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Toxicological information

Developmental toxicity / teratogenicity

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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: Meets generally accepted scientific standards, well documented and acceptable for publication.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Negative test for transplacental carcinogenicity of nickel subsulfide in Fischer rats
Author:
Sunderman FW, McCully KS, and Rinehimer LA
Year:
1981
Bibliographic source:
Res. Comm. Chem. Path. Pharm. 31: 545-554

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Developmental toxicity of nickel subsulfide (Ni3S2) was examined by i.m. administration of Ni3S2 (20 mg) to 8 pregnant Fischer rats on day 6 of gestation.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trinickel disulphide
EC Number:
234-829-6
EC Name:
Trinickel disulphide
Cas Number:
12035-72-2
Molecular formula:
Ni3S2
IUPAC Name:
(trinickel-1-ylidene)-1λ⁴-disulfene
Details on test material:
- Name of test material (as cited in study report): nickel subsulfide (alpha-Ni3S2)
- Physical state: particulate
- Other: median particle diameter < 2 um; provided by INCO Ltd., Toronto, Canada

Test animals

Species:
rat
Strain:
Fischer 344
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, MA
- Age at study initiation: 120 - 150 days at time of breeding; offspring studied from birth
- Housing: dams housed singly in polypropylene cages
- Diet (e.g. ad libitum): Purina rat chow ad libitum
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
intramuscular
Vehicle:
other: penicillin
Details on exposure:
The test group of 8 pregnant dams was injected i.m. with 20 mg Ni3S2 in 0.2 ml of penicillin vehicle on day 6 of gestation. The i.m. injections were performed with a 20 gauge needle deep into the musculature of the right thigh.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not applicable
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:3
- Length of cohabitation: 4pm to 8am
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Single i.m. injection of dam on gestational day 6
Frequency of treatment:
Once
Duration of test:
Approximately 26 months
No. of animals per sex per dose:
8 dams
Control animals:
yes, concurrent vehicle
Details on study design:
The dams delivered their litters on days 21 or 22 of gestation. The 8 litters of the control dams contained an average of 8.8 pups (SD ±1.5; range = 7 to 11). The 8 litters of Ni3S2-treated dams contained an average of 7.5 pups (SD ± 2.2; range = 2 to 10; 0.10 > P > 0.05 versus controls by Student's t test). The pups were weaned at 4 weeks, and no more than 8 offspring/litter were included in the carcinogenesis test. The rats that were observed for tumor development comprised 53 offspring of control dams (29 males, 24 females) and 50 offspring of Ni3S2-treated dams (17 males, 33 females). The rats were weighed and examined at biweekly intervals. The rats either died spontaneously or were killed when they had become so cachectic that they could not move around in their cages, and hence could not obtain food or water. The study was terminated at approximately 26 months. Complete autopsies were performed, including examination of the brain. Tissue specimens were fixed in 10% neutral buffered formalin, and paraffin embedded sections stained with hematoxylin and eosin for examination by light microscopy.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No data
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data
Statistics:
Body weights of rats in test and control groups were compared by Student's t test; mortality data in the test and control, groups were compared by the Mann-Whitney U test; tumor incidences in the test and control groups were compared by Fisher's exact test.
Indices:
Not applicable
Historical control data:
Not applicable

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:not examined

Details on maternal toxic effects:
Not applicable

Effect levels (maternal animals)

Dose descriptor:
dose level:
Effect level:
20 other: mg Ni3S2/dam
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
There was no significant difference between the litter sizes of control vs. treated rats (0.1 > p > 0.05; Student's t-test). No congenital malformations were observed in pups of control dams or Ni3S2-treated dams. The body weights of progeny of treated dams were significantly lower than progeny of control dams. Sex-specific mortality rates did not differ between progeny of treated vs. control dams. There was no significant difference in tumor incidence between progeny of treated (4/33 female; 0/17 male) vs. control (4/24 females; 1/29 males) dams.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Age                   Number                     Body weights (grams, mean +/- SD)

Category             (months)                 of rats                            Males                    Females      

Progeny of              6                 53 (29 M, 24 F)                   288 +/- 32             172 +/- 11

Control Dams       12               48 (25 M, 23 F)                   325 +/- 40             198 +/- 10

18                33 (14 M, 19 F)                   330 +/- 44             212 +/- 10

Progeny of               6                 50 (17 M, 33 F)                   264 +/- 30*           167 +/- 15

Treated Dams       12               46 (16 M, 30 F)                  302 +/- 44#           191 +/- 13#

18               36 (11 M, 25 F)                    291 +/- 33*           197 +/- 19*

* = p < 0.05 vs. control progeny

# = p < 0.01 vs. control progeny

Applicant's summary and conclusion

Conclusions:
Intramuscular administration of 20 mg Ni3S2 to pregnant rats resulted in lower progeny body weights relative to progeny of control dams. This exposure had no significant effect upon litter size, the development of congenital malformations, or progeny mortality rates.
Executive summary:

Sunderman et al. (1981) studied the potential for Ni3S2 to induce transplacental carcinogenicity by exposing 8 pregnant Fischer rats on day 6 of gestation to 20 mg Ni3S2 via i.m. injection into the right thigh; control dams received a similar injection of a penicillin vehicle. Gestation day 0 was determined when the presence of sperm was observed in vaginal smears following the cohousing of 3 female rats with 1 male rat. There were 50 offspring (17 males, 33 females) born to Ni3S2-treated dams and 53 offspring (29 males, 24 females) of control dams. The only notable effect observed was lower progeny body weights relative to progeny of control dams; no treatment-related effects on litter size, the development of congenital malformations, progeny mortality rates, or incidences of non-neoplastic lesions or tumors in the progeny were noted. The results of this particular gestational exposure design indicated that Ni3S2 was not embryotoxic or teratogenic, although the decrease in progeny body weight relative to control suggests some degree of developmental toxicity is associated with Ni3S2. See the Carcinogenicity Section for findings related to carcinogenicity in progeny. STUDY RATED BY AN INDEPENDENT REVIEWER