Vinyl acetate

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Data source

Reference

Reference Type:

publication

Title:

Effects of vinyl acetate and acetaldehyde on sperm morphology and meiotic micronuclei in mice

Author:

Lähdetie J

Year:

1988

Bibliographic source:

Mutation Research 202, 171-178

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The testicular genotoxic effects of vinylacetate and its hydrolysis product, acetaldehyde, were studied in mice by analyzing the induction of morphologically abnormal sperm. Mice were given five daily ip injections of test substance or control substance. Three weeks after the first dose, epidermal sperm were obtained from anaesthetised mice. Five weeks after the first dose, the mice were killed and testicles and seminal vesicles (with contents) were weighed. Sperm smears were prepared. The 2 caudae epididymum of each mouse were removed and the number of sperm determined. 500 sperm per mouse were examined and classified as normal, banana-like, lacking hook, amorphous, folded with abnormal head, or double-tailed.

GLP compliance:

not specified

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Vinyl acetate

EC Number:

203-545-4

EC Name:

Vinyl acetate

Cas Number:

108-05-4

Molecular formula:

C4H6O2

IUPAC Name:

ethenyl acetate

Constituent 2

Reference substance name:

108-0504

IUPAC Name:

108-0504

Details on test material:

- Name of test material (as cited in study report): Vinylacetate
- Supplied by: Fluka AG, Buchs, Switzerland

Test animals

Species:

mouse

Strain:

other: (C57B1/6J x C3H/He)F1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: University of Helsinki, Finland (parents from Zentralinstitut fur Versuchstierzucht GmbH, Hannover, FRG) or Zentralinstitut fur Versuchstierzucht GmbH, Hannover, FRG directly.

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

other: olive oil for vinylacetate (cold physiological saline for acetaldehyde)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 days

Frequency of treatment:

daily

Duration of test:

5 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

125 mg/kg diet

Remarks:

other: nominal in olive oil - vinylacetate

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day

Remarks:

other: nominal in olive oil - vinylacetate

Doses / concentrations 3

Dose / conc.:

500 mg/kg bw/day

Remarks:

other: nominal in olive oil - vinylacetate

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

other: nominal in olive oil - vinylacetate

Doses / concentrations 5

Dose / conc.:

62.5 mg/kg bw/day

Remarks:

other: nominal in cold physiological saline - acetaldehyde

Doses / concentrations 6

Dose / conc.:

125 mg/kg bw/day

Remarks:

other: nominal in cold physiological saline - acetaldehyde

Doses / concentrations 7

Dose / conc.:

250 mg/kg bw/day

Remarks:

other: nominal in cold physiological saline - acetaldehyde

No. of animals per sex per dose:

1, 7, 4, 5, 4 for 750, 500, 250, 125 and 0 (olive oil) mg/kg vinyl acetate. 10, 7, 5, 9 for 250, 125, 62.5 and 0 (saline) mg/kg acetaldehyde. 6 for the positive control group.

Control animals:

yes, concurrent vehicle

Details on study design:

positive control: 50 mg/kg bw cyclophosphamide

Statistics:

Sperm count, testis and seminal vesicle weights: regression analysis. Group means were compared to controls by Student's t-test.
Frequencies of abnormal sperm: chi-square test (2 x 2 contingency table, 1 degree of freedom).

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

sperm abnormailies vinylacetate

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

2

Dose descriptor:

NOAEL

Remarks:

sperm abnormalities acetaldehyde

Effect level:

62.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: lowest dose tested

Observed effects

Although a dose response on body weight is observed after both compounds, it appears that the effects of VA and AA are different, VA causing a rapid decrease of body weight during the injection week, while the effect of AA is smaller and slower.

Any other information on results incl. tables

Acute toxicity: Vinylacetate and acetaldehyde showed acute toxicity and lethality at high dose levels. At 1000 mg/kg/day vinylacetate, all 8 animals died, most immediately after the first injection. At 750 mg/kg/day only 1 out of 5 survived. At the lower dose levels (500, 250 and 125 mg/kg/day) all animals survived. At 250 mg/kg/day acetaldehyde killed 9 out of 19 mice, but none of them died immediately after the first injection. No mortalities at the lower doses of acetaldehyde. Vinylacetate caused a rapid decrease in body weight during the week of dosing, the effect of acetaldehyde on bodyweight was smaller and slower.

 

Testicular toxic effects:

Both VA and AA showed acute toxicity and lethality at high dose levels. In the sperm morphology assay at 1000 mg/kg/day VA, all 8 animals treated died, most of them immediately after the first injection. At 750 mg/kg/day only 1 of the 5 mice in the group survived. At the lower dose levels (500, 250 and 125 mg/kg/day) all animals survived. At 250 mg/kg/day AA killed 9 out of 19 mice, but none of them died immediately after the first injection. The lower AA doses were not lethal.

Regression analysis suggested that sperm count decreased by increasing VA dose, although there were no significant differences in the means of sperm counts in pairwise comparison to olive oil controls. Testicular weights were reduced by VA doses 500 and 125 mg/kg/day but seminal vesical weights were not significantly affected. AA did not decrease sperm count, testis weight or seminal vesicle weight significantly, as compared to saline controls. Sperm count was, in fact, slightly higher in all treated animals than in the controls.

At 3 weeks, there was no significant increase in the frequency of abnormal sperm in mice treated with VA at 125 and 250 mg/kg/day, nor in mice treated with AA. Two out of the 7 animals treated with VA 500 mg/kg/day showed high abnormality frequencies yielding a significant effect.

In summary, sperm count decreased by increasing vinylacetate dose (p < 0.01), but no significant differences in the means of sperm counts in pairwise comparison to olive oil controls. Testicular weights reduced at 500 and 125 mg vinylacetate/kg/day (p < 0.05) but seminal vesical weights were not significantly affected. Actetaldehyde did not decrease sperm count, testis weight or seminal vesicle weight significantly, as compared to saline controls.

 

Sperm morphology: At 3 weeks, there was no significant increase in the frequency of abnormal sperm in mice treated with vinylacetate at 125 and 250 mg/kg/day, nor in mice treated with acetaldehyde or with cyclophosphamide (positive control). Following a dose of 500 mg vinylacetate/kg/day, 2 out of 7 animals showed high abnormality frequencies (p < 0.001). Five weeks after the treatment, no significant increase in sperm abnormalities was observed by vinylacetate at 125 and 250 mg/kg/day or by acetaldehyde. At 500 mg vinylacetate/kg/day, 3 mice out of 7 had exceptionally high percentages of abnormal sperm (p < 0.001). Also the one mouse surviving a dose of 750 mg vinylacetate/kg/day showed an increased frequency of abnormal sperm.

 (Table based on Lahdetie J 1988, Table 1)

treatment	vinylacetate				olive	acetaldehyde			saline	cp
dose level (mg/kg)	750	500	250	125	-	250	125	62.5	-	50
number of mice	1	7	4	7	4	10	7	5	9	6
relative testicular weight	5.54	5.78 ± 0.73*	6.04 ± 0.72	5.67 ± 0.81*	6.49 ± 0.19	6.80 ± 0.50	6.79 ± 0.35	7.00 ± 0.34	7.02 ± 0.80	5.81 ± 0.82**
relative seminal vesicle weight	11.31	6.37 ± 1.58	7.05 ± 0.89	6.65 ± 0.69	7.19 ± 0.07	7.14 ± 0.98	7.12 ± 0.86	7.27 ± 0.16	7.45 ± 0.90	5.80 ± 0.45***
sperm count (millions/mL)	0.23	4.10 ± 1.80	6.17 ± 1.03	5.58 ± 1.35	5.60 ± 0.51	6.38 ± 1.13*	6.25 ± 1.60	5.60 ± 1.01	4.95 ± 1.18	2.62 ± 0.33***
olive = olive oil, cp =cyclophosphamide *   p<0.05 compared to respective controls **  p<0.01 compared to saline controls *** p<0.001 compared to saline controls

Applicant's summary and conclusion

Conclusions:

The testicular genotoxic effects of vinylacetate and its hydrolysis product, acetaldehyde, were studied in mice by analyzing the induction of morphologically abnormal sperm. Vinylacetate significantly increased the frequency of sperm abnormalities at 500 mg/kg/day while lower doses were ineffective. Acetaldehyde did not induce abnormal sperm. Vinylacetate, but not acetaldehyde, caused a dose-dependent decrease in sperm production and a reduction of testicular weight at 500 and 125 mg/kg/day.

Due to the unphysiological route of exposure (i.p.) and the high doses, which even induced high mortality, this study is of no relevance for regulatory purposes.

Executive summary:

The testicular genotoxic effects of vinylacetate and its hydrolysis product, acetaldehyde, were studied in mice by analyzing the induction of morphologically abnormal sperm. Vinylacetate significantly increased the frequency of sperm abnormalities at 500 mg/kg/day while lower doses were ineffective. Acetaldehyde did not induce abnormal sperm. Vinylacetate, but not acetaldehyde, caused a dose-dependent decrease in sperm production and a reduction of testicular weight at 500 and 125 mg/kg/day.

Due to the unphysiological route of exposure (i.p.) and the high doses, which even induced high mortality, this study is of no relevance for regulatory purposes.