Reaction mass of aluminium fluoride and chromium trifluoride and nickel difluoride

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1960-1962 (in-life phase)

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study in accordance with generally accepted methods, but limited level of parameters examined and data reported

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1976

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

A limited set of investigations (siblings gross observation, F3 weanlings histopathology) were conducted for evaluation of teratologic effects as part of this 3-generation study.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel sulfate hexahydrate (NiS04.6H20)

IUPAC Name:

Nickel sulfate hexahydrate (NiS04.6H20)

Details on test material:

Nickel sulfate hexahydrate fines containing 22.3% nickel by analysis (theoretically 22.32%) served as the test material in this study.

Test animals

Species:

rat

Strain:

other: Wistar-derived

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Albino Farms, Red Bank, New Jersey, USA
- Age at study initiation: (P) 4 wks
- Weight at study initiation: (P) 56-65 g
- Fasting period before study: No data
- Housing: individually caged
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet: ad libitum, Radlston Purina, St. Louis, Missouri, USA
- Water: ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
No details provided

IN-LIFE DATES: From: 1960 To: 1962

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Radlston Purina feed

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Finely ground laboratory chow served as the basic diet. Stock aqueous solutions of nickel sulfate hexahydrate were prepared in appropriate concentrations so that the addition of 100 mL for each 6 kg of diet resulted in the desired nickel content, respectively. Additions of nickel solutions were thoroughly blended into the diet by mixing in a rotary-type blender.
- Storage temperature of food: No data

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: 7 days
- Proof of pregnancy: No data
- Further matings after two unsuccessful attempts: No
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: On the 20th mating day all males were removed.

Duration of treatment / exposure:

11 weeks prior to mating, during mating, gestation, and lactation

Frequency of treatment:

Daily

Duration of test:

Approximately 2 years (3 generations)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 250, 500 and 1000 ppm
Basis:
nominal in diet
equivalent to 0, 22.5, 45 and 90 mg/kg bw nickel, respectively

No. of animals per sex per dose:

30

Control animals:

yes, plain diet

Details on study design:

No further details provided

Examinations

Maternal examinations:

Weekly body weight records were obtained, except during mating through weaning of litters.
Records were maintained of mating and number of pregnancies.
Following weaning of F/1b litters, surviving F/0 rats were sacrificed and autopsied.

Records were maintained of litters cast (alive and dead), pups in litter at 1, 5, and 21 days (weaning), and total weight of the litter at weaning.
At weaning of F/2b rats, F/1b parents were sacrificed and autopsied.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: No
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: No
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

Gross observations at necropsy were performed for all 3 generations.
Histopathologic examinations were performed on 10 male and 10 female F/3b weanlings from each diet level. Absolute and relative organ-to-body weight ratios for heart, spleen, kidneys, liver, and testes were analysed statistically. Tissues preserved in formalin for histopathologic study were in addition to the above: lung, urinary bladder, stomach, small and large intestine, skeletal muscle, brain, skin, bone marrow, pituitary, thyroid, adrenal, pancreas, and gonad.

Statistics:

No data

Indices:

The following indices were calculated for each generation:
- Fertility (F.l.) = (pregnancies/matings) x 100
- Gestation (G. I.) = (litters cast/pregnancies) x 100
- Viability (V.I.) = (live pups at day 5/live pups born) x 100
- Lactation (L.I.) = (weaned/live pups-discards on day 5) x 100

Historical control data:

No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: decreased body weight at 1000 ppm (90 mg/kg nickel)

Details on maternal toxic effects:
Rats on 1000 ppm (90 mg/kg nickel) exhibited slightly lower body weights. The average decrease in body weight did not exceed 8% for females.

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: up to 1000 ppm (90 mg/kg nickel) throughout the 3 generations

Details on embryotoxic / teratogenic effects:
Gross observations on siblings cast, at all dietary levels of nickel through three generations showed no teratogenic effects. Histopathologic findings on F/3b weanlings, 10 of each sex on each dietary level, were entirely negative.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

1 000 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the absence of abnormalities in pups throughout 3 generations, the NOAEL for teratogenicity can be set at 1000 ppm (90 mg/kg nickel).

Executive summary:

In a 3-generation study, Wistar-derived rats were fed with 0, 250, 500, or 1000 ppm of nickel sulfate hexahydrate (equivalent to 0, 22.5, 45, or 90 mg/kg of nickel, respectively).

In the parental generation, body weights for rats on 250 and 500 ppm diets (22.5 and 45 mg/kg nickel, resp.), before mating and at weaning of respective litters, were not adversely affected, but rats on 1000 ppm (90 mg/kg nickel) exhibited slightly lower body weights. The average decrease in body weight did not exceed 8% for females.

Gross observations on siblings cast, at all dietary levels of nickel through three generations showed no teratogenic effects. Histopathologic findings on F/3b weanlings, 10 of each sex on each dietary level, were entirely negative.