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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, non-guideline study, published in peer-reviewed literature, minor restrictions in design and reporting, but otherwise adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Vinyl chloride: Dominant lethal studies in male CD-1 mice.
Author:
Anderson D, Hodge MCE, Purchase IFH
Year:
1976
Bibliographic source:
Mut Res 40:359-370.

Materials and methods

Principles of method if other than guideline:
In vivo dominant lethal assay
GLP compliance:
no
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Vinyl chloride was obtained from Air Products Limited, Worsley, Walkden, Lanc.

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
Mice (CD-1) were obtained from Charles River, Manston, Kent. Groups of male mice (8-10 weeks old) of proven fertility and groups of virgin femal mice (8-10 weeks old) were used.

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Administration / exposure

Route of administration:
inhalation: gas
Vehicle:
Air
Details on exposure:
Groups of male mice (8-10 weeks old) of proven fertility were given 5 daily (6 hr) exposures of air (N=20), vinyl chloride (VC) at 3000 (N=20), 10000 (N=20) and 30000 ppm (N=20). The highest dose of VC was shown to be toxic in a previous test. Two undosed, virgin female mice (8-10 weeks old) were housed with a treated male of proven fertility (total of 106 males) for 5 days. Males were then housed without females for a week. The mating procedure was then repeated until the males had been mated at weekly intervals for 8 weeks with virgin, untreated females. Males were then killed and were not examined. Evidence of positive mating was not obtained. Female mice were killed 15 or 16 days after being housed with males.
Duration of treatment / exposure:
5 days
Frequency of treatment:
5 daily (6 hr) exposures
Post exposure period:
8 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 3000, 10000 and 30000 ppm
Basis:

No. of animals per sex per dose:
20 males/dose
Control animals:
yes
Positive control(s):
Additional groups of mice were given either 200 mg/kg of cyclophosphamide by i.p. injection on day 5 (N=15) or 200 mg/kg ethyl methanesulphonate (EMS) in water for 5 days (N=25).

Examinations

Tissues and cell types examined:
Uteri of female mice were examined for live implantations, early deaths and late deaths.
Statistics:
A chi-square test was used to assess significant differences in frequency of successful mating and pregnancy, and the number of pregnancies with early deaths. Mean values of implantation data were adjusted to take the unequal number of pregnant females per male into account and were compared using ANOVA and a Dunnett's t test. Data for the number of early deaths per pregnancy and the percentage of total deaths recorded as early deaths per pregnancy were transformed prior to analysis by the variance ratio test.

Results and discussion

Test resultsopen allclose all
Sex:
female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Males:
A significant increase in mortality was noted in males treated with 30000 ppm VC (9/20 vs. 0/20 in controls). No significant differences in the mating frequency of males treated with VC were found with respect to controls. There was a significant decrease in mating frequency of mice treated with EMS at week 1.

Females Mated with Vinyl Chloride-treated Males:
The frequency of pregnancies remained high throughout the experiment in females mated with males treated with VC. The number of average total implants per pregnant female mated with mice treated with 0, 3000, 10000 or 30000 ppm VC ranged from 11.75 to 13.68, 11.56 to 13.56, 11.76 to 14.13, and 10.00 (the only value significantly different from control) to 13.67. There was no significant increase in the number of post-implantational early fetal deaths (as shown by the number of females with one or more early deaths, number of early deaths/pregnancy, or the number of early deaths/total implants/pregnancy). There also was no effect of vinyl chloride on fertility or late deaths. The percentage of pre- and post-implantation dominant lethality in mice mated with males treated with the highest dose of VC was only significantly different from typical values (-14 to +12) at one time point (week 4, +19).

Females Mated with EMS or Cyclophosphamide-treated Males (positive controls):
The frequency of pregnancy decreased in those mated with EMS-treated males at weeks 1 and 2. The number of implants per female, pregnancies with early deaths, and deaths per pregnancy in those mated with mice treated with cyclophosphamide or EMS were significantly different from control at week 1 and weeks 1 and 2, respectively. The number of early deaths/total implants/pregnancy in those mated with mice treated with cyclophosphamide or EMS was significantly different from control at weeks 1 and 2. The percentage of pre- and post-implantation dominant lethality in mice mated with males treated with cyclophosphamide or EMS was significantly different from typical values (-14 to +12) at week 1 (+62.3 and +95.9, respectively), week 2 (+49.3 and +51.3, respectively) and week 3 (+19.1, cyclophosphamide only).

Applicant's summary and conclusion