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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 with acceptable restrictions
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Effects of NiCl2 and NiO in Wistar rats after oral uptake and inhalation exposure respectively.
Author:
Weischer CH, Kordel W, Hochrainer D
Year:
1980
Bibliographic source:
Zentralbl Bakteriol Mikrobiol Hyg [B]. 17(4-5): 336-51.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Effects of a 21-day exposure to NiO-aerosols were evaluated in pregnant rats and their fetuses. Endpoint evaluated included changes in body weight, organ weight, hematological assessment, urinalysis, various clinical chemistry assays, and fetal survival.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Nickel monoxide
EC Number:
215-215-7
EC Name:
Nickel monoxide
Cas Number:
1313-99-1
Molecular formula:
NiO
IUPAC Name:
Nickel (ii) oxide
Details on test material:
- Name of test material (as cited in study report): NiO-aerosols
- Generation of NiO: NiO aerosols were generated via pyrolysis of Ni-acetate. The degree of pyrolosis was measured in a series of experiments where the tube furnace was operated at different temperatures. Aerosol particles were sampled each time; the sample was weighed and the amount of Ni in the sample determined by titration. The relative content of the Ni from the aerosol samples peaks between 500°C and 600°C with a Ni-content exactly as expected for NiO. Thus it was assumed that with a tube furnace temperature of 550°C, a complete pyrolysis of the Ni acetate to Ni oxide was obtained.
- Particle size distributions were measured with a spiral centrifuge.

Test animals

Species:
rat
Strain:
other: TNO W 74
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: TNO W 74, virgin females
- Housing: fully climatized room
- Diet (e.g. ad libitum): to minimize oral nickel uptake, new uncontaminated food was offered in the evening only and remaining food was taken away in the morning.
- Water (e.g. ad libitum): ad libitum



Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure (if applicable):
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Details characterizing the test atmosphere/chamber description were not described.

TEST ATMOSPHERE
- Brief description of analytical method used: filter samples were taken on 0.2µm pore size membrane filters; sample volume of about 1m3 was drawn through the filters
- Samples taken from breathing zone: samples were taken of the aerosol immediately before and after the inhalation chamber. The concentration in the chamber was calculated as the mean of the two values. The concentration before the chamber was usually 5% higher than after the chamber.
- Particle size distributions were measured with a spiral centrifuge:
Arithmetic mean diameter = 0.58µm
Standard deviation of the distribution = 0.82 µm
Geometric mean diameter = 0.43 µm
Geometric standard deviation = 1.6
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Aerosol samples were taken from breathing zone before and after the inhalation chamber. The concentration in the chamber was calculated as the mean of the two values. The concentration before the chamber was usually 5% higher than after the chamber.
Details on mating procedure:
Virgin Wistar rats were mated with males of the same strain overnight. The following morning, a vaginal smear was examined microscopically for sperm. The positive animals were then selected for the inhalation study.
Duration of treatment / exposure:
21 days
Frequency of treatment:
24 hours a day (except for daily 10-20 minute interruptions for cleaning of the inhalation chambers and feeding
Duration of test:
Clinical and clinico-chemical parameters were determined following exposure.
No. of animals per sex per dose:
10-13 pregnant rats/group
Control animals:
yes, concurrent no treatment
Details on study design:
Not Applicable

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: beginning and end of experiment

FOOD CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: kidney, liver, lung


OTHER:

HAEMATOLOGY:
- Time schedule for collection of blood: following the exposure period
- Anaesthetic used for blood collection: yes; blood was taken from the carotid artery via PVC tube
- Animals fasted: No data
- How many animals: all animals (10-13 per dose group and controls)
- Parameters checked: erythrocytes, leukocytes, hematocrit, hemoglobin, MCV (mean cell volume of erythrocytes) in blood

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: following the exposure period
- Animals fasted: No data
- How many animals: all animals (10-13 per dose group and controls)
- Parameters checked: alkaline phosphatase, urea, bilirubin, glucose in serum


URINALYSIS: Yes
- Time schedule for collection of urine: 0.5 to 1.5 ml urine was collected in a PVC tube following the exposure period
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: creatinine, alkaline phosphotase and urea in urine.

Ovaries and uterine content:
Not Reported
Fetal examinations:
- External examinations: No data
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data
- Other: number of fetuses, number of placentas, body weight, wet weight of placentas, hemoglobin, hematocrit, erythrocytes, leukocytes, MCB in blood, and urea and alkaline phosphatase in serum.
Statistics:
The mean and standard deviation were determined; results were proved using test of Kruskal and Wallis and the rank test of Wilcoxon, Whitney and Mann
Indices:
Not Reported
Historical control data:
Not Reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal Rats:
Significant reductions were observed in
- body weight (all exposure groups)
- wet weights of kidneys (1.6 and 3.2 mg/m3 exposure groups)
- erythrocytes (1.6 and 3.2 mg/m3 exposure groups)
- urea in serum (3.2 mg/m3 exposure group)

Significant increases were observed in:
- wet weight of lungs (all exposure groups)
- hematocrit (3.2 mg/m3 exposure group)
- MCV (1.6 and 3.2 mg/m3 exposure groups)
- leukocytes (0.8 mg/m3 exposure group)

No changes were observed in alkaline phosphatase in serum or urine, bilirubin, urea in urine, or liver weight.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
dose level:
Effect level:
> 1.6 - < 3.2 mg/m³ air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
other:
Basis for effect level:
other: effect type not specified

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Body weights were reduced in mid- and high dose groups (1.6 and 3.2 mg/m3). Leukocytes and urea in serum in mid-dose group were increased. No effects of exposure were observed for: number of fetuses or placentas, wet weight of placenta, hemoglobin, hematocrit, erythrocytes, MCV, or alkaline phosphatase in serum.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Not Applicable

Applicant's summary and conclusion

Conclusions:
The authors did not provide a conclusion to their study.
Executive summary:

In a multi-part study, Weischer et al (1980) evaluated the effects of a continuous, 21-day gestational inhalation exposure to NiO (unspecified color) aerosols (0.8, 1.6 and 3.2 mg/m3) in rats (note: effects in males and non-pregnant animals reported in the repeated dose toxicity section). NiO aerosols were generated by the authors via pyrolysis of nickel acetate at 550°C. Virgin Wistar rats (TNO W 74) were mated with males of the same strain overnight. The following morning, a vaginal smear was examined microscopically for sperm and positive animals were then selected for the inhalation study (10-13 per exposure group, 13 controls). On GD 21, fetuses were removed by cesarean section and fetal blood collected. Maternal blood, serum and urine were also collected. Endpoints evaluated included changes in body weight, organ weight, hematological assessments, urinalysis, various clinical chemistry assays, and fetal survival (very limited traditional evaluations of teratogenic or developmental toxicities, such as soft tissue or skeletal examinations, were included). In maternal rats, significant reductions were observed in body weight (all exposure groups), wet weights of kidneys and erythrocyte count (1.6 and 3.2 mg/m3 exposure groups), and urea in serum (high exposure only). Significant increases were observed in wet weight of lungs (all exposure groups), hematocrit (3.2 mg/m3 exposure group), MCV (1.6 and 3.2 mg/m3 exposure groups), and leukocytes (low exposure group only). No changes were observed in alkaline phosphatase in serum or urine, bilirubin, urea in urine, or liver weight. In fetuses, body weights were reduced in mid- and high exposure groups. Leukocytes and urea in serum in mid-dose group were increased. No effects of exposure were observed for: number of fetuses or placentas, wet weight of placenta, hemoglobin, hematocrit, erythrocytes, MCV, or alkaline phosphatase in serum. Though the authors did not offer a general conclusion, data generally suggest that both maternal and developmental toxicities (as assessed by evaluation of hematological and clinical chemistry endpoints only) occurred in a dose-dependent fashion. STUDY RATED BY AN INDEPENDENT REVIEWER