Comment - 22098 - Dr. Norman Forsberg, Arcadis U.S., Inc.

Arcadis U.S., Inc. (Arcadis) appreciates the opportunity to provide comments on the Office of Environmental Health Hazard Assessment’s (OEHHA’s) proposed no significant risk level (NSRL) for vinyl acetate. Arcadis reviewed the technical basis for the proposed NSRL and participated in OEHHA’s pre-regulatory workshop on September 30, 2026. We recognize OEHHA’s efforts to develop a scientifically sound and health-protective assessment and welcome the agency’s engagement with interested parties during the pre-regulatory process. Based on our review and the information presented at the workshop, we identified three aspects of the methodology that we believe warrant further consideration. The following comments describe these issues and offer recommendations intended to strengthen the scientific basis, transparency, and applicability of the final assessment. We respectfully encourage OEHHA to consider these recommendations as it finalizes the NSRL for vinyl acetate. Comment 1: Evidence shows that an NSRL derived from the Lijinsky and Reuber (1983) drinking water bioassay is not relevant to the inhalation exposure route Vinyl acetate is a volatile substance that is used regularly by workers to manufacture polymeric materials in industrial settings (IARC, 1995). As such, the magnitude of the NSRL is of particular importance to worker exposure assessments, as is having a value that is representative of exposure routes relevant to workers (i.e., inhalation and dermal). However, OEHHA’s proposed NSRL for vinyl acetate (11 µg/day) was derived using data from a cancer bioassay that exposed female F344 rats to vinyl acetate via drinking water (Lijinksy and Reuber, 1983) (OEHHA, 2026a). OEHHA indicated in their pre-regulatory workshop that the agency’s intent was for the proposed NSRL to be applied to all routes of exposure (i.e., oral, inhalation, dermal) (OEHHA 2026b). This could be a defensible decision if carcinogenicity data were unavailable from non-oral routes of exposure. However, inhalation carcinogenicity data of sufficient quality are available in rats and mice of both sexes (Bogdanffy et al., 1994). OEHHA’s documentation for the proposed NSRL makes no mention of this study or the inhalation route of exposure (OEHHA 2026a). Bogdanffy et al. (1994) showed that chronic inhalation exposure to vinyl acetate produces tumors in the respiratory tract (mainly nasal cavity) of male rats. Importantly, the tumor sites and tumor types that OEHHA (2026a) used to derive the proposed NSRL (i.e., hepatocellular adenoma, uterine adenocarcinoma and endometrial stromal polyp, thyroid C-cell adenoma, and pituitary gland adenoma) from the Lijinksy and Reuber (1983) drinking water study have never been observed in animals exposed to vinyl acetate via inhalation (despite a lifetime of exposure at levels comparable to those used in Lijinsky and Reuber (1983)). Additionally, the tumor sites and tumor types from the Lijinsky and Reuber (1983) drinking water study have not been observed in animals exposed via inhalation to acetaldehyde (i.e., vinyl acetate’s main genotoxic metabolite) (see Table 31 in OEHHA, 2024). This is an important distinction because 27 CCR § 25703(a)(4) emphasizes that the tumor data from the most sensitive study “…shall be applicable to all routes of exposure for which the results are relevant” [emphasis added]. The data from Bogdanffy et al. (1994) show that the tumor findings from Lijinsky and Reuber’s (1983) drinking water study are not relevant to the inhalation route of exposure. There are numerous examples where OEHHA has derived route-specific NSRLs for Prop 65 substances that show differential tumorgenicity responses based on exposure route (e.g., benzene, chloroform, ethylbenzene, trichloroethylene, etc.). There are also examples where OEHHA has not generalized an NSRL as being applicable to all exposure routes (e.g., acetaldehyde, benz[a]anthracene, chrysene, etc.). Given 1), these regulatory precedents, 2) that a reliable inhalation cancer study is available, and 3) that inhalation exposure to vinyl acetate produces tumors at sites distinct from those produced from oral exposure, we recommend that OEHHA take the following steps in finalizing the assessment for vinyl acetate: • Designate an NSRL derived from the Lijinksy and Reuber (1983) drinking water study as being specific to the oral route of exposure. • Use the tumor data reported by Bogdanffy et al. (1994) to derive a route-specific NSRL that is specific to the inhalation route of exposure. Comment 2: The tumor endpoints that OEHHA used in the MS-Combo dose-response evaluation for female F344 rats from Lijinsky and Reuber (1983) are too broad and may not all be related to treatment In their dose-response evaluation of the female F344 rat tumor data from the Lijinsky and Reuber (1983) drinking water study, OEHHA chose to include 5 tumor types from 4 tumor sites (see Table 1 from OEHHA, 2026a). The only treatment-related malignant tumor observed in the rats was uterine adenocarcinoma, which was observed in the low and high dose group. All other tumor types are benign and would normally be evaluated on a case-by-case basis under current USEPA cancer risk assessment guidelines (USEPA, 2005). Combining the uterine adenocarcinoma with endometrial stromal polyps for MS-combo dose-response modeling could be argued to be a reasonable starting assumption given that they share the same tumor site (even though they are not of the same cell lineage). Additionally, the pituitary adenomas, while benign, were noted to be large and encroached on the adjacent brain of female rats (Lijinsky and Reuber, 1983). However, including the hepatocellular adenomas (high dose only - benign), thyroid C-cell adenoma (benign), and pituitary adenoma (benign) tumor observations in the MS-combo analysis is difficult to defend given the lack of evidence for a shared systemic mode of action. Additionally, historical data on spontaneous neoplasm incidences in female F344 rats from the time period near when Lijinsky and Reuber (1983) reported their study results show that several of the tumor types are at sites with a high historical background of tumor incidences (e.g., pituitary adenoma, thyroid gland C-cell adenoma, and uterine endometrial stromal polyps) (Goodman et al., 1979; Haseman et al., 1998; NTP, 1999). Thus, a large part of the tumor response for these endpoints could reasonably be explained by background tumor processes that were common to this strain of rat at the time of Lijinsky and Reuber’s (1983) study. Given this information, we recommend that OEHHA update the cancer dose-response assessment to include a discussion of background rates of spontaneous neoplasms for each of the endpoints evaluated from the Lijinsky and Reuber (1983) study, and update the benchmark dose modeling assessment to specifically include those endpoints with the strongest and most biologically relevant tumor responses (e.g., uterine adenocarcinoma, hepatocellular adenoma, and thyroid C-cell adenoma). Comment 3. The tumor incidence data from Lijinsky and Reuber (1983) should be used for quantitative dose-response assessment, rather than the incidence data from the EPL (1982) report In the dose-response evaluation of the female F344 rat tumor data, OEHHA chose to use the tumor incidences reported in the EPL report (EPL, 1982), rather than in the original peer-reviewed publication by Lijinsky and Reuber (1983). The EPL report was a non peer-reviewed re-analysis of samples from the Lijinsky and Reuber study, provided to EPL by the study authors. The re-analysis done by EPL was conducted simultaneously with peer-review of the manuscript by Lijinsky and Reuber. As is noted in the materials provided with the EPL report, not all tissues examined in the original study were examined initially by EPL, and some tissues were re-processed by EPL for analysis and inclusion in the final report. Lijinsky and Reuber did not update their data to reflect the tumor incidence rates in the EPL report, although the EPL report was available to them prior to final acceptance of their manuscript for publication. There are discrepancies between the Lijinsky and Reuber manuscript and the reliability of the EPL report with regard to both the sample size (number of animals examined in each treatment group) as well as noted tumor incidence. Given that the Lijinsky and Reuber (1983) publication is peer-reviewed (whereas the EPL report was not), and the samples missing in the EPL analysis, the data presented in the original Lijinsky and Reuber manuscript should be used for further analysis rather than the data presented in the EPL report. References: Bogdanffy, M.S., van der Meulen, H.D., Beems, R.B., Feron, V.J., Cascieri, T.C., Tyler, T.R., Vinegar, M.B. and Rickard, R.W., 1994. Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse. Toxicological Sciences, 23(2), pp.215-229. EPL. 1982. Bioassay of Vinyl Acetate in F344 Rats Pathology Report Addendum. Goodman, D.G., Ward, J.M., Squire, R.A., Chu, K.C., Linhart, M.S., 1979. Neoplastic and Nonneoplastic Lesions in Aging F344 Rats. Toxicology and Applied Pharmacology, 48, pp.237-248. Haseman, J.K., Hailey, J.R. and Morris, R.W., 1998. Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update. Toxicologic pathology, 26(3), pp.428-441. IARC. 1995. Dry cleaning, Some Chlorinated Solvents and Other Industrial Chemicals. (IARC Monogr Eval Carcinog Risks Hum). Lyon, France: International Agency for Research on Cancer. Available: https://publications.iarc.fr/Book-And-Report-Series/IarcMonographs-On-The-Identification-Of-Carcinogenic-Hazards-To-Humans/Dry-CleaningSome-Chlorinated-Solvents-And-Other-Industrial-Chemicals-1995. Lijinsky, W. and Reuber, M.D., 1983. Chronic toxicity studies of vinyl acetate in Fischer rats. Toxicology and Applied Pharmacology, 68(1), pp.43-53. NTP. 1999. Historical F344 rats 1984-1994 19 oral feed route. Available at: https://ntp.niehs.nih.gov/ntp/historical_controls/nih-07_1999/r_hcrpt_rte19991223.rpt. OEHHA. 2024. Proposition 65: Evidence on the Carcinogenicity of Vinyl Acetate. October. Available at: https://oehha.ca.gov/sites/default/files/media/downloads/crnr/vinylacetatehid100424.pdf. OEHHA. 2026a.Pre-regulatory Draft – For discussion Purposes Only, Possible Amendments to: Section 25705(b) Specific Regulatory Level Posing No Significant Risk and Article 9: Miscellaneous. September. Available at: https://oehha.ca.gov/sites/default/files/media/2026-09/Vinyl%20Acetate%20pre-regulatory%20workshop%20explanatory%20document_092126.pdf. OEHHA. 2026b.Proposition 65: Vinyl Acetate Pre-Regulatory Workshop. September 21. Available at: https://oehha.ca.gov/proposition-65/crnr/proposition-65-vinyl-acetate-pre-regulatory-workshop. USEPA. 2005. Guidelines for Carcinogen Risk Assessment. EPA/630/P-03/001F. Risk Assessment Forum. Washington, D.C. March. Available at: https://www.epa.gov/sites/default/files/2013-09/documents/cancer_guidelines_final_3-25-05.pdf.