Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water

Abstract

Carcinogenicity and Chronic Toxicity in Mice and Rats Administered Vinyl Acetate Monomer in Drinking Water: Yumi Umeda, et al. Japan Bioassay Research Center, Japan Industrial Safety and Health Association—Carcinogenicity and chronic toxicity of vinyl acetate monomer (VA) were examined in male and female Crj:BDF1 mice and F344/DuCrj Rats. Groups of 50 mice and 50 rats of each sex were orally administered VA in drinking water containing 0, 400, 2,000 or 10,000 ppm (g/g) VA for 104 wk. Squamous cell tumors were clearly evident in the upper digestive tract of treated mice and rats, and in the larynx of treated mice of both sexes. In mice, squamous cell carcinomas and papillomas were observed in the oral cavity, esophagus, forestomach and larynx of the 10,000 ppm group, together with basal cell hyperplasia, squamous cell hyperplasia and epithelial dysplasia. In rats, incidences of squamous cell carcinomas and papillomas were increased in the oral cavity of the 10,000 ppm group of both sexes, and an esophagus squamous cell carcinoma was observed in a 10,000 ppm female. Pre‐neoplastic hyperplasias were also noted. Mapping of the neoplastic and pre‐neoplastic lesions in the oral cavity of the 10,000 ppm group revealed that both the lesions occurred predominantly at Level V in mice and at Level VI in rats. A lower confidence limit of a benchmark dose (BMDL10) of 477 mg/kg/d was obtained from a dose‐response relationship between combined incidence of squamous cell carcinomas and papillomas in the oral cavity of mice and rats and the estimated daily VA intakes per body weight, and compared with literature values.

Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells

“…This would equate to an air concentration of 26 ppt for a 60 kg individual inhaling 20 m 3 /day. In contrast, lifetime inhalation and drinking water ingestion studies in rats have shown that VAM causes site of contact mucosal tumors of the nasal and upper digestive tract, respectively, but at air concentrations in the hundreds of parts per million and drinking water concentration in the low parts per thousand range [Bogdanffy et al, ,; Umeda et al, ].…”

Scientific Opinion on the safety of polyvinylpyrrolidone‐vinyl acetate copolymer for the proposed uses as a food additive

“…Incidence of squamous cell carcinomas and papillomas in mice and rats induced by VA in the oral cavity as reported by Umeda et al (2004).…”

“…Results of a BMD analysis of the data from Umeda et al (2004) on the incidence of squamous cell carcinomas and papillomas in mice and rats induced by VA in the oral cavity using BMDS version 2.1.2. software and the default settings of extra risk, a Benchmark Response (BMR) of 10%, and a 95% confidence limit. Using the data reported by Umeda et al (2004) on squamous cell papillomas plus carcinomas for male and female mice and rats, a BMDL 10 of 440 mg/kg bw/day was calculated.…”

“…The Panel noted that the studies provide evidence for a VA-induced animal carcinogenicity. The Panel also noted that according to the IARC evaluation, VA is considered as a possibly human carcinogen of Group 2B (IARC, 1995).The Panel derived a lower confidence limit on the benchmark dose (BMDL 10 ) of 440 mg/kg bw/day from the combined incidence of squamous cell carcinomas and papillomas in mice and rats induced by VA in the oral cavity as reported by Umeda et al in 2004. Taking the total combined exposure to VA at 0.12 µg/kg bw/day for adults and 0.08 µg/kg bw/day for children, this would lead to a Margin of Exposure (MOE) of respectively 3.7 x 10 6 for adults and 0.6 x 10 7 for children, and therefore the Panel concluded that the presence of VA at levels up to 5 mg/kg is unlikely to be of safety concern.…”

CMR substances in consumer products: from food contact materials to toys

“…Although acetaldehyde is thought to be a genotoxic metabolite, a threshold dose appears to exist for vinyl acetate below which no tumor formation occurs (SCHER 2008). Chronic drinking water studies in rats (Umeda et al 2004) found a dose-dependent increase in carcinomas in the upper gastrointestinal tract of female rats at ≥ 400 ppm ("lowest observed adverse effect level", LOAEL = 31 mg/kg bw/day for female and 21 mg/kg bw/day for male rats, respectively), of which the latter was suggested to be used as POD for oral risk assessment (ECHA 2008;Health Canada 2008). A threshold mechanism for tumor formation in the gastrointestinal tract following oral administration seems, therefore, likely (ECHA 2008).…”