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SUMMARY
Background:
Diisopropylcarbodiimide is used as a chemical reagent. We tested if diisopropylcarbodiimide could cause cancer in two different strains of genetically modified mice.
Methods:
We applied solutions containing diisopropylcarbodiimide in ethanol to the backs of female Tg.AC mice five times per week for 20 weeks and to female p53 haploinsufficient mice for 27 weeks. The daily doses were 4.38, 8.75, 17.5, 35, or 70 milligrams of diisopropylcarbodiimide per kilogram body weight. Animals given the ethanol solution alone served as the control groups. Tissues from over 20 sites were examined for every animal.
Results:
Exposure to diisopropylcarbodiimide had no effect on the Tg.AC mice. In p53 haploinsufficient mice, the only response seen was an increase in minimal epidermal hyperplasia in the skin at the site of dermal application in mice receiving 70 milligrams of diisopropylcarbodiimide per kilogram of body weight.
Conclusions:
We conclude that diisopropylcarbodiimide did not cause cancer in the genetically modified mice used in these studies.
ABSTRACT
Diisopropylcarbodiimide is used as a reagent for a variety of reactions including peptide syntheses. The National Cancer Institute nominated diisopropylcarbodiimide for study as a representative chemical in the alkyl-carbodiimide class because of its acute toxicity, widespread low-level human exposure, and the absence of data on health effects. Female Tg.AC hemizygous or p53 haploinsufficient mice were administered diisopropylcarbodiimide (greater than 99% pure) dermally for 20 or 27 weeks, respectively.
20-Week Study in Tg.AC Hemizygous Mice:
Groups of 10 female Tg.AC hemizygous mice received dermal applications of 0, 4.38, 8.75, 17.5, 35, or 70 mg diisopropylcarbodiimide/kg body weight in ethanol, 5 days a week for 20 weeks. Twelve animals died or were sacrificed moribund prior to the end of the study; two each from vehicle controls, 4.38, 8.75, and 17.5 mg/kg groups, and four from the 35 mg/kg group. Premature deaths were not associated with chemical-related lesions. Odontoma, a common spontaneous finding in Tg.AC hemizygous mice, resulting in jaw malformation, malocclusion, and loss of body condition, occurred in the majority of control, 4.38, 8.75, and 17.5 mg/kg animals that died prematurely. Of the surviving animals, mean body weights were similar to those of vehicle controls. There were no significant changes in organ weights and no treatment-related clinical findings. No neoplasms or nonneoplastic lesions were attributed to administration of diisopropylcarbodiimide.
27-Week Study in p53 Haploinsufficient Mice:
Groups of 15 female p53 haploinsufficient mice received dermal applications of 0, 4.38, 8.75, 17.5, 35, or 70 mg/kg diisopropylcarbodiimide in ethanol, 5 days a week for 27 weeks. All animals survived to the end of the study. Mean body weights were similar to those of vehicle controls, and there were no treatment-related clinical findings. At necropsy there were no treatment-related gross lesions. Microscopically, there was a higher incidence of treatment-related, predominantly minimal epidermal hyperplasia at the site of application in 70 mg/kg mice than in vehicle controls. No neoplasms were attributed to the administration of diisopropylcarbodiimide.
Conclusions:
Under the conditions of this 27-week study, there was no evidence of carcinogenic activity* of diisopropylcar bodiimide in female p53 haploinsufficient mice adminis tered 4.38, 8.75, 17.5, 35, or 70 mg/kg in ethanol.
There were no treatment-related neoplasms or nonneoplastic lesions in female Tg.AC hemizygous mice administered 4.38, 8.75, 17.5, 35, or 70 mg/kg in ethanol for 20 weeks.
Summary of the 20-Week Toxicology Study of Diisopropylcarbodiimide in Female Tg.AC Hemizygous Mice
Doses in ethanol by dermal application | Vehicle control, 4.38, 8.75, 17.5, 35, and 70 mg/kg |
---|---|
Body weights | Exposed groups similar to the vehicle control group |
Survival rates | 8/10, 8/10, 8/10, 8/10, 6/10, 10/10 |
Nonneoplastic effects | None |
Neoplastic effects | None |
Summary of the 27-Week Carcinogenesis Study of Diisopropylcarbodiimide in Female p53 Haploinsufficient Mice
Doses in ethanol by dermal application | Vehicle control, 4.38, 8.75, 17.5, 35, and 70 mg/kg |
---|---|
Body weights | Exposed groups similar to the vehicle control group |
Survival rates | 15/15, 15/15, 15/15, 15/15, 15/15, 15/15 |
Nonneoplastic effects | Skin: epidermal hyperplasia (0/15, 0/15; 0/15, 0/15, 0/15, 8/15) |
Neoplastic effects | None |
Level of evidence of carcinogenic activity | No evidence |
- *
Explanation of Levels of Evidence of Carcinogenic Activity is on page 8. A summary of the Technical Reports Review Subcommittee comments and the public discussion on this Report appears on page 10.
Contents
- FOREWORD
- CONTRIBUTORS
- EXPLANATION OF LEVELS OF EVIDENCE OF CARCINOGENIC ACTIVITY
- 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 FEMALE Tg.AC HEMIZYGOUS MICE IN THE 20-WEEK DERMAL STUDY OF DIISOPROPYLCARBODIIMIDE
- APPENDIX B. SUMMARY OF LESIONS IN FEMALE p53 HAPLOINSUFFICIENT MICE IN THE 27-WEEK DERMAL STUDY OF DIISOPROPYLCARBODIIMIDE
- APPENDIX C. ORGAN WEIGHTS AND ORGAN-WEIGHT-TO-BODY-WEIGHT RATIOS
- APPENDIX D. CHEMICAL CHARACTERIZATION AND DOSE FORMULATION STUDIES
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