National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/9760

Abstract for TR-479 - Coconut Oil Acid Diethanolamine Condensate (CASRN 68603-42-9)

ABSTRACT

Toxicology and Carcinogenesis Studies of Coconut Oil Acid Diethanolamine Condensate (CAS No. 68603-42-9) in F344/N Rats And B6C3F 1 Mice (Dermal Studies)

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Chemical Formula: C(7+n)H(15+2n)O 3N Where: n = 7, 9, 11, 13, or 15

Coconut oil acid diethanolamine condensate, a mixture of fatty acid diethanolamides of the acids found in coconut oil, is widely used in cosmetics, shampoos, soaps, and related consumer products. Because of the lack of information about potential risks associated with long-term exposure, coconut oil acid diethanolamine condensate was selected as a representative of the diethanolamine chemical class for evaluation of toxicity and carcinogenic potential.

Male and female F344/N rats and B6C3F 1 mice received dermal applications of coconut oil acid diethanolamine condensate for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes.

14-WEEK STUDY IN RATS

Groups of 10 male and 10 female F344/N rats received dermal applications of 0, 25, 50, 100, 200, or 400 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol, five times per week for 14 weeks. All rats survived until the end of the study. Final mean body weights and body weight gains of 200 and 400 mg/kg males and females were significantly less than those of the vehicle controls. Clinical findings included irritation of the skin at the site of application in 100, 200, and 400 mg/kg males and females. Cholesterol concentrations were significantly decreased in 200 and 400 mg/kg males and in females administered 100 mg/kg or greater; triglyceride concentrations were also decreased in 200 and 400 mg/kg males. Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females. The incidences of renal tubule regeneration in 100, 200, and 400 mg/kg females were significantly greater than the vehicle control incidence, and the severities in 200 and 400 mg/kg females were increased.

14-WEEK STUDY IN MICE

Groups of 10 male and 10 female B6C3F 1 mice received dermal applications of 0, 50, 100, 200, 400, or 800 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol, five times per week for 14 weeks. All mice survived until the end of the study. Final mean body weights and body weight gains of dosed males and females were similar to those of the vehicle controls. The only treatment-related clinical finding was irritation of the skin at the site of application in males and females administered 800 mg/kg. Weights of the liver and kidney of 800 mg/kg males and females, the liver of 400 mg/kg females, and the lung of 800 mg/kg females were significantly increased compared to the vehicle controls. Epididymal spermatozoal concentration was significantly increased in 800 mg/kg males. Histopathologic lesions of the skin at the site of application included epidermal hyperplasia, sebaceous gland hyperplasia, chronic active inflammation, parakeratosis, and ulcer. The incidences and severities of these skin lesions generally increased with increasing dose in males and females.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female F344/N rats received dermal applications of 0, 50, or 100 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol five times a week for 104 weeks.

Survival, Body Weights, and Clinical Findings
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 most of the study. The only chemical-related clinical finding was irritation of the skin at the site of application in 100 mg/kg females.

Pathology Findings
There were marginal increases in the incidences of renal tubule adenoma or carcinoma (combined) in 50 mg/kg females. The severity of nephropathy increased with increasing dose in female rats. Nonneoplastic 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 group.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female B6C3F 1 mice received dermal applications of 0, 100, or 200 mg coconut oil acid diethanolamine condensate/kg body weight in ethanol five times a week for 104 to 105 weeks.

Survival, Body Weights, and Clinical Findings
Survival of dosed male and female mice was generally similar to that of the vehicle controls. Mean body weights of 100 mg/kg females from week 93 and 200 mg/kg 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.

Pathology Findings
The incidences of hepatic neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) were significantly increased in male and/or female mice. Most of the incidences exceeded the historical control ranges. 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 males.

Several nonneoplastic 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 ulcer in 200 mg/kg males and inflammation and parakeratosis in 200 mg/kg females were greater than those 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.

GENETIC TOXICOLOGY

Coconut oil acid diethanolamine condensate did not show genotoxic activity in vitro. It was not mutagenic in Salmonella typhimurium, nor did it produce an increase in mutant L5178Y mouse lymphoma cell colonies. In addition, no increases in the frequencies of sister chromatid exchanges or chromosomal aberrations were observed in Chinese hamster ovary cells after incubation with coconut oil acid diethanolamine condensate. All these in vitro assays were conducted with and without induced S9 activation enzymes. In contrast to the uniformly negative results in vitro, positive results were obtained in a peripheral blood micronucleus test in male and female mice from the 14-week dermal study.

CONCLUSIONS

Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of coconut oil acid diethanolamine condensate in male F344/N rats administered 50 or 100 mg/kg. There was equivocal evidence of carcinogenic activity in female F344/N rats based on a marginal increase in the incidences of renal tubule neoplasms. There was clear evidence of carcinogenic activity in male B6C3F 1 mice based on increased incidences of hepatic and renal tubule neoplasms and in female B6C3F 1 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.

Exposure of rats to coconut oil acid diethanolamine condensate by dermal application in ethanol for 2 years resulted in epidermal hyperplasia, sebaceous gland hyperplasia, hyperkeratosis, and parakeratosis in males and females and ulcer in females at the site of application. There were increases in the incidences of chronic inflammation, epithelial hyperplasia, and epithelial ulcer in the forestomach of female rats. The severities of nephropathy in dosed female rats were increased.

Exposure of mice to coconut oil acid diethanolamine condensate by dermal application for 2 years resulted in increased incidences of eosinophilic foci of the liver in males. Increased incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and hyperkeratosis in males and females, ulcer in males, and parakeratosis and inflammation in females at the site of application and of follicular cell hyperplasia in the thyroid gland of males and females were chemical related.

Synonyms: Cocamide DEA; cocamide diethanolamine; coconut oil diethanolamine; N,N-bis(hydroxyethyl)coco amides; N,N-bis(hydroxyethyl)coco fatty amides

Trade names: Clindrol 200CGN; Clindrol 202CGN; Clindrol Superamide 100CG; Comperlan KD; Comperlan LS; Comperlan PD; Conco Emulsifier K; Elromid KD 80; Empilan CDE; Ethylan LD; Ethylan A 15; Lauridit KDG; Marlamid D 1218; Monamid 150D; Monamid 150DB; Ninol 1281; Ninol 2012E; Ninol 2012 Extra; Ninol P 621; P and G Amide 72; Purton CFD; Schercomid CDA; Steinamid DC 2129; Steinamid DC 2129E; Varamide A 2; Varamide A 10; Varamide A 83; Witcamide 82; Witcamide 5133


 

 

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Coconut Oil Acid Diethanolamine Condensate
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F 1 Mice
Female
B6C3F 1 Mice
Doses in ethanol by dermal application

Vehicle control, 50, or 100 mg/kg

Vehicle control, 50, or 100 mg/kg

Vehicle control, 100, or 200 mg/kg

Vehicle control, 100, or 200 mg/kg

Body weights

Dosed groups similar to vehicle controls

Dosed groups similar to vehicle controls

Dosed groups similar to vehicle controls

Dosed groups less than vehicle controls

Survival rates

8/50, 12/50, 11/50

28/50, 24/50, 22/50

41/50, 37/50, 36/50

35/50, 36/50, 26/50

Nonneoplastic effects

Skin, site of application: epidermal hyperplasia (0/50, 46/50, 50/50); sebaceous gland hyperplasia (0/50, 45/50, 50/50); parakeratosis (0/50, 9/50, 28/50); hyperkeratosis (0/50, 36/50, 48/50);

Skin, site of application: epidermal hyperplasia (3/50, 46/50, 50/50); sebaceous gland hyperplasia (2/50, 46/50, 49/50); parakeratosis (1/50, 11/50, 23/50); hyperkeratosis (3/50, 45/50, 47/50); ulcer (2/50, 0/50, 9/50)

Forestomach: chronic active inflammation (1/50, 3/50, 10/50); epithelial hyperplasia (2/50, 5/50, 13/50); epithelial ulcer (1/50, 3/50, 11/50)

Kidney: severity of nephropathy (1.6, 2.1, 2.7)

Liver: eosinophilic foci (20/50, 29/50, 31/50)

Skin, site of application: epidermal hyperplasia (5/50, 47/50, 50/50); sebaceous gland hyperplasia (0/50, 44/50, 49/50); hyperkeratosis (0/50, 24/50, 23/50); ulcer (1/50, 0/50, 7/50)

Thyroid gland: follicular cell hyperplasia (11/50, 20/50, 23/50)

Skin, site of application: epidermal hyperplasia (9/50, 47/50, 50/50); sebaceous gland hyperplasia (0/50, 42/50, 48/50); hyperkeratosis (5/50, 30/50, 40/50); chronic active inflammation (3/50, 2/50, 11/50); parakeratosis (3/50, 4/50, 16/50)

Thyroid gland: follicular cell hyperplasia (27/50, 36/50, 33/50)

Neoplastic effects

None

None

Liver: hepatocellular adenoma (22/50, 35/50, 45/50); hepatoblastoma (1/50, 1/50, 10/50); hepatocellular adenoma, carcinoma, or hepatoblastoma (29/50, 39/50, 49/50)

Kidney: renal tubule adenoma (1/50, 1/50, 7/50); renal tubule adenoma or carcinoma (1/50, 1/50, 9/50)

Liver: hepatocellular adenoma (32/50, 44/50, 43/50); hepatocellular carcinoma (3/50, 21/50, 32/50); hepatocellular adenoma, carcinoma, or hepatoblastoma (33/50, 46/50, 48/50)

Uncertain Findings

None

Kidney: renal tubule adenoma or carcinoma (standard evaluation - 0/50, 2/50, 0/50; standard and extended evaluations combined - 0/50, 4/50, 1/50)

None

None

Level of evidence of carcinogenic activity

No evidence

Equivocal evidence

Clear evidence

Clear evidence

Genetic toxicology
Assay Results
Salmonella typhimurium gene mutations:

Negative in strains TA97, TA98, TA100, and TA1535

Mouse lymphoma gene mutations:

Negative with or without S9

Sister chromatid exchanges
Cultured Chinese hamster ovary cells in vitro:


Negative with or without S9
Chromosomal aberrations
Cultured Chinese hamster ovary cells in vitro:

Negative with or without S9
Micronucleated erythrocytes
Mouse peripheral blood in vivo:

Positive in males and females

Report Date: January 2001

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies


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