Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are sufficient data available for assessment from a 2-Generation study in rats. Some minor and slight effects on male fertility, not forming a specific pattern, were observed in the high dose group receiving 5000 ppm orally in drinking water, which also induced slight parental toxicity. No effects were observed on any parameters of female fertility. Based on the available data it can be concluded that Vinyl Acetate shows no specifically toxic effects on fertility. A conservative NOAEL of 1000 ppm in drinking water could be derived for male fertility, and 5000 ppm for female fertility. 

Another study on testicular genotoxic effects of VA after administration of very high doses using a non-physiological route of exposure (i.p.) was considered of no regulatory relevance.

All in all, a clear and conservative NOAEL of 1000 ppm in drinking water (76 to 145 mg/kg/day [differences are due to the decline in water consumption relative to body weight that occurred over this time period]) could be derived for male fertility. No indication of effects in females in doses up to 5000 ppm in drinking water (431 to 765 mg/kg/day [differences are due to the decline in water consumption relative to body weight that occurred over this time period]) were detected.

These data are sufficient for an adequate hazard and risk assessment. Based on the available data, no classification for fertility (RF) is justified. No further studie are considered necessary.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

ENDOCRINE DISRUPTIVE POTENTIAL

A non-conventional two-generation reproduction toxicity study in which Sprague Dawley CD rats were treated orally with vinyl acetate over two generations (Mebus et al., 1995) yielded the following findings that were interpreted as being substance-related (and not, e.g., secondary to the reduced water consumption):

- Although not statistically significant, the F1 fertility index of the 5000-ppm group was lower than that for the control group. The number of litters produced in the high-dose F1 generation was slightly reduced, and this was interpreted by the authors as being caused by reduced fertility.

- When the high-dose group F1 males were cross-mated with the corresponding control F1 females, fewer pups were produced. This was caused by poor mating performance.

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

In the F1 cross-mating, there were 12 control males available to mate 24 females from the 5000-ppm group and 13 males from the 5000-ppm group available to mate 25 control females. The pregnant females were killed on gestation day 13 and the intrauterine contents examined. The mating index of the female controls/5000-ppm males was 19/25 females mated while the mating index for the 5000-ppm females/control males was 23/24 female mated. The fertility index of the female control/5000-ppm male mating was 19/19 pregnancies while the fertility index for the 5000-ppm female/control male mating was 22/23 pregnancies. Mebus et al. suggested a possible male-specific effect based on the reduced fertility in the F1a ‘standard’ mating and the reduced mating index in the F1b cross-mating. However, the data do not support this suggestion. First, all of the 13 males in the 5000-ppm group used in the cross-mating experiment produced a pregnancy. This suggests that the reduced fertility index in the F1a mating was probably due to the female animals, not the males used for breeding. The reduced mating index in the F1b female control/male 5000 ppm animals (despite all of the males producing at least one pregnancy) is not easily explained although the method used to mate these animals was extremely unconventional.

Therefore, although the Mebus et al. (1995) indicated that the non-statistically significant finding might be attributed to male fertility, the data do not support this suggestion. The variances observed in this study, and the non-standard, non-guideline approach do not lend enough credible evidence to support that the findings are linked to an endocrine mode of action, nor do they support that there would be sufficient evidence to conclude that endocrine disruption had occurred.

Effects on developmental toxicity

Description of key information

There are sufficient data to assess the potential of vinyl acetate to cause developmental toxicity. Data is available from:

-       an oral drinking water developmental toxicity study in rats

-       an inhalation study also in rats

-       a drinking water two-generation study in rats

-       a DRF and a main developmental toxicity study in rabbits.

In a developmental toxicity study in rats, administration of vinyl acetate in thedrinking water during the period of organogenesis (days 6 to 15 of gestation, inclusive) at dose levels up to and including those which produced a degree of drinking water unpalatability did not elicit any developmental effects. Thus, a developmental NOAEL of 5000 ppm v/v in drinking water (477 mg/kg/day) could be determined.

In another developmental toxicity study in rats after administration of VA by the inhalation route at concentrations up to and including those which produced maternal toxicity did not elicit embryolethality or teratogenicity. At the highest concentration employed (1000 ppm v/v vinyl acetate), there was evidence of growth retardation of the foetuses, however this was considered to be a secondary effect of marked maternal growth retardation, and not a direct effect of exposure to vinyl acetate. Thus, the developmental NOAEL of 1000 ppm v/v could be determined for inhalation exposure. Unfortunately, no data were available on the degree of absorption of VA. 

In a two-generation study in rats, a minor, slight and inconsistent decrease in pup weight on day 21 pp in the F1 generation, but not in the F2, was the only finding of a developmental effect in the high dose group receiving 5000 ppm orally in drinking water. This is considered secondary to a decreased body weight gain and water consumption of dams during lactation. Consequently, 5000 ppm in drinking water (431 to 765 mg/kg/day [differences are due to the decline in water consumption relative to body weight that occurred over this time period) was found to be the NOAEL for developmental toxicity. Moreover, it can be concluded that VA shows no specifically toxic effects on development.

In a developmental toxicity study in rabbits, no developmental or maternal toxicity was observed, though the study, based on a DRF, was clearly planned in order to aiming at some maternal toxicity, thus fulfilling the criteria of a valid OECD 414 Guideline study. A NOAEL of 100 mg/kg/day could be determined, which is also supported by the fact that no developmental toxicity (litter size, pup weight, external anomalies) was observed in the DRF study at 200 mg/kg/day, a dose that caused significant maternal toxicity.

 

Species

Route of administration

Study type

Developmental NOAEL

Rat

Oral via drinking water

Developmental toxicity study

477 mg/kg

Rat

Inhalation

Developmental toxicity study

1000 ppm v/v

Rat

Oral via drinking water

Two-generation study

431 - 765 mg/kg

Rabbit

Oral gavage

Developmental toxicity study

100 mg/kg

 

Furthermore, in none of these studies, any indications for a developmentally toxic potential of vinyl acetate could be observed.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Species:
rabbit
Quality of whole database:
GLP study or equivalent
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Endocrine Disruption Potential

Two prenatal developmental toxicity studies did not yield any maternal or developmental findings that could be attributed as substance-induced ED mediated effects:

- Upon oral exposure via drinking water; and inhalation exposure via whole-body exposure) in Sprague Dawley CD rats (Hazleton, 1980); findings also published in (Hurtt et al., 1995);

- Upon oral gavage exposure in New Zealand White rabbits (Van Otterdijk (2018a, b, c).

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

Justification for classification or non-classification

These data are sufficient for an adequate hazard and risk assessment. Based on the available data, no classification for reproductive and developmental toxicity (RD) according to Regulation (EC) No 1272/2008 is justified. No further studies are considered necessary.