Amides, vegetable-oil, N,N-bis(hydroxyethyl)

Carcinogenicity

Description of key information

No cancerogenic after dermal exposure

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

In order to classify the PRODUCT L6143 for carcinogenicity, the available classification (from Harmonized classification, Registration dossier and CLP notification) and the results of the reported studies of every known component and the similar substances have been taken into account.

Amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl), CAS 68155-07-7: not classified for carcinogenicity

Amides, C12-18 (even-numbered) and C18 (unsatd.), N,N-bis(hydroxyethyl), CAS 90622-74-5: not classified for carcinogenicity

Amides, C16-18 and C18-unsatd., N,N-bis(hydroxyethyl), CAS 68603-38-3: not classified forcarcinogenicity

Lauramide diethanolamine (LDEA) CAS 120-40-1: not classified for carcinogenicity

Coconut fatty acid diethanolamide,Amides, coco, N,N-bis(hydroxyethyl)CAS 68603-42-9: not classified for carcinogenicity. This substance

is being included in the list of substances nominated for possible review for future editions of the Report on Carcinogens (RoC).

The Personal Care Council and the REACH Fatty acid Alkanolamides (FAA) consortium argued with the NTP National Toxicology Program about this inclusion and a decision is under evaluation.

Diethanolamine CAS 111-42-2: not classified for carcinogenicity

Amides, vegetable-oil, N,N-bis(hydroxyethyl) are the major component (a 86 %), followed by diesters of fatty acids of diethanolamine.

A small amount of diethanolamine (2-5%) is present, and for the evaluation of the carcinogenicity the presence between 0.1% to >=1% shall be taken into account.

According to the CLP Regulation 1272/2008/EC, 3.7 section, point 3.6.4.1., Table 3.6.3, generic concentration limits shall be used to determine if the mixture is considered to be or not a cancerogen.

Based on the information available, the intermediate PRODUCT L6143 is not classified as a cancerogen.

Additional information

No data the major component (ca 86 %) are available, but data of similar substances with a defined number of carbons and insaturation are available. No data on diesters are available. Information on products containing Cocamide DEA and diethanolamine has been taken into account, in fact, a small amount of diethanolamine (2-5%) is present in the intermediate, PRODUCT L6143.

 

A two-year dermal study was conducted in F344/N rats to evaluate the carcinogenic potential of coconut oil acid diethanolamine condensate, CAS 68603-42-9. The NTP full technical report is available.

Doses studied include 0, 50, or 100 mg/kg bw test material (0, 85, or 170 mg/mL in ethanol). 50 male/female test animals were used in each group. 5 exposures per week were given for 104 weeks. 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 only chemical-related clinical finding was irritation of the skin at the site of application in 100 mg/kg bw females. There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg bw 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.

Under the test conditions, 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.^{1 2 3 5 6}

A similar study, two-year dermal study was conducted in B6C3F1 mice to evaluate the carcinogenic potential of the same similar substance coconut oil acid diethanolamine condensate.

Doses studied include 0, 100, or 200 mg/kg bw of the test material (0, 50, or 100 mg/mL in ethanol). 50 male/female test animals were used in each group. 5 exposures per week were given for 104 to 105 weeks. 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 dosed male and female mice was generally similar to that of the vehicle controls. Mean body weights of 100 mg/kg bw females from Week 93 and 200 mg/kg bw females from Week 77 were less than those of the vehicle controls. The only clinical finding attributed to treatment was irritation of the skin at the site of application in males administered 200 mg/kg bw .

The incidences of hepatic neoplasms (hepatocellular adenoma, 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 dosed groups of males and females were significantly greater than those in the vehicle control groups. 

Based on the above results, there was a 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.

These increases were associated with the concentration of free diethanolamine present as a contaminant in the diethanolamine condensate. However, recent evidences suggest that 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/renal tumours are not relevant to humans/primates.^{1 2 3 5 6}

 

Results from a two-year dermal study conducted in rats to evaluate the carcinogenic potential of the similar substance lauric acid diethanolamine condensate, (LDEA, CAS No.120-40-1) are reported on an available NTP technical report. Doses studied included 0, 50, or 100 mg/kg bw (0, 85, or 170 mg/mL). 50 male and 50 female F344/N rats were used in each group. 5 exposures per week were given for 104-105 weeks. 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.

No significant differences was reported between the vehicle control groups and dosed groups in the incidences of neoplasms. Incidences of chronic inflammation, hyperkeratosis, and parakeratosis in all dosed groups were significantly greater than those in the vehicle controls, as were the incidences of ulceration in 100 mg/kg bw males and females. The non neoplastic skin lesions at the site of application were considered to be indicative of local irritation with no neoplastic or pre neoplastic changes.

Under the test conditions, no evidence of carcinogenic activity for the test material was observed at any of the dose levels tested.^{1 2 3 7}

 

A similar study, a two-year dermal study was conducted in rats to evaluate the carcinogenic potential of the same similar substance lauric acid diethanolamine condensate, (LDEA, CAS No.120-40-1). Doses studied include 0, 100, or 200 mg/kg (0, 50, or 100 mg/mL). 50 male/female B6C3F1 mice were used in each group. 5 exposures per week were given for 105-106 weeks.

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 incidences of hepatocellular adenoma or carcinoma were significantly increased in dosed female groups compared to that in the vehicle control group, as was the incidence of hepatocellular adenoma in 100 mg/kg females. Incidences of non neoplastic lesions of the skin at the site of application were significantly increased in dosed males and females. Compared to the vehicle controls, the incidences of chronic inflammation and hyperkeratosis were significantly greater in all groups of dosed males and females, and the incidences of parakeratosis were significantly greater in males and females administered 200 mg/kg. Incidences of focal hyperplasia of thyroid gland follicular cells were increased in dosed male mice; the incidence in the 200 mg/kg group was significantly greater than that in the vehicle control group.

Under the test conditions, no evidence of carcinogenic activity for the test material was reported in male mice.

Some evidence of carcinogenic activity in female mice based on increased incidences of hepatocellular neoplasms. These increases were associated with free diethanolamine, which was present as a contaminant of lauric acid diethanolamine condensate.^{1 2 3 7}

A study on oleic acid diethanolamine condensate CAS 93-83-4, has been performed and data available.

No evidence of carcinogenic activity has been reported.³

Documents regarding the carcinogenicity of coconut diethanolamide DEA and its nomination in the list of substances nominated for possible review for future editions of the Report on Carcinogens (RoC) are available. The Personal Care Council and the REACH Fatty acid Alkanolamides (FAA) consortium argued with the NTP National Toxicology Program about this inclusion. Associations and company are suggesting that coconut diethanolamide not be reviewed for listing in a future edition of the Report on Carcinogens.^{8 9}

The reasons are that:

- The NTP evaluated coconut diethanolamide in F344/N rat and BGC3F1 mouse bioassays, with a result of 'clear evidence of carcinogenic activity" in the mouse, and 'no evidence' in the rat. The positive results seen in the mouse bioassay were concluded to be due to the presence of free diethanolamine in the test material, as is discussed below. Diethanolamine has already been evaluated for listing in the RoC and was found not to meet the criteria for listing. Because the activity in the coconut diethanolamide bioassay was due to a contaminant that did not meet the criteria for RoC listing, it would follow that coconut diethanolamide would likewise not meet the criteria for listing;

- The test material was reported in the NTP technical report to contain 18.2% free DEA as a contaminant. This material exhibited carcinogenic effects in a chronic dermal exposure in mice, but not in rats despite the same concentration of free diethanolamine;

- In 2002, diethanolamine was considered for possible listing in the RoC as "reasonably anticipated to be a human carcinogen". The recommendation from RGl, RG2, and the Board of Scientific Counselors RoC Subcommittee was not to list, as the listing criteria were not met;

- No evidence of in vitro and in vivo genotoxicity (including an in vivo mouse micronucleus assay2) in dedicated genotoxicity assays;

Structurally similar lauric acid diethanolamine (CAS#120-40-1) containing residual levels of 0.8% DEA showed no evidence of carcinogenic activity in NTP dermal carcinogenicity studies in male/female rats and in male mice, but some evidence of carcinogenic activity was observed in female mice;

- Structurally similar oleic acid diethanolamine condensate (CAS# 93-83-4) containing residual levels of only 0.19% DEA showed no carcinogenic activity, neither in mice nor in rats;

- Potential confounding effects of vehicle ethanol in NTP studies.^{8 9}

Reference:

¹ECHA Registration Dossier Amides, C8-18 (even numbered) and C18-unsatd., N,N-bis(hydroxyethyl), CAS 68155-07-7

²ECHA Registration Dossier Amides, C12-18 (even-numbered) and C18 (unsatd.), N,N-bis(hydroxyethyl), CAS 90622-74-5

³ECHA Registration Dossier Amides, C16-18 and C18-unsatd., N,N-bis(hydroxyethyl), CAS 68603-38-3;

⁴ECHA Registration Dossier 2,2'-iminodiethanol CAS 111-42 -2

⁵Amended Final Report on the Safety Assessment of Cocamide DEA, Journal of the American College of Toxicology, 15 (6): 527-542, CosmeticIngredient Review, 1996.

⁶Toxicology and carcinogenesis studies of coconut oil acid diethanolamine condensate (CAS 68603 -42 -9) in F344/N rats and B6C3F1 mice, dermal studies, NTP TR 479, NIH Publication N. 01-3969, January 2001

⁷Toxicology and carcinogenesis studies of lauric acid diethanolamine condensate (CAS 120 -40 -1) in F344/N rats and B6C3F1 mice, dermal studies, NTP TR 480, NIH Publication N. 01-3970, July 1999

⁸Linda Loretz, Ph.D., DABT, RE: Nominations to the Report on Carcinogens; Request for Information (78 Federal Register 57868), Personal Care Products Council;

⁹I. Bruguier, Stephan Europe, Re: Request for public comments on the nomination of coconut diethanolamide to the RoC;

 

Carcinogenicity: via dermal route (target organ): other: skin