Potential for human exposure Human exposure occurs primarily in the occupational setting with very little exposure to vinyl acetate in the general population (Ref. 1). Vinyl acetate is used in the synthesis of pharmaceuticals.
Mutagenicity/genotoxicity The mutagenicity and genotoxicity of vinyl acetate has been reviewed by Albertini (Ref. 2). Vinyl acetate is not mutagenic in the microbial reversion assay (i.e., Ames tests) in multiple strains of Salmonella or in Escherichia coli and vinyl acetate mutagenicity in mammalian cells (at the tk locus human TK6 cells) appears to reflect mainly chromosome level or large mutational events, but “normal growth”
mutants thought to reflect smaller, gene mutations were also reported. Vinyl acetate also induced micronuclei and chromosome aberrations in vitro and chromosome aberrations in vivo and was positive in one out of five in vivo micronucleus studies. Small increases of micronuclei in mouse bone marrow were induced following i.p. administration, but the genotoxicity was associated with elevated toxicity and mortality (Ref. 3).
There is extensive evidence that vinyl acetate genotoxicity is mediated by its metabolite acetaldehyde. Acetaldehyde is produced endogenously and detoxification by aldehyde dehydrogenase is required to maintain intra-cellular homeostasis (Ref. 2). Given its response in mammalian cells, and rapid conversion to acetaldehyde, vinyl acetate is considered mutagenic. See Mode of Action information below for further details.
Carcinogenicity Vinyl acetate is classified as Group 2B, possibly carcinogenic to humans (Ref. 4).
There are two oral carcinogenicity reports cited in the CPDB (Ref. 5). One mouse and one rat study, in which vinyl acetate was administered in drinking water, are limited as there are only two treatment groups and less than 50 animals per group.
Uterine, esophageal and forestomach tumors were observed in Swiss mice; and liver, thyroid and uterine tumors in Fisher rats. A number of non-site of contact tumors (e.g., Zymbal gland, lung, liver, uterine, and mammary gland) were observed in the oral carcinogenicity studies conducted by Maltoni et al. (Ref. 6) and Lijinsky et al. (Ref. 7). These tumors in Maltoni et al. (Ref. 6) all occurred with high background incidence. Therefore, without adjusting for age, these tumor data
cannot be evaluated with certainty. Squamous cell carcinoma of the oral cavity, tongue, esophagus, and forestomach were all treatment related at 5000 ppm.
There were no tumors among mice administered 1000 ppm (Ref. 8). In the oldest published oral carcinogenicity study, Lijinsky et al. (Ref. 7) there are a number of deficiencies in the study design, most notably that the drinking water solutions were prepared only once per week. The authors recognized a decomposition rate of approximately 8.5% per day. Therefore, by the end of the week the animals in the 2500 ppm group, for example, were exposed to approximately 1300 ppm vinyl acetate and significant quantities of breakdown products, including acetaldehyde and acetic acid. The authors also did not purify the vinyl acetate prior to preparation of the drinking water solutions. Thus, the rats were also exposed to unspecified impurities. In addition, only 20 rats were in each group, so the statistical power for detecting true positive responses and for discriminating against false positive and false negative outcomes is compromised (Ref. 8).
In addition to the CPDB, other carcinogenicity studies are available in the literature.
An oral drinking water study was conducted by the Japan Bioassay Research Centre in accordance with OECD guideline 453, including 3 treatment groups and 50 animals per group (Ref. 9, 10). Increases in tumors of the oral cavity, esophagus and forestomach in Crj:BDF1 mice and statistically significant increases of tumors in the oral cavity of female F344:DuCrj rats at all 1366 doses are reported following drinking water administration of vinyl acetate. In another lifetime study, Minardi et al. (Ref. 11) report increases in tumors in oral cavity and lips in 17-week old and 12-day old Sprague-Dawley rats also administered vinyl acetate in the drinking water.
Two treatments groups are included with more than 50 animals per group for the 12-day old rats (offspring) but less than 50 per group for the 17-week old animals (breeders). The 12-day old rats are more sensitive with tumors in the oral cavity and lips, whereas an increase tumor response is not evident in the 17-week old animals.
Finally, Bogdanffy et al. (Ref. 12) administered vinyl acetate in drinking water for 10 weeks to male and female rats that were subsequently mated. The offspring were then culled into two groups of 60 for the main study and 30 for satellite groups and
exposure in the drinking water continued to 104 weeks. The authors concluded that in the offspring there were no non-neoplastic or neoplastic lesions observed that were compound related. Two squamous carcinomas were observed in the oral cavity of treated males, but the incidence of these tumors was within historical control ranges. Therefore, they were not considered related to vinyl acetate treatment.
There are two inhalation carcinogenicity reports cited in the CPDB (Ref. 5). Vinyl acetate is not carcinogenic to CD-1 mice but induces nasal tumors in Sprague-Dawley rats (Ref. 12). All but one of the 11 nasal tumors in rats (benign endo and exophytic papillomas and squamous-cell carcinomas) were observed at the terminal sacrifice at the high dose of 600 ppm, indicating a late life dependency of tumor formation. One benign tumor, of questionable relationship to exposure, was observed at the 200 ppm concentration (Ref. 12). In both species and both sexes, vinyl acetate induced morphological non-neoplastic lesions in the nasal cavity of the 200 and 600 ppm groups and in the trachea (mice only) and in the lungs of the 600 ppm groups.
Vinyl Acetate – Details of carcinogenicity studies
Mode of action for carcinogenicity Vinyl acetate has been reviewed by the European Commission’s Scientific Committee on Health and Environmental Risks (SCHER), who published a Risk Assessment Report in 2008 (Ref. 1). Overall, SCHER supports the conclusion that the carcinogenic potential of vinyl acetate is expressed only when tissue exposure to acetaldehyde is high and when cellular proliferation is simultaneously elevated.
This mode of action suggests that exposure levels, which do not increase intracellular concentrations of acetaldehyde will not produce adverse cellular responses. As long as the physiological buffering systems are operative, no local carcinogenic effect by vinyl acetate should be expected at the NOAEL for histological changes in respiratory rodent tissues. However, the SCHER indicated that local levels at or below the NOAEL are not free of carcinogenic risk, although the risk may be negligibly low. Hengstler et al. (Ref. 8) presented the case for vinyl acetate as a DNA-reactive carcinogen with a threshold dose-response, which has also been described by Albertini (Ref. 2). Like acetaldehyde, vinyl acetate is not-mutagenic in the standard bacterial reversion assay; evidence for DNA-reactivity and site of contact carcinogenicity of vinyl acetate is that it occurs because of metabolic conversion to acetaldehyde.
The genotoxicity profiles for acetaldehyde and vinyl acetate are almost identical and vinyl acetate is not active as a clastogen without the addition of carboxylesterase (Ref. 8). Therefore, the clastogenic activity of vinyl acetate is attributed to metabolic formation of acetaldehyde. At high concentrations, enzyme activities are not able to oxidize all the generated acetaldehyde, and a low pH microenvironment is the result (Ref. 12). From consistent endogenous acetic acid exposure, tissues may sustain a reduction of 0.15 units in pH following vinyl acetate treatment without adverse effects (i.e. cytotoxicity and genotoxicity) (Ref. 14).
However, when this practical threshold is exceeded, DNA damage, cytotoxicity, and regenerative cellular proliferation occur, resulting in tumor formation at the site of contact.
There is clear evidence for the carcinogenicity of vinyl acetate in two animal species, in both sexes and for both inhalation and oral administration. Following both oral and inhalation administration, vinyl acetate is rapidly hydrolyzed at the
site of contact by carboxylesterases, to acetic acid and acetaldehyde (Ref. 3, 15).
Vinyl acetate exposure produces tumors at the site of first contact along the exposure routes. The dose-response is thought to be non-linear, with the observed tumor responses reflecting the target tissue-specific enzyme activities for activation and detoxification (Ref. 2). However, as noted in the acetaldehyde monograph, there are no published measurements which would allow discrimination between the irritating effect and the potential mutagenic effect ion cancer development.
Regulatory and/or published limits For vinyl acetate, the US EPA IRIS database calculated an inhalation Reference Concentration (RfC) for non-carcinogenic effects of 0.2 mg/m3 , or 5.8 mg/day assuming a respiratory volume of 28.8 m3. The RfC was based on a human equivalent concentration of 5 mg/m3 derived from Owen et al. which identified both a NOAEL and a LOAEL for histopathological effects of the nasal olfactory epithelia in rats and mice in a chronic 2-year study. A total adjustment factor of 30 was applied (Ref. 16). The US EPA report did not include a carcinogenicity assessment for lifetime exposure to vinyl acetate. It is stated that RfCs can be derived for the noncarcinogenic health effects of substances that are carcinogens and to refer to other sources of information concerning the carcinogenic potential.
Permissible Daily Exposure (PDE) for
oral exposure Rationale for selection of study for PDE calculation
Following oral administration, vinyl acetate is rapidly hydrolyzed at the site of contact by carboxylesterases, to acetic acid and acetaldehyde. Given the weight of evidence for a non-linear dose response for the carcinogenicity of both vinyl acetate and acetaldehyde following oral administration and considering high background exposure to acetaldehyde from a wide variety of foods, the oral PDE recommended is based on that derived for acetaldehyde of 2 mg/day.
PDE (oral) = 2 mg/day Acceptable intake (AI) for all other
routes Rationale for selection of study for AI calculation
For routes of administration other than the oral route, the inhalation carcinogenicity study in rats (Ref. 12) was used for derivation of an AI. In this study, there were 3 treatment groups with 60 animals per sex per treatment group.
Animals were exposed 6 hours per day, 5 days per week for 2 years to vinyl acetate.
Carcinogenicity was observed in the nasal cavity of rats, with male being the more sensitive sex. The TD50 for the nasal cavity in male rats is 758 mg/kg/day, as reported in CPDB. The only other carcinogenicity study that is available with vinyl acetate administered via the inhalation route in mice is negative (Ref. 12).
Therefore, the rat inhalation study was selected for derivation of an AI.
Although the dose-response relationship for carcinogenicity is thought to be non-linear, as stated above, there are no published measurements which allow discrimination between a true threshold versus a non-linear inflection point.
Therefore, the AI was calculated using linear extrapolation.
Calculation of AI Lifetime AI = TD50/50000 x 50 kg
Lifetime AI = 758 mg/kg/day x 50 kg
Lifetime AI (all other routes) = 758 µg/day References
Note 2
The calculated TD50 for ethyl bromide is illustrated below since it was decided to use the same study data but not the TD50 calculated by CPDB as the positive dose response was not statistically significant (see monograph for ethyl bromide).
A TD50 is calculated for each dose separately with the following equation (Ref. 1, 2):
Where P is the proportion of animals with the specified tumor type observed at a certain dose (D in the equation) and P0 is the proportion of animals with the specified tumor type for the control. Converting β and D into a simple linear equation results in the following:
Plotting the results and using the slope to represent β results in the following graphs for the dose-response and β = 0.0215055234 for low dose, 0.0059671034 for mid-dose and 0.0042161616 for the high dose.
Low Dose
Mid Dose
High Dose
The TD50 can then be calculated as follows.
Solving for TD50 results in in the following equation.
Therefore, the lowest TD50 = 0.693 / 0.0215055234 or 32.2 mg/kg/day.
References