National Toxicology Program

EVIDENCE FOR POSSIBLE CARCINOGENIC ACTIVITY

Human Data:
No epidemiological studies or case reports investigating the association of exposures to IPA and cancer risk in humans were identified in the published literature. IPA may be harmful by inhalation, ingestion or skin absorption and is a skin and eye irritant. Prolonged exposure to IPA may cause nausea, dizziness and headache. IPA has a narcotic effect at high concentrations (Anon., 1994a; Budavari, 1989). According to the Eastern Chemical Material Safety Data Sheet (MSDS) there is no carcinogen list status for IPA; this chemical has not been listed by OSHA, EPA, NTP or IARC (Anon., 1992b).

Animal Data:
No 2-year carcinogenicity studies of IPA in animals were identified in the published literature. The Registry of Toxic Effects of Chemical Substances (RTECS) record for IPA contains only general toxicity and skin and eye irritation data. An oral rat LD₅₀ of 3 gm/kg was reported for IPA (NLM, 1994). IPA was lethal to 3 of 6 rats exposed to 4,000 ppm for 4 hours by inhalation (NLM, 1994)

Short Term Tests:
In studies conducted in the National Cancer Institute's Division of Cancer Etiology Short-Term Test Program, IPA was mutagenic in the mouse lymphoma assay without metabolic activation and equivocal with activation, and non-mutagenic in the Salmonella assay both with and without S9 activation (NCI, 1994).

Metabolism:
The enzymatic hydrolysis of IPA could be expected to produce acetate/acetic acid and acetone (via isopropenol, the enol form of acetone). No mammalian studies on the metabolism of IPA were found in the literature. However, Cherton, et al. (1988, 1990) reported on the enzymatic biotransformation (hydrolysis) of IPA in the hemolymphatic fluid of the insect, Shistocerca gregaria: the enzymatic hydrolysis of this enol ester at pH 7.4 yielded acetone and acetate detectable by NMR. Cherton et al. (1990) reported that their research on the study of xenobiotics in the hemolymph of insects was applicable to the development of proinsecticides.

Structure/Activity Relationships:
Vinyl acetate (VA) is a close analog of IPA. VA was considered by the CSWG in 1978 for nomination to the NTP for carcinogenicity testing but dropped because of a negative chronic (1 year) study unpublished but reported in an editorial in C & E News by Maltoni in 1974. An early IARC review of VA concluded that there was a lack of human data (ND) and insufficient animal data (I) on which to base a determination of evidence for carcinogenicity and placed this chemical in Group 3 (agent not classifiable as to its carcinogenicity to humans) (IARC, 1986). In a later study, Lijinsky and Reuber (1983) reported tumors in a variety of sites in M & F Fischer 344 rats dosed with 10-100 g/kg bw in drinking water 5x/wk for 2 years. At a recent working group meeting (February, 1995), IARC concluded that there was inadequate evidence for carcinogenicity in humans and limited evidence in for carcinogenicity in animals and placed VA in Group 2B (possibly carcinogenic to humans) (correspondence from Dr. Olin dated 2/18/95). The results of genetic toxicity testing of vinyl acetate in the DCE/STTP have been reported as follows: Ames plate, +A; mouse lymphoma, ++A.