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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
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: Comparable to guideline study with acceptable restrictions (non-GLP)

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
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Molecular formula: Ni Sb Ti O
- Analytical purity: technical grade
- Composition of test material, percentage of components: molarity based: Ti 0.88, Sb 0.05, Ni0.075; weight based: TiO2 80%, Sb2O5 15%, NiO 5%

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
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 100, 1000, 10000 ppm in the diet (0.45, 4.5, 45, 450 mg/kg bw/day)
Basis:
nominal in diet
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:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule: weekly
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

HAEMATOLOGY/CLINICAL CHEMISTRY/URINALYSIS: Yes
- Time schedule for collection of blood: after one month and at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 5/sex/dosing group
- Parameters checked: RBC, reticulocytes, platelets, haemoglobin, haematocrit, total and differential WBC, MCV, ALP, GOT (AST), GPT (ALT), creatinine, urea, glucose, cholesterol, total plasma and urine proteins, urinalysis; thromboplastin time and glutamate dehydrogenase activities were measured after 3 months

OTHER: Liver and kidneys from 5 animals/sex/dose were examined for their nickel and antimony content after 1, 2 and 3 months.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. 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
ORGAN WEIGHT: Yes, the following organs were weighed during necropsy: thyroid, thymus, heart, lung, liver, spleen, kidneys, adrenals and gonads
Other examinations:
After 1, 2 and 3 months, liver and kidneys from 5 animals per gender 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 examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs or mortality was observed during the study period.

BODY WEIGHT AND WEIGHT GAIN
The test substance did not have any effect on body weight and weight gain.

FOOD CONSUMPTION
Food consumption of the treated animals was normal throughout the study period.

HAEMATOLOGY/CLINICAL CHEMISTRY/URINALYSIS
No treatment related effects were seen with regard to hematological, biochemical parameters or urinalysis.

ORGAN WEIGHTS
Normal organ weights were observed for thyroid, thymus, heart, lung, liver, spleen, kidneys, adrenals and gonads.

GROSS PATHOLOGY
No gross internal lesions were observed during necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
No indications of treatment related findings were seen in any of the examined tissues.

OTHER FINDINGS
No antimony was detectable in liver and kidneys after 1 and 2 months at any dose. After three months of treatment with 10000 ppm of the 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 (kidney) ppb. Nickel concentrations could not be detected in liver or kidneys of the test animals.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 450 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The detected traces of antimony most likely originate from the acid-soluble impurities of the pigment (10 - 20 mg antimony/kg pigment, that is 5-10 µg/kg bw or 125-250 µg/kg organ weight at the highest dose) and therefore do not indicate bioavailability of the pigment itself. Neither the pigment itself nor the bioavailable traces of leachable metal ion impurities are considered to have toxicological significance even after extremely high oral exposure.

Applicant's summary and conclusion