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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
August 1998 to December 2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific methods. GLP study.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Principles of method if other than guideline:
Similar to OECD 415
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nickel sulphate (NiSO4) hexahydrate, 10101-97-0
- Molecular formula (if other than submission substance): not different than submission substance
- Molecular weight (if other than submission substance): not different than submission substance
- Smiles notation (if other than submission substance): not different than submission substance
- InChl (if other than submission substance): not different than submission substance
- Structural formula attached as image file (if other than submission substance): not different than submission substance
- Physical state: blue green crystalline powder
- Purity: 99%
- Lot No.: 08516TQ
- Other details not reported or not applicable

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, NY, USA
- Age at study initiation: 11 wks
- Weight at study initiation: 269-360 g (males) and 187-247 g (females)
- Fasting period before study: not reported
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 25 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 65-79 deg F
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 per hour
- Photoperiod (hrs dark / hrs light): 12-h light/dark photoperiod.

IN-LIFE DATES: From: August 4, 1998 To: October 30, 1998

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
other: not applicable
Vehicle:
other: reverse osmosis deionized water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was dissolved in reverse osmosis deionized water.  Control animals received appropriate volumes of water only.  The  
homogeneity and stability of the test substance in dosing solutions were determined.  The concentration of the test substance in dosing solutions  
was analytically confirmed at different time intervals during the study period. Groups of 16 test animals of each parental group (8 males/8  
females) received the test substance daily by gavage at the following dosage concentrations:  0, 1.0, 2.0, 3.0, 5.0, and 7.5 mg/ml (equivalent to  
dose levels of 0, 10, 20, 30, 50, and 75 mg/kg/day).  Dose volume was 10 ml/kg, adjusted for body weight.  F0 parental animals received the test substance (or vehicle for control group) daily for 14 days prior to mating and F1 generation on postpartum day 22 and dosing continued until one day 
prior to sacrifice.
Details on mating procedure:
- M/F ratio per cage: Animals were caged as mating pairs (1:1) until copulation was confirmed, then transferred to individual cages. 
- Proof of pregnancy: The presence of a vaginal plug or sperm was designated as day 0 of gestation.
- Dams and pups were caged together during lactation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyzed by AAS
Duration of treatment / exposure:
Exposure period: F0: 14 days prior to mating through gestation until postnatal day 21
F1: On lactation day 0 through day 21
Frequency of treatment:
daily
Details on study schedule:
not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
 0, 10, 20, 30, 50, and 75 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
8 males/8 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: selected to produce a graded response
- Rationale for animal assignment (if not random): random
Positive control:
none reported

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: more detailed clinical observations were made weekly. During gestation and lactation, F0 and F1 females were examined daily for clinical signs of toxicity

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
Oestrous cyclicity (parental animals):
Estrous cycle determinations (length and normality) were made daily prior to mating and during cohabitation.   
Sperm parameters (parental animals):
Sperm was collected from F0 and F1 parental males and examined for sperm count, concentration, motility, and morphology.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 6 and 13 postpartum
- If yes, maximum of [8] pups/litter ([8]/sex/litter as nearly as possible); excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring: [mortality, general health twice daily]

GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]
Postmortem examinations (parental animals):
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS: not reported
Postmortem examinations (offspring):
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS: not reported
Statistics:
One-way analysis of variance (ANOVA) was used to analyze parental and pup body weight, body weight gain, food consumption, organ weights, 
length of gestation and estrous cycle, and litter size.  If significance was detected, Dunnett's test was performed to compare control and treatment  
groups.  Copulation and fertility indices, pup sex ratios, numbers of live and dead pups, and pup survival were evaluated by Chi-Square test.   
Post-implantation loss was evaluated using the Mann-Whitney U test.  The level of significance was 5% (p<0.05).
Reproductive indices:
gestation length, litter size, fertility indices
Offspring viability indices:
litter size, sex rations, number of live/dead pups

Results and discussion

Results: P0 (first parental animals)

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:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

DETAILS ON RESULTS:
Homogeneity and stability of the test substance in gavage dosing solutions was found to be stable for 24 hours at room temperature and up  
to 21 days under refrigeration.

F0 generation: No test substance related mortality of clinical signs of toxicity.  There were no toxicologically meaningful differences in body weight 
gain or food consumption, copulation and fertility indices, gestation length, implantation and post-implantation loss, or sperm parameters.  
Post-implantation loss was significantly higher at 30, 50 and 75 mg/kg/day). No treatment related changes found at gross necropsy. 

Effect levels (P0)

open allclose all
Dose descriptor:
dose level:
Effect level:
75 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: The incidence of dead pups on lactation day 0 was significantly increased and mean live litter size was significantly decreased at the 75 mg/kg/day level.
Dose descriptor:
dose level:
Effect level:
>= 30 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Mean post-implantation loss was significantly increased at dosage levels >= 30 mg/kg/day.

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:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING):
Litter size was significantly decreased at 10, 20, 30, and 75 mg/kg-day. No significant differences in clinical signs, pup weights, weight gain, or
gross necropsy findings.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Effect level was not reported.

Applicant's summary and conclusion

Conclusions:
In conclusion, based on the results of this one-generation reproduction range-finding study, dosage levels of 1.0, 2.5, 5.0 and 10.0 mg/kg-day were selected for a definitive two-generation reproductions study in rats.