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SUMMARY
Background:
Pentaerythritol triacrylate is used in a variety of photoreactive products including inks and coatings. People are exposed to pentaerythritol triacrylate mainly by skin contact. We used a genetically modified strain of mouse with sensitive skin to test if pentaerythritol triacrylate might cause skin cancer.
Methods:
We painted solutions of pentaerythritol triacrylate dissolved in acetone on the backs of male and female Tg.AC mice five times per week for 6 months. The daily doses were 0.75, 1.5, 3, 6, or 12 milligrams of pentaerythritol triacrylate per kilogram body weight. Animals painted with acetone alone served as control groups. Tissues from 15 sites were examined for every animal.
Results:
Almost all mice receiving daily doses of 3, 6, or 12 mg/kg developed a variety of precancerous or cancerous skin lesions at the site of chemical application. These included epithelial hyperplasia, squamous cell papilloma, and squamous cell carcinoma.
Conclusions:
We conclude that pentaerythritol triacrylate caused skin papillomas in the genetically modified mouse model used in these studies.
ABSTRACT
Pentaerythritol triacrylate is used in the production of ultraviolet-curable inks and coatings, electron beam irradiation-curable coatings, and radiation-cured and photocurable coatings of urethanes and epoxy resins; as a component of photopolymer and flexographic printing inks and plates and photoresists; as an ingredient of acrylic glues, adhesives, and anaerobic sealants; and as a modifier for polyester and fiberglass. It is also used in colloidal dispersions for industrial baked coatings, waterborne and solvent-based alkyds, vinyl/acrylic nonwoven binders, paper and wood impregnates, wire and cable extrusion, polymer-impregnated concrete, and polymer concrete structural composites. Pentaerythritol triacrylate was nominated by the National Cancer Institute for testing based on its high production volume and use, its potential for human exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F1 mice were administered technical grade pentaerythritol triacrylate (it is reactive and therefore not available as pure pentaerythritol triacrylate) in acetone dermally for 2 weeks or 3 months. Male and female Tg.AC hemizygous mice were administered technical grade pentaerythritol acrylate in acetone for 6 months. Genetic toxicology was evaluated in Salmonella typhimurium and in B6C3F1 and Tg.AC hemizygous mouse peripheral blood erythrocytes.
2-Week Study in Rats:
Groups of five male and five female F344/N rats were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All rats survived to the end of the study; mean body weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Irritation at the site of application occurred in all dosed groups except 12.5 mg/kg females. Epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation occurred at the site of application in most dosed groups of rats.
2-Week Study in B6C3F1 Mice:
Groups of five male and five female B6C3F1 mice were administered 0, 12.5, 25, 50, 100, or 200 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 17 days. All mice survived to the end of the study. The final mean body weight and body weight gain of 25 mg/kg males were significantly greater than those of the vehicle controls, as was the mean body weight gain of 50 mg/kg males. All dosed groups had irritation at the site of application. Thymus weights of males administered 50 mg/kg or greater and 200 mg/kg females were significantly less than those of the vehicle controls. Most dosed groups of mice had epidermal hyperplasia, hyperkeratosis, sebaceous gland hyperplasia, ulcer, epidermal degeneration, parakeratosis, chronic active inflammation, and suppurative inflammation at the site of application.
3-Month Study in Rats:
Groups of 10 male and 10 female F344/N rats were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. All rats survived to the end of the study. Mean body weights of 12 mg/kg males were significantly less than those of the vehicle controls. Irritation at the site of application occurred in 12 mg/kg rats. Thymus weights of males administered 3 mg/kg or greater were significantly less than those of the vehicle controls. Hematology results indicated that pentaerythritol triacrylate induced a neutrophil count increase that would be consistent with an inflammatory response related to the dermatitis observed histopathologically. Epidermal hyperplasia, hyperkeratosis, epidermal degeneration and necrosis, chronic active inflammation, and sebaceous gland hyperplasia generally occurred at the application site in male and female groups administered 1.5 mg/kg or greater.
3-Month Study in B6C3F1 Mice:
Groups of 10 male and 10 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate/kg body weight in acetone 5 days per week for 14 weeks. One female vehicle control mouse was sacrificed during the first week of the study due to ataxia and one 1.5 mg/kg female died during week 8. Mean body weights of dosed groups were similar to those of the vehicle control groups. Irritation at the site of application occurred in the 6 and 12 mg/kg male groups. Hematology results indicated an increased neutrophil count consistent with an inflammatory response related to the dermatitis observed histopathologically. There also was a minimal decrease in the erythron (hematocrit, hemoglobin concentration, and erythrocyte count) likely secondary to the inflammatory skin process. Males and females administered 1.5 mg/kg or greater generally had increased incidences of epidermal hyperplasia, degeneration, and necrosis; dermal chronic active inflammation, sebaceous gland hyperplasia, and hyperkeratosis at the site of application.
6-Month Study in Tg.AC Hemizygous Mice:
Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg pentaerythritol triacrylate per kg body weight in acetone 5 days per week for 27 weeks. Additional groups of 15 male and 15 female mice maintained as positive controls received dermal applications of 1.25 µg 12-O-tetradecanoylphorbol-13-acetate per 100 mL acetone 3 days per week for 28 weeks. Survival of all dosed groups of mice was similar to that of the vehicle controls. With the exception of the 3 mg/kg group, body weights of male mice were less than those of the vehicle controls during the last 3 to 6 weeks of the study. Females administered 3 mg/kg had generally reduced body weights during the last month of the study. Treatment-related clinical findings included papillomas at the site of application in males and females receiving 3 mg/kg or more; papillomas were also observed in one 1.5 mg/kg male.
Heart and liver weights of 12 mg/kg males were significantly greater than those of the vehicle controls. Lung weights of 6 and 12 mg/kg males and females were significantly decreased, as were thymus weights of 6 and 12 mg/kg females.
Squamous cell neoplasms at the site of application were associated with dermal application of pentaerythritol triacrylate. At 6 months, all 3 and 6 mg/kg males had squamous cell papilloma at the site of application, and the incidences of this neoplasm were significantly increased in males and females receiving 3 mg/kg or more. Squamous cell carcinomas at the site of application occurred in two 3 mg/kg males, three 12 mg/kg males, and one 12 mg/kg female.
Nonneoplastic lesions noted at the site of application in dosed mice included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. Incidences of hematopoietic cell proliferation were increased in various organs, including the liver of 12 mg/kg females, the spleen of 6 and 12 mg/kg males and females, and the mandibular lymph node of 12 mg/kg females. A hematopoietic disorder (myelodysplasia) occurred in 12 mg/kg males.
Genetic Toxicology:
Pentaerythritol triacrylate was not mutagenic in several strains of S. typhimurium, with or without hamster or rat liver S9 activation enzymes. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples from B6C3F1 mice treated with pentaerythritol triacrylate by skin painting for 3 months. In contrast, similar treatment of female Tg.AC hemizygous mice for 6 months induced a significant increase in micronucleated erythrocytes; the increase in micronuclei seen in male Tg.AC hemizygous mice was judged to be equivocal.
Contact Hypersensitivity Studies:
Studies were conducted with female BALB/c mice to evaluate the potential for pentaerythritol triacrylate to induce contact hypersensitization. In an irritancy study in which formulations of pentaerythritol triacrylate (approximately 10% or 45% pure) in acetone were applied to the ear, the maximal nonirritating concentration was 0.1% and the minimal irritating concentration was 0.25% for both mixtures. A mouse ear swelling test yielded negative results for pentaerythritol triacrylate as a potential contact sensitizer using the 10% mixture and positive results with the 45% mixture. Positive responses were seen in local lymph node assays at concentrations of 0.05%, 0.1%, and 0.25% pentaerythritol triacrylate when the approximately 10% pentaerythritol triacrylate mixture was used and at a concentration of 0.25% pentaerythritol triacrylate when the approximately 45% pentaerythritol triacrylate mixture was used.
Conclusions:
Male and female Tg.AC hemizygous mice dosed with pentaerythritol triacrylate for 6 months had significantly increased incidences of squamous cell papillomas of the skin at the site of dermal application. Treatment-related squamous cell carcinomas occurred at the site of application in male mice.
Nonneoplastic lesions noted at the site of application included hyperkeratosis, chronic active inflammation, and epidermal hyperplasia. A hematopoietic disorder (myelodysplasia) occurred in dosed male mice.
Summary of the 6-Month Toxicology and Genetic Toxicology Studies of Pentaerythritol Triacrylate
Male Tg.AC Mice | Female Tg.AC Mice | |
---|---|---|
Doses in acetone by dermal application | Vehicle control, 0.75, 1.5, 3, 6, or 12 mg/kg | Vehicle control, 0.75, 1.5, 3, 6, or 12 mg/kg |
Body weights | All dosed groups except 3 mg/kg less than the vehicle controls during the last 3 to 6 weeks of the study | 3 mg/kg groups generally less than vehicle controls during last month of study |
Survival rates | 12/15, 14/15, 15/15, 15/15, 12/15, 10/15 | 12/15, 14/15, 12/15, 12/15, 13/15, 9/15 |
Nonneoplastic effects |
Skin (site of application): hyperkeratosis 0/15. 0/15. 2/15, 6/15, 10/15, 13/15); inflammation, chronic active (0/15, 0/15, 0/15, 2/15, 5/15, 12/15); epidermis, hyperplasia (0/15, 0/15, 3/15, 8/15, 10/15, 14/15) All organs: myelodysplasia (0/15, 0/15, 0/15, 0/15, 0/15, 5/15) | Skin (site of application): hyperkeratosis (1/15. 0/15. 4/15, 14/15, 11/15, 13/15); inflammation, chronic active (0/15, 0/15, 1/15, 9/15, 10/15, 15/15); epidermis, hyperplasia (0/15, 0/15, 5/15, 14/15, 14/15, 14/15) |
Neoplastic effects | Skin (site of application): squamous cell papilloma (1/15, 0/15, 4/15, 15/15, 15/15, 13/15); squamous cell carcinoma (0/15, 0/15, 0/15, 2/15, 0/15, 3/15) | Skin (site of application): squamous cell papilloma (0/15, 0/15, 1/15, 10/15, 12/15, 13/15) |
Genetic toxicology | ||
Salmonella typhimurium gene mutations: | Negative in strains TA100, TA1535, TA1537, and TA98, with and without S9 | |
Micronucleated erythrocytes | ||
Mouse peripheral blood in vivo: | ||
B6C3F1 | Negative in males and females | |
Tg.AC hemizygous | Equivocal in males and positive in females |
Contents
- FOREWORD
- CONTRIBUTORS
- NATIONAL TOXICOLOGY PROGRAM BOARD OF SCIENTIFIC COUNSELORS TECHNICAL REPORTS REVIEW SUBCOMMITTEE
- SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION AND CONCLUSIONS
- REFERENCES
- APPENDIX A. SUMMARY OF LESIONS IN MALE Tg.AC HEMIZYGOUS MICE IN THE 6-MONTH DERMAL STUDY OF PENTAERYTHRITOL TRIACRYLATE
- APPENDIX B. SUMMARY OF LESIONS IN FEMALE Tg.AC HEMIZYGOUS MICE IN THE 6-MONTH DERMAL STUDY OF PENTAERYTHRITOL TRIACRYLATE
- APPENDIX C. GENETIC TOXICOLOGY
- APPENDIX D. SUMMARY OF NONNEOPLASTIC LESIONS IN RATS AND B6C3F1 MICE IN THE 3-MONTH DERMAL STUDIES OF PENTAERYTHRITOL TRIACRYLATE
- APPENDIX E. CLINICAL PATHOLOGY RESULTS
- APPENDIX F. ORGAN WEIGHTS AND ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS
- APPENDIX G. REPRODUCTIVE TISSUE EVALUATIONS AND ESTROUS CYCLE CHARACTERIZATION
- APPENDIX H. CHEMICAL CHARACTERIZATION AND DOSE FORMULATION STUDIES
- APPENDIX I. INGREDIENTS, NUTRIENT COMPOSITION, AND CONTAMINANT LEVELS IN NTP-2000 RAT AND MOUSE RATION
- APPENDIX J. SENTINEL ANIMAL PROGRAM
- APPENDIX K. CONTACT HYPERSENSITIVITY STUDIES
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