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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant guideline study, study results also published in peer-reviewed literature, no restrictions, fully adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Embryo-fetal developmental and reproductive toxicology of vinyl chloride in rats.
Author:
Thornton, S.R., Schroeder, R.E., Robison, R.L., Rodwell, D.E., Penney, D.A., Nitschke, K.D. and Sherman, W.K.
Year:
2002
Bibliographic source:
Toxicol Sci; 68(1):207-19

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Chloroethylene
EC Number:
200-831-0
EC Name:
Chloroethylene
Cas Number:
75-01-4
Molecular formula:
C2H3Cl
IUPAC Name:
chloroethene
Details on test material:
Vinyl chloride was supplied by the Geon Company, Pedricktown, NJ (Lot #1). Purity was > 99.9%.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
Mating Procedures: One male and one female rat from the same exposure group were co-housed nightly until evidence of mating (microscopic observation of sperm in vaginal smear and/or copulation plug in vagina) or for 14 consectutive days. Unmated females were randomly redistributed to a
sexually active male rat within the same exposure group for an additional 6 days. P2 animals were randomly chosen from a pool of F1 pups (2/litter)
that had been exposed to the same concentration as parents. For the P2 generation, care was taken to avoid brother-sister cohabitations. Once
mated, females were housed individually for the remainder of gestation.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Females: premating period to gestation day 20, and lactation day 4 until sacrifice. F1 pups selected to become P2 generation were exposed from postnatal day 26 until all litters were weaned. Males (both generations): parallel to females.
Frequency of treatment:
6 hr/d, 5 d/wk during premating; 6 hr/d, 7 d/wk during mating, gestation, lactation, and post-weaning
Details on study schedule:
F1 pups selected to become P2 generation were exposed from postnatal day 26 until all litters were weaned.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100, 1100 ppm
Basis:

No. of animals per sex per dose:
Thirty animals/sex/group (for both P1 and P2 generation)
Control animals:
yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Parental (F0 and F1) Toxic Effects by Dose Level:
No effect of exposure was noted on mortality, physical examination, body weight or body weight gain, food consumption, mating indices, pregnancy rate, male fertility, gestation length, parturition data, or litter size. Effects on organs were limited to liver. Liver weights were significantly increased (by 13-20%) in F0 males exposed to 10, 100 and 1100 ppm and F1 males exposed to 100 and 1100 ppm (Table 1).  The relative liver weight in F0 males exposed to 10 ppm was comparable to control F1 male weights and thus was not considered to be VCM-related.  Dose-related centrilobular hypertrophy, considered to be a compensatory reaction, occurred in F0 and F1 males exposed to 100 or 1100 ppm and females exposed to 10, 100 or 1100 ppm (Table 2). Increased incidences of altered hepatocellular foci (basophilic, acidophilic and clear well) were observed in livers of F1 males and females exposed to 100 or 1100 ppm.

Effect levels (P0)

Dose descriptor:
NOAEC
Remarks:
parental
Effect level:
10 ppm
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: F0 and F1 (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not specified
Histopathological findings:
not specified

Details on results (F1)

Offspring (F1 and F2) Toxic Effects by Dose Level:
No adverse effect of vinyl chloride exposure on pup survival or growth, sex distribution, age for vaginal opening or preputial separation was found.  Organ weights were not affected by exposure.

Effect levels (F1)

Dose descriptor:
NOAEC
Remarks:
offspring
Generation:
F1
Effect level:
1 100 ppm
Basis for effect level:
other: No effects observed at highest dose level tested

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEC
Remarks:
offspring
Generation:
F2
Effect level:
1 100 ppm
Basis for effect level:
other: No effects observed at highest dose level tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

                                              Table 1

          Relative liver weights for the F0 and F1 generation

                                     ppm VCM
Generation/sex
   Control            10                 100               1100
  F0 males         2.83+0.26    3.05+0.29*    3.09+0.20*    3.26+0.19**
  F1 males         2.98+0.33    3.01+0.19     3.32+0.36**   3.38+0.19**
  F0 females      3.31+0.32    3.34+0.36     3.40+0.30      3.55+0.31
  F1 females      3.54+0.66    3.37+0.42     3.60+0.45      3.74+0.38
* p0.05;
  ** p0.01.

                                              Table 2
            Summary of F0 and F1 generation liver histopathology

                                                                 ppm VCM
                                                     0       10        100      1100
F0 generation
male rats
 centrilobular hypertrophy            0        0         15        30
 acidophilic foci                            0        0           0          1
 basophilic foci                              0        0           0          1
female rats
centrilobular hypertrophy
            0        2         26        30

F1 generation
male rats
 centrilobular hypertrophy           0        0         19        30
 acidophilic foci                           1        0           4          5
 basophilic foci                             0        0           0          8
 clear cell foci                               0        0           0          5
female rats
 centrilobular hypertrophy           0        6         30        30
 acidophilic foci                            0        0           0          8
 basophilic foci                            0        0           1        11


N = 30 for each dose level

Applicant's summary and conclusion