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Abstract for GMM-10

Toxicology Study of Diispropylcarbodiimide in Genetically Modified (FVB Tg.AC Hemizygous) Mice and Carcinogenicity Study of Diispropylcarbodiimide in Genetically Modified [B6.129-Trp53tm1Brd (N5) Haploinsufficient] Mice (Dermal Studies)

CASRN: 693-13-0
Chemical Formula: C7H14N2
Molecular Weight: 126.20
Synonyms/Common Names: 1,3-Diisopropylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N'-methanetetraylbis (2-propanamine)
Report Date: March 2007

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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 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 of carcinogenic activity no evidence 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.

Studies

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