National Toxicology Program

National Toxicology Program
https://ntp.niehs.nih.gov/go/37176

Abstract for TR-576 Trimethylolpropane Triacrylate

Toxicology and Carcinogenesis Studies of Trimethylolpropane Triacrylate (Technical Grade) (CASRN 15625-89-5) in F344/N Rats and B6C3F1/N Mice (Dermal Studies)

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Abstract

Trimethylolpropane triacrylate is a multifunctional monomer with a wide range of industrial applications. It is used in the production of ultraviolet-curable inks, electron beam irradiation-curable coatings, and polymers and resins; as a component of photopolymer and flexographic printing plates and photoresists; and as an ingredient in acrylic glues, adhesives, and anaerobic sealants. Additionally, trimethylolpropane triacrylate is used in paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Trimethylolpropane triacrylate was nominated by the National Cancer Institute for study due to its high production volume and use, the potential for human exposure, and the lack of adequate chronic toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were administered technical grade trimethylolpropane triacrylate (greater than 78% pure) in acetone dermally for up to 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli.

2-YEAR STUDY IN RATS

Groups of 65 male and 65 female rats received dermal applications of 0, 0.3, 1.0, or 3.0 mg trimethylolpropane triacrylate/kg body weight in acetone, 5 days per week for 104 to 105 weeks (core study). At 2 weeks, 13 weeks, and 12 months, five animals per sex per dose group were randomly selected for histological examination of skin tissue. Survival and mean body weights of all dosed groups were similar to those of the vehicle control groups.

In male rats, there was a positive trend in the incidences of malignant mesothelioma; the incidence in 3.0 mg/kg males was significantly greater than the vehicle control incidence and exceeded the historical control ranges by only one tumor.

Nonneoplastic skin lesions at the site of application in core study rats included epidermal hyperplasia and hyperkeratosis. The incidences of these lesions in male rats administered 1.0 or 3.0 mg/kg were significantly increased. In females at the site of application, incidences of epidermal hyperplasia were significantly increased at 1.0 and 3.0 mg/kg and incidences of hyperkeratosis were significantly increased in all dosed groups. At the interim evaluations, increased incidences of epidermal hyperplasia, sebaceous gland hyperplasia, and or hyperkeratosis were observed at the site of application in males and females.

2-YEAR STUDY IN MICE

Groups of 65 male and 65 female mice received dermal applications of 0, 0.3, 1.0, or 3.0 mg trimethylolpropane triacrylate/kg body weight in acetone, 5 days per week for 105 to 106 weeks (core study). At 2 weeks, 13 weeks, and 12 months, five animals per sex per dose group were randomly selected for histological examination of skin tissue. Survival and mean body weights of all dosed groups were similar to those of the vehicle control groups.

Liver neoplasms in female mice included hepatoblastoma in the 0.3 and 3.0 mg/kg groups and hepatocholangiocarcinoma in the 1.0 and 3.0 mg/kg groups. Based on the rarity of these neoplasms in female mice, and their absence in the concurrent vehicle controls, hepatoblastoma and hepatocholangiocarcinoma were considered to be treatment-related lesions.

The incidences of uterine stromal polyp and stromal polyp or stromal sarcoma (combined) in female mice occurred with positive trends, and the incidences were significantly increased in the 3.0 mg/kg group.

Compared to the vehicle control incidences, incidences of epidermal hyperplasia, melanocyte hyperplasia, and chronic inflammation at the site of application were significantly increased in core study males and females administered 3.0 mg/kg; incidences of epidermal hyperplasia in 1.0 mg/kg females and chronic inflammation in 1.0 mg/kg males were also significantly increased. At the interim evaluations, increased incidences of epidermal hyperplasia and inflammation or chronic active inflammation were observed at the site of application in males and females.

GENETIC TOXICOLOGY

Trimethylolpropane triacrylate (1,500 to 10,000 μg per plate; lot no. 08409HI) did not induce gene mutations in S. typhimurium strains TA98 or TA100 or in E. coli strain WP2 uvrA/pKM101, with or without exogenous metabolic activation.

CONCLUSIONS

Under the conditions of these 2-year dermal studies, there was equivocal evidence of carcinogenic activity of trimethylolpropane triacrylate in male F344/N rats based on marginally increased incidences of malignant mesothelioma. There was no evidence of carcinogenic activity of trimethylolpropane triacrylate in female F344/N rats administered 0.3, 1.0, or 3.0 mg/kg. There was no evidence of carcinogenic activity of trimethylolpropane triacrylate in male B6C3F1/N mice administered 0.3, 1.0, or 3.0 mg/kg. There was some evidence of carcinogenic activity of trimethylolpropane triacrylate in female B6C3F1/N mice based on increased incidences of uncommon malignant hepatic neoplasms (hepatoblastoma and hepatocholangiocarcinoma) and stromal polyp or stromal sarcoma of the uterus.

Dermal application of trimethylolpropane triacrylate for 2 years resulted in increased incidences of nonneoplastic lesions in the skin (site of application) of male and female rats and mice.

Synonyms: Acrylic acid, 2-ethyl-2-(((1-oxo-2-propenyl)oxy)methyl)-1,3-propanediol triester; A-TMPT; 2,2-bis(prop-2-enoyloxymethyl)butyl prop-2-enoate; 2-ethyl-2-(hydroxymethyl)-1,3-propanediol triacrylate; 2-ethyl-2-(((2-oxo-2-propenyl)oxy)methyl)-1,3-propanediyl ester; 2-propenoic acid, 2-ethyl-2-(((1-oxo-2-propenyl)oxy)methyl)-1,3-propanediol ester; TMPTA; 1,1,1-trimethylolpropane triacrylate

Trade names: Aronix M 3090, Monosizer TD 1500A, NK Ester A-TMPT, SARTOMER SR 351, Setalux UV 2241, SR 351, Viscoat


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Trimethylolpropane Triacrylate
  Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1/N Mice
Female
B6C3F1/N Mice
Concentrations in acetone by dermal application 0, 0.3, 1.0, or 3.0 mg/kg 0, 0.3, 1.0, or 3.0 mg/kg 0, 0.3, 1.0, or 3.0 mg/kg 0, 0.3, 1.0, or 3.0 mg/kg
Body weights Dosed groups within 10% of the vehicle control group Dosed groups within 10% of the vehicle control group Dosed groups within 10% of the vehicle control group Dosed groups within 10% of the vehicle control group
Survival rates 23/50, 18/50, 28/50, 23/50 27/50, 31/50, 24/50, 32/50 30/50, 35/50, 29/50, 38/50 39/50, 31/50, 30/50, 30/50
Nonneoplastic effects Skin (site of application): epidermis, hyperplasia (1/50, 0/49, 12/50, 28/50); hyperkeratosis (2/50, 4/49, 33/50, 49/50) Skin (site of application): epidermis, hyperplasia (0/50, 4/50, 11/50, 25/50); hyperkeratosis (0/50, 11/50, 42/50, 50/50) Skin (site of application): epidermis, hyperplasia (10/50, 7/50, 15/50, 44/50); hyperplasia, melanocyte (0/50, 0/50, 0/50, 19/50); inflammation, chronic (13/50, 17/50, 26/50, 43/50) Skin (site of application): epidermis, hyperplasia (7/50, 7/50, 15/50, 34/50); hyperplasia, melanocyte (1/50, 1/50, 3/50, 33/50); inflammation, chronic (37/50, 36/50, 43/50, 48/50)
Neoplastic effects None None None Liver: hepatoblastoma (0/50, 4/50, 0/50, 3/50); hepatocholangiocarcinoma (0/50, 0/50, 1/50, 2/50)

Uterus: stromal polyp or stromal sarcoma (0/50, 1/50, 2/50, 6/50)

Equivocal Findings Malignant mesothelioma: (0/50, 2/50, 2/50, 5/50) None None None
Level of evidence of carcinogenic activity Equivocal evidence No evidence No evidence Some evidence
Genetic Toxicology
Assay Results
Bacterial gene mutations:
 
Negative in Salmonella typhimurium strains TA98 and TA100 and Escherichia coli strain WP2 uvrA/pKM101, with and without S9

 

Date: December 2012


NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.