical findings were recorded periodically. Necropsy and histopathology was performed on all animals. The survival rates of treated male and female rats were similar to those of the vehicle controls. The mean body weights of dosed males and females were similar to those of the vehicle controls throughout the study. The only chemical-related clinical finding was skin irritation at the site of application in the 100 mg/kg bw dose group (females). There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg bw dose group (females). The severity of nephropathy increased with increasing dose in female rats. Non-neoplastic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, parakeratosis, and hyperkeratosis, and the incidences and severities of these lesions increased with increasing dose. The incidences of chronic active inflammation, epithelial hyperplasia, and epithelial ulcer of the forestomach increased with dose in female rats, and the increases were significant in the 100 mg/kg bw group. There was no evidence of carcinogenic activity of the test material in male rats administered 50 or 100 mg/kg bw. There was an equivocal evidence of carcinogenic activity in female rats based on a marginal increase in the incidences of renal tubule neoplasms. However, the absence of an increase in neoplasms in the 100 mg/kg group in the presence of increased hyperplasia makes the association with chemical exposure uncertain (NTP report 479, 2001).

In a two year dermal toxicity study conducted in B6C3F1 mice, the carcinogenic potential of amides, C8-18 and C18-unsatd., N,N-bis(hydroxyethyl) was evaluated. Doses of 0, 100 or 200 mg/kg bw (0, 50 or 100 mg/mL in ethanol) were administered to 50 male and female mice. Five exposures per week were given for 104 to 105 weeks. The animals were observed twice daily, body weights and clinical findings were recorded periodically. At necropsy, a complete histopathology was performed on all animals. Survival of dosed male and female mice was generally similar to that of the vehicle controls. Female mean bodyweights of 100 mg/kg bw from Week 93 and 200 mg/kg bw from Week 77 were lower than those of the vehicle controls. The only clinical finding attributed to treatment was skin irritation at the site of application in males administered 200 mg/kg bw. The incidences of hepatic neoplasms (hepatocellularadenoma, hepatocellular carcinoma, and hepatoblastoma) were significantly increased in male and/or female mice. The incidences of eosinophilic foci in dosed groups of male mice were increased relative to that in the vehicle controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in 200 mg/kg bw males. Several non-neoplastic lesions of the skin at the site of application were considered treatment-related. Incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and hyperkeratosis were greater in all dosed groups of males and females than in the vehicle controls. The incidences of thyroid gland follicular cell hyperplasia in all test groups of males and females were significantly greater than those in the vehicle control groups. Based on the above results, there was clear evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F1 mice based on increased incidences of hepatic neoplasms (NTP report 479, 2001).

It is important to consider, that in both two years dermal rat and mouse studies described above, the test substance amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl) contained free DEA as a contaminant at a concentration of at least 0.5 %. As described in a recent review by Leunget al.(2005), studies conducted by The National Toxicology Program have indicated that lifetime dermal exposure to DEA increased the incidence and multiplicity of liver tumours in mice but not in rats. DEA was not carcinogenic when tested in the Tg.Ac transgenic mouse model and short term genotoxicity tests have provided negative results. It has been shown that DEA induces mouse liver and kidney tumours by a non-genotoxic mode of action that involves its ability to cause choline deficiency. Choline is an essential nutrient in mammals and therefore this mode of action is qualitatively applicable to human. However there are marked species differences in susceptibility to choline deficiency, with rats and mice being much more susceptible that other mammalian species including humans. These differences are due to the quantitative differences in the enzyme kinetics controlling choline metabolism. The fact that DEA is carcinogenic in mice and not in rats has therefore important implications for human health risk assessment. Since DEA has also been shown to be less readily absorbed across rat and human skin compared to mouse skin and a NOAEL for DEA-induced choline deficiency in mice has been established to be 10 mg/kg/day, thus indicating there is a critical level of DEA that must be attained in order to affect choline homeostasis. The lack of carcinogenic response in rats suggest that exposure to DEA did not reach the critical level and since rodents are more sensitive to choline deficiency that humans, it can be concluded that the carcinogenic effects of DEA in mice is not predictive of similar susceptibility in humans and also suggests DEA should not be classified as a carcinogen, as the hepatic tumours seen in mice and the proposed mode of non-genotoxic mechanism for liver and renal tumours are not relevant to humans and primates.

In another two year dermal study conducted in rats and mice, the carcinogenic potential of structurally similar lauric acid diethanolamine (LDEA, CAS No.120-40-1) was investigated. Dose of 0, 50, or 100 mg/kg bw (0, 85, or 170 mg/mL) were administered to 50 male and 50 female F344/N rats and 0, 100, or 200 mg/kg (0, 50, or 100 mg/mL) were administered to 50 male and 50 female B6C3F1mice. Five exposures per week were given for 104-105 weeks (rats) 105-106 weeks (mice). The animals were observed twice daily, body weights and clinical findings were recorded periodically. Necropsy was performed on all animals and complete histopathology was performed. The results revealed no evidence of carcinogenic activity of structurally similar lauric acid diethanolamine (LDEA, CAS No.120-40-1) in male or female rats at any of the dose levels. There was also no evidence of carcinogenic activity in male mice administered 100 or 200 mg/kg bw. However there was some evidence of carcinogenic activity in female mice based on increased incidences of hepatocellular neoplasms (NTP report 480, 1999). The authors concluded that the increases seen were associated with the presence of free diethanolamine, present as a contaminant in the LDEA at a concentration of approximately 5 %.

Two year dermal studies were conducted in 50 F344/N male/female rats and 50 B6C3F1 male/female mice to evaluate the carcinogenic potential of structurally similar oleic acid diethanolamine condensate (ODEA, CAS No. 93-83-4).ODEA contained up to 0.19 % free diethanolamine.Rats were administered 0, 50, or 100 mg/kg bwODEAin ethanol (0, 85, or 170 mg/mL) and mice were administered 0, 15, or 30 mg/kg bwODEAin ethanol (0, 7.5, or 15 mg/mL), 5 exposures per week for 104 (rats) or 105 weeks (mice). The animals were observed twice daily, body weights and clinical findings were recorded periodically. Necropsy was performed on all animals and complete histopathology was performed. Survival of test groups (male and female rats was similar to that of the vehicle control groups. The only significant treatment-related clinical finding was mild to moderate irritation of the skin at the site of application in dosed male and female rats. Minimal to moderate non-neoplastic skin lesions at the site of application on rats was observed. These lesions included epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, parakeratosis, chronic active dermal inflammation, and ulcers. There was no evidence of carcinogenic activity fromODEAin male or female F344/N rats administered 50 or 100 mg/kg bw. Survival of test groups (male and female mice) was similar to that of the vehicle control groups. Mean body weights of all dosed male mice and the 15 mg/kg bw female mice were similar to those of the vehicle controls throughout the study. Mean body weights of 30 mg/kg bw female mice dose group were less than those of the vehicle controls from Week 76 until the end of the study. The only significant treatment-related clinical finding was irritation of the skin at the site of application in the 30 mg/kg bw male mice dose group. The incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and chronic active inflammation of the dermis in all dosed groups were significantly increased relative to the vehicle controls at 3 months and at 2 years. The increased incidences of hyperkeratosis in dosed males at 3 months and in dosed males and females at 2 years, of parakeratosis in 30 mg/kg bw males at 3 months and 2 years, and of ulcer in 30 mg/kg bw males and exudates in 30 mg/kg bw males and females at 2 years were also attributed to the administration ofODEA. There was no evidence of carcinogenic activity from ODEAin male or female B6C3F1 mice administered 15 or 30 mg/kg bw (NTP report 481, 1999).