Registration Dossier

Administrative data

Description of key information

In 90 day oral studies in drinking water in Sprague Dawley rats and CD-1 mice, the NOAEL was 5000 ppm, which was equivalent to 684 mg/kg/day for male rats and 810 mg/kg/day for female rats and equivalent to 285 mg/kg/day for male mice and 281 mg/kg/day for female mice. In the 90 day inhalation studies the NOAEC for systemic effects was 1500 ppm in both rats and mice. For local effects the NOAEC was 50 ppm (176 mg/m³) in mice and 150 ppm (528 mg/m³) in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
281 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
176 mg/m³

Additional information

INHALATION ROUTE OF ADMINISTRATION

Note: The conversion of ppm to mg/m³ is based on Rm of 86.09, 25°C, 1 atmosphere.

For whole-body inhalation exposure of vinyl acetate, the key study was a combined repeated dose and carcinogenicity study using rats and mice. The study was conducted and reported (Hazleton, 1988b) and some details published subsequently (Bogdanffy et al, 1994b). The study was GLP compliant, conducted to current testing guidelines and therefore considered to represent the most reliable data for risk characterisation. Supporting studies include the preceding 4 -week sighting studies (Hazleton 1979a; 1979b) and 90 day studies (Hazleton 1980d; 1980e) in rats and mice. An investigative study was conducted to evaluate nasal epithelial cell proliferation in male rats (Bogdanffy et al., 1997).

The key combined repeated dose and carcinogenic study exposed rats and mice to vinyl acetate vapour at concentrations of 0, 50, 200 or 600 ppm (6 hours/day, 5 days/week) over a period of 2 years (Hazleton, 1988b). The study also included satellite groups for interim evaluation at week 53, interim evaluation at week 83 and, post-recovery evaluation (70 weeks exposure / 15/16 weeks recovery). A reduction in body weight gain was observed for rats and for mice exposed to 600 ppm and for mice exposed to 200 ppm. Thus the NOAEC for systemic toxicity was 200 ppm for rats (704 mg/m³) and 50 ppm for mice (176 mg/m³). For both species, local effects of vinyl acetate exposure were confined to the respiratory system. Morphological non-neoplastic lesions were observed in the nasal cavity of rats and mice exposed to 200 or 600 ppm, in the trachea of mice exposed to 200 or 600 ppm and, in the lungs of the rats and mice exposed to 600 ppm.Thus the NOAEC for local toxicity was 50 ppm (176 mg/m³).

Two supporting studies exposed rats and mice to vinyl acetate vapour at concentrations of 0, 50, 200 or 1000 ppm (6 hours/day, 5 days/week) for 90 days (Hazleton 1980d; 1980e). Although the quality of the rat study may have been affected by parasitic infection (indicated by eosinophilic gastritis and colon nematodiasis in most control and high dose animals),exposure to 1000 ppm vinyl acetate resulted in lower body weight gain, intermittent clinical signs including respiratory distress, hunched posture and ruffled fur, increased lung weight and mild histomorphological changes in the respiratory tract.The NOAEC for local and systemic effects was 200 ppm (704 mg/m³). For mice exposed to 1000 ppm, clinical signs included ruffled fur, hunched posture and respiratory distress and body weight gain was reduced; histomorphological changes were seen in the respiratory tract. Respiratory distress and hunched posture were observed during the first 9 days of exposure to 200 ppm in the absence of any effect of vinyl acetate on body weight gain. The NOAEC for local and systemic effects was 50 ppm (176 mg/m³).

These two 90 day studies were preceded by 4-week sighting studies in which rats and mice were exposed to 0, 50, 150, 500 or 1000 ppm of vinyl acetate vapour (6 hours/day, 5 days/week) (Hazleton 1979a; 1979b).The exposure concentration of the 50 ppm group was increased to 1500 ppm on exposure day 8 (mice) or on exposure day 10 (rats). Mice exposed to 150 ppm or more and rats exposed to 500 ppm or more showed transient signs of hunched posture and respiratory distress which were dose-related. There was no clear effect of vinyl acetate on body weight. Histopathological examination revealed hyperplastic and metaplastic change in the epithelium of the respiratory tract of mice. The NOAEC for systemic effects was 1500 ppm in rats and mice and the NOAEC for local effects was 50 ppm in mice (176 mg/m³) and 150 ppm in rats (528 mg/m³). The relatively high NOAEC value for systemic effects may be a consequence of the limited test parameters of this range-finding study and reduces the reliability of the value.

An investigative study evaluated the effects of vinyl acetate exposure on nasal epithelial cell proliferation in male rats exposed for 1, 5 or 20 days (6 hours/day, 5 days/week) to 0, 50, 200, 600 or 1000 ppm (Bogdanffy, Gladnick et al.,1997).Cell proliferation was assessed by histopathological evaluation of 5 cross sections of the nose and by immunocytochemistry (level of BrdU incorporation following BrdU injection 16 hours after the last exposure). No treatment-related difference in the labelling index of the respiratory epithelium was observed but a significant difference in the labelling index of the olfactory epithelium was observed after 20 days of exposure to 600 or 1000 ppm. The NOAEC for nasal effects was 200 ppm (704 mg/m³).

In conclusion, the NOAEC for local and systemic toxicities induced by vinyl acetate inhalation are similar across most of the studies reported. Where the values differ, close inspection of the experimental protocol or interpretation of results reveals the basis of the difference. The 2 year combined chronic toxicity and carcinogenicity study on Sprague-Dawley rats and CD-1 mice (Hazleton 1988b, Bogdanffy et al., 1994b) was considered to be the most appropriate study from which to derive the NOAEC values.

Local toxicity (respiratory tract effects). The NOAEClocal is 50 ppm (176 mg/m³).

Systemic toxicity (bodyweight effects). The NOAECsys is 50 ppm (equivalent to 176 mg/m³).

 

ORAL (drinking water) ROUTE OF ADMINISTRATION

Two key 90 day studies were identified where vinyl acetate was administered to rats and mice in the drinking water (Hazleton 1980b; 1980c). These studies were performed according to GLP and current testing guidelines and were considered to represent the most reliable data for risk characertisation. They were preceded by 4 week sighting studies (for rats the NOAEL was 200 ppm (20 mg/kg bw) with reduced body weight gain seen at 1000 ppm and for mice, the NOAEL was 1000 ppm (150 mg/kg bw) with tremor and hypothermia observed in one female and reduced thymus weight in males at 5000 ppm).

In each 90 day study, groups of rats or mice were exposed to vinyl acetate in drinking water at concentrations of 0, 200, 1000 or 5000 ppm (v/v). The equivalent received doses were 31, 163, 684 mg/kg bw/d for male rats; 36, 193, 810 mg/kg bw/d for female rats; 11, 60, 285 mg/kg/bw/d for male mice; 10, 72, 281 mg/kg bw/d for female mice. The vinyl acetate was 99.9% pure and contained 0.01% acetaldehyde, 0.005% acetic acid, and 0.4% water. There were no deaths during the study and no adverse clinical signs. There was a slight (non-significant) reduction of food consumption and growth retardation in male rats at 5000 ppm that was considered to reflect the 23% reduction in water consumption. There were no treatment-related effects reported for haematology, blood chemistry, organ weights, gross pathology, or histopathology. The NOAEL for both species was 5000 ppm (684 and 810 mg/kg/day for male and female rats, respectively, and 285 and 281 mg/kg/day for male and female mice, respectively).

Other supporting 90 day drinking water studies in male rats and mice were conducted more recently (E. I. du Pont de Nemours, 2000, also published by Valentine et al., 2002). These GLP, non-guideline studies included the evaluation of oral cavity cell proliferation using pulsed 5-bromodeoxyuridine (BrdU) uptake techniques and histopathology to determine if repeated exposure to vinyl acetate correlated with tissue toxicity. Concentrations of 0, 1000, 5000, 10000 or 24000 ppm vinyl acetate (99.98%) were evaluated. For rats this was equivalent to 81, 350, 660 and 1400 mg/kg bw/day and for mice, 250, 1200, 2300 and 5300 mg/kg bw/day.

Rats in the 10,000 and 24,000 ppm groups had lower mean body weights and food consumption and lower body weights were seen in the 5000 ppm group; water consumption was lower in these three groups. No gross lesions in the oral mucosa, oesophagus, or fore-stomach of rats were observed at any exposure level. No microscopic lesions were observed in the oral mucosa of rats in the 24000 ppm group although increases in cell proliferation occurred in the upper and lower jaws. Labelling indices were less than 2-fold more than controls and therefore of equivocal biological significance.

For mice, there was no effect of vinyl acetate on body weight although there was some reduction in food consumption in all test groups. Water consumption was lower in all test groups. No gross lesions were observed in the oral mucosa, oesophagus, or fore-stomach were observed at any exposure level and no microscopic lesions were reported in the oral mucosa of mice in the 24000 ppm group. Proliferation index increases were approximately 2.4 - to 3.4-fold above controls for the 10,000 and 24,000 ppm groups and were considered attributable to vinyl acetate.

Additional supporting studies include long term (2 year) drinking water studies in rats (Hazleton 1988a, also published by Bogdanffy, Tyler et al., 1994) and in rats and mice (Umeda, 2004). A 2 year drinking water study in mice (Maltoni et al., 1997) was considered to be less reliable due to the omission of critical laboratory investigations. These studies are detailed in section 7.7 carcinogenicity.

ENDOCRINE DISRUPTION POTENTIAL

A set of guideline-conform 28-day and 90-day repeated dose toxicity studies provides no evidence for either endocrine activity, nor for adverse effects on endocrine organs caused by vinyl acetate upon 28-day / 90-day oral or inhalation exposure in rats or mice.

For further information, please check Section 13.2 of the IUCLID dossier.

OVERALL CONCLUSION

No specific organ toxicity was recorded after repeated oral administration of vinyl acetate in drinking water to rats and mice. The NOAEL for both species was estimated from the 13-week studies to be 5000 ppm (Hazleton 1980b; 1980c). This value is in good agreement with long-term studies for rats receiving drinking water for 2 years (Hazleton, 1988a, also published by Bogdanffy, Tyler et al., 1994) and in rats and mice (Umeda, 2004). The NOAEL of 5000 ppm reported by Maltoni, (1997) was considered to be less reliable. The NOAEL for systemic and local effects of vinyl acetate exposure in drinking water is 5000 ppm (684 mg/kg bw/day for the rat and 281 mg/kg bw/day for the mouse). Available studies provided no evidence for either endocrine activity, nor for adverse effects on endocrine organs.

Justification for classification or non-classification

Lesions of the respiratory tract epithelia occurred at concentrations above the critical concentration values according to the criteria of Regulation (EC) No 1272/2008, consequently no classification and labelling is warranted for this endpoint. There were no significant toxic effects observed in the 90-day rat and mouse studies which would warrant classification for STOT-RE according to CLP guidance (i.e. no relevant adverse effects below 1000 mg/m³).