Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: basic data given

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Long term toxicologic assessment of nickel in rats and dogs.
Author:
Ambrose, A. M. et al.
Year:
1976
Bibliographic source:
Journal of Food Science and Technology 13, 181-187
Reference Type:
secondary source
Title:
Nickel Sulphate, CAS-No.: 7786-81-4, EINECS-No.: 232-104-9, RISK ASSESSMENT Final version March 2008, Chapters 0, 1, 2, 4, 5, 6 & 7 – human health only
Author:
Danish Environmental Protection Agency
Year:
2008
Bibliographic source:
European Union Risk Assessment Report

Materials and methods

Principles of method if other than guideline:
An oral three-generation study in rats was performed, however, examinations were limited.
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Reference substance name:
10101-97-0
EC Number:
600-152-3
Cas Number:
10101-97-0
IUPAC Name:
10101-97-0
Constituent 2
Reference substance name:
Nickel sulphate
EC Number:
232-104-9
EC Name:
Nickel sulphate
Cas Number:
7786-81-4
IUPAC Name:
nickel(2+) sulfate
Constituent 3
Reference substance name:
nickel (II) sulfate hexahydrate
IUPAC Name:
nickel (II) sulfate hexahydrate
Details on test material:
- Name of test material (as cited in study report): nickel sulfate hexahydrate containing 22.3% nickel by analysis
- Molecular formula (if other than submission substance): NiSO4X6H2O
- Physical state: fines
- Analytical purity: no data

Test animals

Species:
rat
Strain:
other: albino Wistar derived
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Albino Farms, Red Bank, New Jersey
- Age at study initiation: (P) 4 wks; (F1) 2 wks
- Housing: Rats were individually caged.
- Diet (e.g. ad libitum): Radiston Purina, St. Louis, Missouri

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): 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. Addition of nickel solutions were thoroughly blended into the diet by mixing in a rotary-type blender.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- After successful mating each pregnant female was caged (how): individually in a breeding cage
- Any other deviations from standard protocol: Male rats of each group were rotated to a different female on each of three successive 7-day periods. On the 20th mating day alle males were removed.
Duration of treatment / exposure:
11 weeks prior to mating
Frequency of treatment:
continuously for 11 weeks; for F1 litters the treament started after weaning
Duration of test:
The parent generation (F0) was mated for F1 litters (For procedure refer to "Details on mating procedure"). Following weaning of F1 litters, surviving F0 rats were sacrificed and autopsied. For the production of F2 and F3 litters, the same procedure was followed.
The exposure regimen was stopped at weanling of the F3 generation.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 500 and 1000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
30 (20 were used for mating procedures)
Control animals:
yes, plain diet
Details on study design:
Litters containing more than 10 offsprings were reduced to 10 on day 5.

Examinations

Maternal examinations:
Weekly body weight records were obtained, except during mating through weaning of litters.
Fetal examinations:
Gross observations on all offspring.
Histopathologic studies were performed on 10 male and 10 female F3 weanlings from each diet level. Tissues included: heart, spleen, kidneys, liver, testes, lung, urinary bladder, stomch, small and large intestine, skeletal muscle, brain, skin, bone marrow, pituitary, thyroid, adrenal, pancreas and gonad.

Results and discussion

Results (fetuses)

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

Effect levels (fetuses)

Dose descriptor:
LOAEL
Effect level:
250 ppm (nominal)
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Body weights of F0 animals were decreased at the high dose only.

The number of pups born dead was increased at all nickel doses in the F1a generation and at 500 ppm and 1000 ppm in the F1b generation, but there was no effect on pup mortality in later generations.

There was a clear and consistent decrease averaging 27% in mean weanling body weight at 1000 ppm in all generations.

Gross observations at all dietary levels through three generations showed no teratogenic effects. Histopathologic findings of F3 weanlings were negative.

Applicant's summary and conclusion