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Description of key information

Oral exposure: Tin sulfide showed no effects considered as adverse in a subchronic toxicity study 
according to OECD guideline 408. The NOAEL was defined at 1000 mg/kg and the NOEL at 300 mg/kg.
Inhalation exposure: In accordance with column 2 of REACH Regulation EC (No) 1907/2006 Annex IX,

the test repeated dose toxicity after inhalation (section 8.6) does not need to be conducted as a
repeated dose toxicity study for oral application is available. Due to the identified uses an inhalative
exposure is not expected. Therefore the test is not required (annex IX column 2, 8.6.2).
Dermal exposure: In accordance with column 2 of REACH Regulation EC (No) 1907/2006 Annex IX,

the test repeated dose toxicity after dermal application (section 8.6) does not need to be conducted a
repeated dose toxicity study for oral application is available. In addition, the acute dermal study showed
also no toxicity. Therefore no long-term dermal toxicity study is required (annex IX column 2, 8.6.2).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-12-02 to -2010-06-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline compliant study
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Version / remarks:
, 1995
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Species and strain: Wistar rat
- Supplier: BioTest s.r.o., Czech Republic
- Quality: SPF
- Age on delivery: 6-7 weeks
- Age at treatment start: 7-8 weeks
- Body Weight at delivery: DRF Study: Males 202-227g, Females 169-178g 90-Day Subchronic Study: Males 166-188g, Females 126-160g


- Housing: Macrolon 2000P cages (Tecniplast, 2-3 animals of the same sex/cage)
- Diet: standard pelletized diet NOE H4 (Racio Břeclav, CZ) ad libitum
- Water: drinking water ad libitum
- Acclimatization time: 5 or 6 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 2 °C
- Humidity: 30 - 70 %
- Photoperiod: 12 hours daily
Route of administration:
oral: gavage
Vehicle:
other: methylcellulose
Details on oral exposure:
PREPARATION OF THE TEST ITEM FORMULATION:
For the preparation of a homogenous suspension the following procedure was adopted: at first the weighted amount of the respective substance was ground in a grinding mortar with a small volume of carrier liquid. Then the content of the mortar is transferred into a calibrated vessel. Another amount of carrier liquid is poured into the mortar, stirred and the mortar with the pestle is rinsed, the rinsing liquid being added into the same calibrated vessel. This rinsing is repeated once more. Then the volume in the calibrated vessel is made up with the carrier liquid to the required volume and mixed on magnetic stirrer using 1000 rpm for 10 minutes. Immediately before the application, the suspension is again stirred by means of an electromagnetic stirrer.

VEHICLE
methylcellulose is used as vehicle in this study in a concentration of 0.5%

Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
90 days
Frequency of treatment:
Three treated groups were administered with doses of 100 mg and 300mg/kg and 1000 mg/kg bw per day. Control group was administered by the vehicle (0.5%) methylcellulose, only.

Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
orally by gavage
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
orally by gavage
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
orally by gavage
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
DRF Study METHOD
Three groups of rats (each group 4 males and 4 females) were daily administered with the Test Item suspension in 0.5% methylcellulose orally by gavage for 14 days. The first two groups were administered with doses of 500 mg/kg (D1 group) and 1000 mg/kg (D2 group). The third group (Control) was administered in the same manner by vehicle (0.5% methylcellulose). All animals were daily checked for clinical signs. Individual body weight and food consumption were recorded weekly. Before the first administration (Day -1) and after the last administration (Day 15) blood and urine samples were taken from all animals for hematology, clinical chemistry and urinalysis examinations. At the end of the study (Day 15) gross necropsy of all rats was performed and gross lesions were recorded.
90-Day Subchronic Toxicity Study METHOD
Four groups of rats (each of 10 males and 10 females) were daily administered with the Test Item suspension in 0.5% methylcellulose orally by gavage for 90 days. Three treated groups were administered with doses of 100 mg/kg (D1 group), 300 mg/kg (D2 group) and 1000 mg/kg body weight/day (D3 group). The fourth group (Control) was administered in the same manner by the vehicle (0.5% methylcellulose). All animals were daily checked for clinical signs. Individual body weight and food consumption were recorded weekly. Before the first administration (Day -1) and at the end of the study (Day 90) blood and urine samples were taken from all animals for hematology, clinical chemistry and urinalysis examinations. Ophthalmoscopy was also performed initially and terminally on all animals. At the end of the study (Day 90), gross necropsy of all rats was performed and organ and tissue samples according to Study plan were taken for histopathological examination.
Positive control:
No
Observations and examinations performed and frequency:
All animals were checked daily for clinical signs. Individual body weight and food consumption were recorded weekly.Before the first administration (day -1) and at the end of the study (day 90) blood and urine samples were taken from all animals for hematology, clinical chemistry and urinalysis examinations. Ophthalmoscopy was also performed initially and termininally on all animals. At the end of the study (day 90), gross necropsy of all rats was performed and organ and tissue samples according to study plan were taken for histopathological examinations.
Sacrifice and pathology:
At the end of the study (day 90), gross necropsy of all rats was performed and organ and tissue samples according to study plan were taken for histopathological examinations.
Other examinations:
Clinical observations, body weight, food consumption, ophthalmoscopy, hematology, clinical chemistry, urinalysis, pathology (organ weights, macroscopy, microscopy)
Statistics:
DRF Study
Data of body weight, food consumption, hematology including bone marrow smears and clinical chemistry as well as gross pathology were not statistically processed in the DRF study. Group mean values and SD values were counted only.
90-Day Subchronic Toxicity Study
Group mean and standard deviations were calculated for body weights, food consumption, clinical pathology (except for urinalysis) values and organ weights (absolute and relative weights). Absolute and relative organ weights for test article treated groups were compared to those of controls (D1, D2 and D3 versus C) using the Student’s t-Test. In addition, body weights, food consumption and clinical pathology values were subjected to analysis of variance (ANOVA) followed by Dunnett’s Test, if applicable; additional statistical analyses (Kruskall-Walis) were performed as required by the data. Statistical evaluation was performed
using Graph Pad Prism software, version 4, validated on September 22, 2009.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Tin sulfide caused a slight increase in food consumption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg. This was not considered as adverse effect.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Tin sulfide caused a slight increase in food consumption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg. This was not considered as adverse effect.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Slight dose dependent decreases in serum Na and Cl, varying within physiological range, were observed. Increased serum glucose concentrations in females dosed at 1000 mg/kg was most probably due increased food consumption and not considered as adverse.
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Description (incidence and severity):
No observations indicating neurotoxicity were noted.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No adverse test item and/or treatment related changes
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No adverse test item and/or treatment related changes
Details on results:
Tin sulfide orally administered to rats for 90 consecutive days caused a slight increase in food consuption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg. These were however not considered as adverse effects. Slight dose dependent decreases in serum Na and Cl, varying within physiological range, were observed. Except for the above mentioned changes, tin sulfide did not cause any negative effect on body weight, food consumption, ophthalmoscopy, hematology and clinical chemistry parameters and organ weights.
Tin sulfide further did not cause any organ weight changes nor gross or histopathological changes in the liver, kidneys, gastrointestinal tract or other organs of survived animals indicative of a toxic effect. Other lesions found in the treated animals were either of spontaneous character or they were not in direct relation with the administration of tin sulfide.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Under the test conditions used, 90 - day administration of the test item tin sulfide to rats was safe and well tolerated up to the dose of 1000 mg/kg bw/day. The NOAEL was defined at 1000mg/kg and the NOEL at 300 mg/kg.
Critical effects observed:
not specified

RESULTS of DRF Study:

All rats survived till their scheduled necropsy. No signs of toxicity were recorded in all administered animals of all tested groups during the observation period. Variability observed in body weight and food consumption were not treatment related and both recorded parameters were not influenced with the test item administration. No treatment-related changes were found in the red blood cells, white blood cells and coagulation parameters. The decrease in APTT values in dose group D1 was probably no treatment related. No treatment related changes were observed during the study in the clinical chemistry and urinalysis parameters monitored. No gross pathology findings were found during necropsy of the animals. In conclusion, 14 days oral administration of tin sulfide at doses of 500 and 1000 mg/kg body weight/day in rats was safe and well tolerated. Based on the obtained results it was proposed to design the 90-day Subchronic Toxicity Study with doses of 100, 300 and 1000 mg/kg body weight/day.

Conclusions:
Tin sulfide showed no effects considered as adverse in a subchronic toxicity study according to OECD guideline 408. The NOAEL was defined at 1000 mg/kg and the NOEL at 300 mg/kg.
Executive summary:

A 90-day study according to OECD guideline 408 with tin sulfide was performed in rats to provide information on the possible health hazards likely to arise from repeated oral exposure over a prolonged period of time covering post-weaning maturation and growth well into adulthood. Three treated groups were administered with doses of 100 mg and 300mg/kg and 1000 mg/kg bw per day. Tin sulfide caused a slight increase in food consumption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg. These were however not considered as adverse effects. Slight dose dependent decreases in serum Na and Cl, varying within physiological range, were observed. Except for the above mentioned changes, tin sulfide did not cause any negative effect on body weight, food consumption, ophthalmoscopy, hematology and clinical chemistry parameters and organ weights. Tin sulfide further did not cause any organ weight changes nor gross or histopathological changes in the liver, kidneys, gastrointestinal tract or other organs of survived animals indicate of a toxic effect.Under the test conditions used, 90-day administration of the test item to rats was safe and well tolerated up to the dose of 1000 mg/kg bw/day. The NOAEL was defined at 1000mg/kg and the NOEL at 300 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline compliant study on tin sulfide

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

A 90-day study according to OECD guideline 408 with tin sulfide was performed in rats to provide information on the possible health hazards likely to arise from repeated oral exposure over a prolonged period of time covering post-weaning maturation and growth well into adulthood. Three treated groups were administered with doses of 100 mg and 300 mg/kg and 1000 mg/kg bw/day. Tin sulfide caused a slight increase in food consumption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg. These were however not considered as adverse effects. Slight dose dependent decreases in serum Na and Cl, varying within physiological range, were observed. Except for the above mentioned changes, tin sulfide did not cause any negative effect on body weight, food consumption, ophthalmoscopy, hematology and clinical chemistry parameters and organ weights. Tin sulfide further did not cause any organ weight changes nor gross or histopathological changes in the liver, kidneys, gastrointestinal tract or other organs of survived animals indicate of a toxic effect.Under the test conditions used, 90-day administration of the test item to rats was safe and well tolerated up to the dose of 1000 mg/kg bw/day. The NOAEL was defined at 1000 mg/kg bw/day and the NOEL at 300 mg/kg bw/day.

Justification for classification or non-classification

According to the results of a subchronic repeated oral dose toxicity study, no classification and labelling is required according to Regulation No (EC) 1272/2008 (CLP) or Directive 67/548/EEC (DSD) criteria.

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