Toxicology study of diispropylcarbodiimide (CAS No. 693-13-0) in genetically modified (FVB Tg.AC Hemizygous) mice and carcinogenicity study of diispropylcarbodiimide in genetically modified [B6.129-Trp53tm1Brd (N5) haploinsufficient] mice (dermal studies).
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 alkylcarbodiimide 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 diisopropylcarbodiimide in female p53 haploinsufficient mice administered 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. Synonyms: 1,3-Diisopropylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N'-methanetetraylbis (2-propanamine).
D000279:Administration, Cutaneous; D000818:Animals; D002234:Carbodiimides / Q000008:administration & dosage / Q000633:toxicity*; D015197:Carcinogenicity Tests; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006965:Hyperplasia / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012867:Skin / Q000187:drug effects* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D002234:Carbodiimides; D016159:Tumor Suppressor Protein p53; C081611:1,3-diisopropylcarbodiimide