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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Subchronic Oral Toxicity and Analytical Studies on Nickel Rutile Yellow and Chrome Rutile Yellow with Rats
Author:
Bomhard E et al.
Year:
1982
Bibliographic source:
Toxicol. Letters, 14, 189-194

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
Levels of nickel and antimony in liver and kidneys, respectively, were measured after 1 and 2 months after exposure
Principles of method if other than guideline:
Method: T26-16 (comparable to OECD guideline 408)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
other: SPF-derived Wistar TNO W74
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: 4-5 weeks
- Housing: macrolon cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): Altromin
- Water (e.g. ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- reported as "standard conditions"

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Mixing appropriate amounts of powdered food with test substance
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg diet
Remarks:
0 mg/kg bw/day
Dose / conc.:
10 mg/kg diet
Remarks:
0.5 mg/kg bw/day
Dose / conc.:
100 mg/kg diet
Remarks:
5 mg/kg bw/day
Dose / conc.:
1 000 mg/kg diet
Remarks:
50 mg/kg bw/day
Dose / conc.:
10 000 mg/kg diet
Remarks:
500 mg/kg bw/day
No. of animals per sex per dose:
15 (control: 30). Additionally, 10 animals were used for analytical investigations (control: 20).
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure period: no

Examinations

Observations and examinations performed and frequency:
The animals were observed daily, food consumption and body weight were determined once a week. Haematological, clinical and biochemical investigations (RBC, reticulocytes, platelets, haemoglobin, haematocrit, total and differential WBC, MCV, ALP, GOT, GPT, creatinine, urea, glucose, cholesterol, total plasma and urine proteins, urinalysis) were conducted using recommended methods after one month and at the end of the study on 5 male and 5 female rats of each group. In addition, thromboplastin time and glutamate dehydrogenase activities were measured after 3 months.
Sacrifice and pathology:
All animals, killed at the end of treatment by exsanguination under ether anaesthesia, were subjected to detailed macroscopic examination. Thyroid gland, thymus, heart, lung, liver, spleen, kidneys, adrenals, gonads were weighed. Liver, aorta, eyes, intestines, femur, brain, urinary bladder, pituitary, cervical lymph nodes, stomach, oesophagus, epididymides, pancreas, prostate, seminal vesicle, sternum (bone marrow), trachea, uterus, skeletal muscle (M. quadriceps with N. ischiadicus) from 5 males and 5 females of the control and top dose groups were investigated histopathologically. Paraffin slices were stained with haematoxylin and eosin. Additional kidney slices were stained by PAS and cryostat slices of liver with Oil Red O.
Other examinations:
After 1, 2 and 3 months, liver and kidneys from 5 animals per sex and dose group were analysed for their nickel and antimony contents by AAS. The detection limit for antimony was 5 ppb and for nickel 10 ppb.
Statistics:
The results of the body and organ weight determination as well as the haematological and clinical chemical data were compared using the U-test according to WiIcoxon (1947). A difference was considered to be significant at P<=0.05.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
No substance related effects on mortality, clinical signs, body weight, hematology, clinical chemistry, organ weights, gross pathology and histopathology

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

CHEMICAL ANALYSIS Antimony

No antimony detectable in liver and kidneys after 1 and 2 months at any dose.

After three months treatment with 10000 ppm test substance antimony was detectable in liver (6 ppb) and kidney (5 ppb) of males slightly above the detection limit and in females at levels of 6 (liver) and 10 ppb (kidney). 

Applicant's summary and conclusion