Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
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

Referenceopen allclose all

Reference Type:
publication
Title:
The effects of maternally inhaled vinyl chloride on embryonal and fetal development in mice, rats, and rabbits
Author:
John JA, Smith FA, Leong BKJ, Schwetz BA.
Year:
1977
Bibliographic source:
Toxicol Appl Pharmacol 39:497-513
Reference Type:
publication
Title:
Vinyl chloride: Inhalation teratology study in mice, rats, and rabbits.
Author:
John JA, Smith FA, Schwetz BA.
Year:
1981
Bibliographic source:
Environ Health Perspect 41:171-177

Materials and methods

Principles of method if other than guideline:
Exposure of pregnant rats during the period of major organogenesis.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Inhibited vinyl chloride monomer from Matheson Gas Products, Joliet, IL

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposure was conducted in 3.7 cubic meter chambers. The atmosphere was generated by diluting gaseous vinyl chloride with filtered room air.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
The day on which a vaginal plug or sperm was seen in a vaginal smear was considered to be Day 0 of pregnancy.
Duration of treatment / exposure:
The animals were exposed during days 6-19 (7 h/day) of gestation
Frequency of treatment:
7 h/day
Duration of test:
Animals were sacrificed on day 21 of gestation.
No. of animals per sex per dose:
Twenty eight animals (controls) were exposed to air and 31 animals were exposed to 500 ppm vinyl chloride by inhalation in the first experiment.
Nineteen animals (controls) were exposed to air, 16 animals were exposed to 2500 ppm VC by inhalation, and 16 animals were exposed to 2500 ppm by inhalation plus 15% ethanol in drinking water in the second experiment.
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
BODY WEIGHT:
Days 6, 10, 16 and 21

FOOD CONSUMPTION AND COMPOUND INTAKE
Food consumption was examined every 3 days
Fetal examinations:
Number and position of live, dead and resorbed fetuses, sex, weight and length (crown-rump) and external and skeletal condition of fetuses were measured.  Soft tissues of one-third of each litter were examined microscopically.
Statistics:
The Fishers exact probability test was used to evaluate the incidence of resorption among litters. Body weights, body measurements and maternal liver weights were analyzed using ANOVA and a Dunnett's test.  The incidence of fetal anomalies was analyzed using a Wilcoxon test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Decreased weight gain was found in rats exposed to 500 ppm Vinyl chloride (VCM) (Table 1).  Decreased feed consumption and increased absolute and relative liver weight were found in animals exposed to 2500 ppm VCM.  There was no significant effect of exposure on maternal death.
Reproductive Indices:
There was no significant effect of exposure on the number of litters, number of implantation sites/dam, number of implanations or litters resorbed, or percent pregnant. The number of corpora lutea/dam and pregnancy wastage (the number of corpora lutea minus the number of implants) decreased in rats exposed to 500 ppm VCM, but not 2500 ppm VCM (Table 2).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEC
Effect level:
500 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
2 500 ppm
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No significant effect of exposure on number of live fetuses/litter, sex ratio, or overall incidence of gross, soft tissue or skeletal anomalies was noted. A significant decrease in fetal body weight and an increase in crown-rump length were observed in animals exposed to 500 ppm VCM but not 2500 ppm VCM (Table 2). The incidence of unilateral or bilateral dilated ureters increased in animals exposed to 2500 ppm VCM but not 2500 ppm VCM + ethanol (Table 3). An increased incidence of rib spurs was noted in animals exposed to 500 VCM but not 2500 ppm VCM. In general, effects were augmented in animals exposed to VCM and ethanol.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Maternal weight gain, liver weights and feed consumption in rats exposed to VCM

                                                                      ppm VCM
Parameters
                                                0                500        
Number of dams
                                      28                31       
Weight gain days 6-21
                           148+11        125+19*  
Relative liver weight, mg/g
                    36.5+4.1      37.1+2.6
Feed consumption days 6-15
                21+2           22+2

                                       ppm VCM
Parameters
                     0           2500              2500^
Number of dams
           19             16                  16
Weight gain
                 127+15     138+23          120+15**
  days 6-21
Relative liver
              34.4+3.3   37.8+2.6*       42.1+2.4**
  weight, mg/g
Feed consumption
        22+2         21+2*             13+2**
  days 6-15  
^ also treated with 15% ethanol in drinking water
* p0.05 from control; ** p0.05 from VCM alone

Table 2.  Observations made during C-section of rats exposed to VCM

                                                         ppm VCM
Parameters
                                    0                500        
Number of dams
                          28                31 
Corpora lutea/dam
                     15+3            13+2*
Fetal body weight, g
               5.67+0.29     5.44+0.38*
Fetal crown-rump length, mm 42.6+1.2
       43.6+0.8*

                                                              ppm VCM
Parameters
                                   0           2500             2500^
Number of dams
                          19               16                16
Corpora lutea/dam
                     14+2          15+2*           14+2**
Fetal body weight, g
                5.59+0.27  5.62+0.29    5.34+0.32**
Fetal crown-rump
                    43.6+1.5    43.3+1.1      42.4+0.9**
  length, mm
^ also treated with 15% ethanol in drinking water
* p0.05 from control; ** p0.05 from VCM alone

Table 3.  Incidence of skeletal malformations of rats exposed to VCM

                                                           ppm VCM
Parameters
                                      0               500        
Number examined, fetuses (litters)
  gross                                          339 (28)        387 (31)
  soft tissue                                   113 (28)       129 (31)
  skeletals                                     337 (28)       387 (31)
                   fetuses affected (%) (litters affected, %)
gross anomalies
 omphalocele                                    0                 1 (3)
soft tissue
 micropthalmia                                  0                 0
 dilated ureter (uni or bilateral)      2 (7)           2 (6)
 small kidney                                     0                 0
skeletal tissue
 sternebrae
   unfused                                          0                 1 (6)
 ribs
   spurs                                              1 (4)            9 (52)*
 vertebrae
   missing cervical centra              0.3 (4)         2 (16)
 skull
   delayed ossification                    16 (61)        12 (61)
   unfused                                         0                 0
 

                                        ppm VCM
Parameters
                        0                       2500                    2500^
Number examined, fetuses (litters)
  gross                            229 (19)               214 (16)                188 (16)
  soft tissue                       76 (19)                 73 (16)                  63 (16)
  skeletals                       229 (19)               214 (16)                188 (16)
                   fetuses affected (%) (litters affected, %)
gross anomalies
 omphalocele                      0.4 (5)                  0                           0.5 (6)
soft tissue
 micropthalmia                    0                          0                           2 (6)
 dilated ureter                     5 (10)                  27 (50)*                 5 (19)**
   (uni or bilateral)
 small kidney                      0                           0                           2 (6)
skeletal tissue
 sternebrae
   unfused                           3 (32)                   0.5 (6)                   1 (12)
 ribs
   spurs                               0.4 (5)                  0                            0.5 (6)
 vertebrae
   missing cervical            14 (68)                 12 (69)                  35 (69)
     centra     
 skull
   delayed ossification     18 (58)                   6 (31)                    3 (25)
   unfused                          53 (90)                   3 (12)                    2 (12)
^ also treated with 15% ethanol in drinking water
* p0.05 from control; ** p0.05 from VCM alone

Applicant's summary and conclusion