Tin titanium zinc oxide

Endpoint summary

Description of key information

Repeated dose toxicity:
- oral: NOAEL = 1000 mg/kg bw/d (OECD 407)

In accordance with Annex IX, section 8.6.2, column 2, a subchronic toxicity study has been waived. For further information please refer to the respective study record.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Experimental Toxicology and Ecology, BASF SE

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld
- Age at study initiation: 42 +/- 1 days
- Weight at study initiation: mean 173.5 g (males), 138.9 g (females)
- Housing: (5 animals per cage) in H-Temp (PSU) cages supplied by TECNIPLAST, Hohenpeißenberg, Germany (floor area about 2065 cm2);
- Diet (e.g. ad libitum): ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water (e.g. ad libitum): drinking water (from water bottles); ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was applied as a suspension. To prepare the suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then the vehicle (drinking water with 1% Carboxymethylcellulose) was filled up to the desired volume, subsequently mixed using a magnetic stirrer. The suspension was hold homogeneous by magnetic stirrer during application. The test-substance preparations were prepared daily, because no stability analysis was carried out. The test substance does not change chemical identity in aqueous suspensions. The sponsor approved the stability of the test substance in physiologic vehicles.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses were carried out as a separate study at the test facility GKA Competence Center Analytics BASF SE, Ludwigshafen, Germany under the response of the Study Director of this test facility. The study was carried out in complaince with the Principles of Good Laboratory Practice.
Determination by inductively coupled plasma-optical emission specrometry (ICP-OES) after acid digestion

Duration of treatment / exposure:

28 d

Frequency of treatment:

daily

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: by request of the sponsor

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: made twice daily on working days and once daily on Saturdays, Sundays and public holidays
- Cage side observations checked in table were included.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the administration period and thereafter at weekly intervals


BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period in order to randomize the animals. During the administration period the body weight was determined on day 0 (start of the administration period) and thereafter at weekly intervals


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


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes


WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily by visual inspection of the water bottles for any overt changes in volume


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: in the morning at the end of application period
- Anaesthetic used for blood collection: Yes (isofluran)
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters examined: leukocyte count, erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, differential blood count, reticulocytes, clotting analyses, prothrombin time


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in the morning at the end of application period
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters examined: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholsetsreol, magnesium


URINALYSIS: Yes
- Time schedule for collection of urine: in the morning at the end of application period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters examined: pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment, color, turbidity, volume


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: after about 4 weeks of treatment
- Battery of functions tested: sensory activity / grip strength / motor activity / FOB

METABOLIC PROFILE
- Time schedule for collection of serum: in the morning at day 29
- Method: GC-MS and LC-M
- Analysis of data: MetaMap Tox-database

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
No animal died prematurely in the present study. Discolored feces (orange) was observed in all rats of both sexes of group 2 (300 mg/kg bw).
In addition, all animals of both sexes of group 3 (1000 mg/kg bw) showed red-discolored feces.
These findings were most probably caused by the physical property of the test compound (solid, orange) and therefore assessed as toxicologically irrelevant as well as not adverse.

BODY WEIGHT AND WEIGHT GAIN
No substance-related significantly changes in body weight data were measured.
When compared to control group, no mean absolute weight parameters were significantly changed.

FOOD CONSUMPTION AND COMPOUND INTAKE
Regarding food consumption, no significantly differences were obtained between treated animals and controls throughout the entire study.

FOOD EFFICIENCY
Food efficiency was statistically significantly decreased in female animals of group 3 (1000 mg/kg bw/day) on day 28, only. This single occurrence was assessed as spontaneous in nature and therefore not substance-related.

WATER CONSUMPTION AND COMPOUND INTAKE
No substance-related overt changes in water consumption were observed


HAEMATOLOGY
There were no treatment-related, adverse effects measured in the hematological parameters.

CLINICAL CHEMISTRY
There were no treatment-related adverse changes measured in the clinical chemistry
parameters.

URINALYSIS
There were no treatment-related changes in the urinalyses parameters measured

NEUROBEHAVIOUR
- FOB: No substance-related findings were observed
- Motor activity measurement: Regarding the overall motor activity, no substance-related findings were observed. Comparing the single intervals with the control groups, no substance-related deviations were measured.

ORGAN WEIGHTS
When compared to control group 0, in the dose group 2 (300 mg/kg body weight) the adrenal glands showed a mild but significant decrease and the spleen a mild, but significant increase in the organ weight. As there was no histopathologic correlate to these weight deviations and the 1000 mg/kg body weight group did not show any effect on the organ weight, this is regarded to be an incidental finding and not related to the test substance. All other mean relative weight parameters did not show significant differences when compared to the control groups.

GROSS PATHOLOGY
Observed gross lesions occurred singly or they were biologically equally distributed between control and treatment groups. In the high dose groups (1000 mg/kg body weight) of males and females the content of the cecum showed an orange discoloration, which was not regarded to be an adverse effect.

HISTOPATHOLOGY: NON-NEOPLASTIC
All findings noted were either single observations or they were biologically equally distributed between control and treatment group. All of them are considered to be incidental or spontaneous in origin and without any relation to treatment.

METABOLISM
The test substance did not match established metabolite profiles for specific toxicity in both males and females at all dose levels.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no substance-related adverse findings at all dose levels

Critical effects observed:

no

Reference 2

Endpoint:

sub-chronic toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a sub-chronic toxicity study (90 days) does not need to be conducted because the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day 'limit test' and human exposure is limited

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
Please refer to the attached justification for further information.

Reason / purpose for cross-reference:

exposure-related information

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity was evaluated in a study performed under GLP according to OECD guideline 407, where groups of five male and five female Wistar were dosed by gavage with concentrations of 100, 300 1000 mg/kg bw/d for 28 days (BASF, 2008). Beside observations for clinical sings and mortality, hematology, clinical chemistry, urinalysis were performed and behavioral parameters were recorded. At the end of the study, serum metabolites were analyzed and compared to the profiles known toxic substances of the MetaMap Tox-database. As result, no substance-related adverse effects were noted in both males and females at all dose level and the test substance did not match established metabolite profiles for specific toxicity. Thus, the NOAEL was found to be 1000 mg/kg bw/d.

Justification for classification or non-classification

Based on the found effect level obtained in an OECD guideline study, no classification according to EU and GHS criteria is necessary.