Tin disulphide

Endpoint summary

Description of key information

In a dose escalation inhalation toxicity study with Tin disulfide, Wistar rats were exposed to a fixed target aerosol concentration of 5.0 mg/L for 1.5 hour, 3 hours and 6 hours for 3 days (phase 1). Based on the results, Wistar rats were exposed to 1.0 mg/L and 5 mg/L for 3 and 6 hours per day for a period of 5 days (Phase 2). In Phase 1 the MMAD was 2.90 micron (GSD: 1.95); in Phase 2 the MMAD ranged from 2.53-2.68 micron (GSD: 1.92-2.02).  Exposure to Tin disulphide did not cause any clinical signs or any treatment related effect in the body weight, necropsy, clinical pathology or histopathology. One female (1/3) died on day 2, without a clear cause of death, the relationship with chemical toxicity of the test item is equivocal. Lung weights appeared to be increased and residual test item (often in macrophages) was observed in the lungs and associated lymphatic system and in the upper airways. The MTC and the NOAEC are considered to be the High dose (5.0 mg/L) in this short term study.

 

In a 28-day dose range finding inhalation toxicity study with Tin disulfide, Wistar rats were exposed to the test atmosphere at target concentrations of 0.2, 1.0 and 5.0 mg/L.  The MMAD varied from 2.28 -2.8 µm  (GSD 1.92-2.10).  The absolute and relative (to body weights and brain weights) lung weights were significantly higher in test item exposed rats, with a dose dependent trend in both sexes. Decreased absolute and relative thymus weights were measured in High Dose males and decreased spleen weight (relative to BW) was observed in High Dose females. Test item-related yellow discolouration of all lobes of lungs and mediastinal lymph nodes was observed in all test item exposed animals. The enlargement of these organs was also observed. In the lavage fluid following bronchoalveolar lavage, the level of LDH showed statistically significant, dose dependent increase, total cell number also increased statistically significantly  In histopathology, test item-related changes were seen at all concentrations, the accumulation of the test item in the lungs, in the mediastinal lymph nodes and the degeneration of the olfactory epithelium in the rostral part of the nasal cavity was observed. As these changes might be expressed as more severe lung effects in the 90-day study (due to a longer study duration and a probably slow clearance), lower dose levels for the 90-day study are recommended based on the results of this DRF study.

 

In a key 90-day inhalation toxicity study in rats with Tin disulfide, 10 male and  10 female Wistar Hannover rats Crl:WI(Han) in each main group were treated by a 6 hour nose-only exposure to filtered air or three fixed aerosol concentrations (target concentrations of 0.02, 0.2 and 1.0 mg/L, as the Low, Mid and High Dose Concentration, respectively) for 5 days/week. The MMAD varied from 2.01-3.91 µm (GSD 2.01-2.05).  The main animals were sacrificed on the day following the last exposure on Day 91 (histopathology evaluation and BALF analysis were performed). Additionally, 5 females per group were treated and allowed to recover for 6 weeks and sacrificed on Day 132 (histopathology evaluation and BALF analysis were performed) and 15 males per group were treated and allowed to recover and sacrificed on Day 91, Day 132 (6-week recovery) and Day 174 (approximately 3-month recovery) for histopathology and/or lung burden evaluation. There were no significant changes outside the respiratory system. All the changes observed in the respiratory tract or associated lymph system were considered to be related to the presence of test item or normal physiological responses to the presence of dust. However, the High dose level involved a lung burden that was higher than the clearance systems could process, with little or no recovery of lung weights or of histological changes (although there was no evidence of any degeneration, inflammatory changes or progression after 13 weeks of recovery). In the Mid and Low dose groups, there was good evidence of progress towards a recovery. In conclusion, under the conditions of this study, the No Observed Effect Concentration (NOEC) for systemic effects was the High dose level of 1 mg/L. Local changes in the respiratory tract were seen in all groups treated with test item. Recovery was significant in the Low and Mid dose groups, hence the No Adverse Observed Effect Concentration (NOAEC, based on local effects) for the study was the Mid dose (0.2 mg/L).

 

A 90-day repeated dose oral gavage toxicity study in rats daily dosed with Tin sulfide at doses of 100, 300 and  1000 mg/kg bw per day resulted in a slight increase in food consumption, associated with slight increases in body weight and serum glucose concentrations in females dosed at 1000 mg/kg, as well as slight decreases in serum Na and Cl. Except for the above mentioned changes, Tin sulfide did not cause any other changes. Therefore Tin sulfide was considered safe and well tolerated up to the dose of 1000 mg/kg bw/day. The NOAEL was defined at 1000 mg/kg and the NOEL at 300 mg/kg.

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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:

High (Klimisch 1)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 000 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Klimisch 1

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

200 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Klimisch 1

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 supporting dose escalation inhalation toxicity study was conducted with Tin disulfide in Wistar rats. In Phase 1, single male and female Wistar rats Crl:WI(Han) were exposed nose-only to fixed target aerosol concentration of 5.0 mg/L for 1.5 hour, 3 hours and 6 hours in the first day. In Phase 1 the MMAD was 2.90 micron (GSD: 1.95).  As no clinical signs were observed, the exposure was continued at this concentration for two more consecutive days. In Phase 1, mortality, clinical observations and body weight was measured. The objective of this phase was to find the maximum tolerated concentration (MTC) and to determine suitable concentrations for Phase 2.  The mean achieved atmospheric concentration was 5.11 mg/L. The MMAD ranged from 2.53-2.68 micron (GSD: 1.92-2.02)No mortality occurred in Phase 1. No adverse clinical signs were observed in animals in Phase 1. Fur staining by test item (nose/head/whole body) was noted in the test item-treated groups. Body weight and body weight gain was normal in all animals. There were no treatment related macroscopic observation and no effect on the respiratory tract.

Based on the results of Phase 1, two atmosphere concentrations, 1.0 and 5.0 mg/L, were set up in two inhalation systems and three male and three female Wistar rats Crl:WI (Han) were exposed to the test atmosphere in each tower for 3 and 6 hours per day for a period of 5 days. All animals including controls were terminated on the day following the last exposure on Day 6.

In Phase 2, the exposure to Tin disulphide did not cause any clinical signs or any treatment related effect in the body weight, necropsy, clinical pathology or histopathology. One female (1/3) died on day 2, without a clear cause of death, the relationship with chemical toxicity of the test item is equivocal. Lung weights appeared to be increased and residual test item (often in macrophages) was observed in the lungs and associated lymphatic system and in the upper airways. The MTC and the NOAEC are considered to be the High dose (5.0 mg/L) in this short term study. Dose setting for the main study will need to account for the lung burden and expected clearance rates.  Based on the results of the DRF study, the dose levels for the subsequent 28-day study should be 5.0, 1 and 0.2 mg/L.

 

A supporting 28-day dose range finding inhalation toxicity study was conducted with Tin disulfide in Wistar rats (5/sex/group) by a 6 hour nose-only exposure to filtered air or three fixed aerosol concentrations (target concentrations: 0.2, 1.0 and 5.0 mg/L) for 5 days/week (or 7 days in the last week) for 4 weeks to determine the dose levels for a subsequent 90-day subchronic inhalation study and to provide information to assist in setting recovery periods for the main study. The animals were sacrificed on the day following the last exposure in Week 4. The test item was generated using a rotating brush generator connected to pressurized air supply. The atmosphere concentrations of 0.20 mg/L, 1.02 mg/L and 5.05 mg/L were achieved in the respective groups. The treatment was performed in 4 inhalation towers parallel, one tower for each treatment groups and an additional tower for the filtered air control group. The MMAD varied from 2.28 -2.8 µm  (GSD 1.92-2.10).

The exposure to the test item Tin Disulphide to Hannover Wistar rats for 4 weeks for 6 hours/day on a 5 day per week basis at dose levels 0.2 to 5.0 mg/L did not cause any clinical signs. There were no statistically significant adverse effects on body weight, food consumption, neurological assessment or clinical pathology. No systemic toxicity was indicated at any dose level. Treatment-related organ weight effects were observed in the lungs both in the male and female Low, Mid and High dose groups and in thymus weights in the male High dose group and in the spleen weight of the female Mid and High dose groups. In gross pathology, test item-related yellow discoloration (due to the colour of the test item) in every dosed animals and enlargement of the lungs were observed in Low, Mid and High dose males and in Mid and High dose females. The mediastinal lymph nodes showed yellow discoloration in all dosed animals (correlated with the colour of the test item) and were enlarged in males and females of all dosed groups. Microscopically, pigment/dust were present in the alveolar/bronchiolar lumen and in the broncho-alveolar lymphoid tissue of the lungs in all dosed animals were observed. In the mediastinal lymph node, pigmented macrophages and increased cellularity (lymphocytes) were present in all dosed groups. In the nasal cavity, degeneration of the olfactory epithelium in every dosed groups of males and females and erosion/ulceration of the olfactory epithelium was detected in High dose males and females. The LDH level was dose dependently increased in the BAL fluid, statistically significant increase in total cell number was also observed (with dose dependence in females). In histopathology, test item-related changes were seen at 0.2, 1.0, 5.0 mg/L concentration, the accumulation of the test item in the lungs, in the mediastinal lymph nodes and the degeneration of the olfactory epithelium in the rostral part of the nasal cavity was observed. As these changes might be expressed as more severe lung effects in the 90-day study (due to a longer study duration and a probably slow clearance), lower dose levels for the 90-day study are recommended based on the results of this DRF study.

 

A key 90-day repeated dose toxicity inhalation study in rats with Tin disulfide was available (Krajcs, 2022). Additional subgroups were used to evaluate the recovery of the animals and to investigate the clearance rate of the Test Item from the lung. Ten male and 10 female Wistar Hannover rats Crl:WI(Han) in each main group were treated by a 6 hour nose-only exposure to filtered air or three fixed aerosol concentrations (target concentrations of 0.02, 0.2 and 1.0 mg/L, as the Low, Mid and High Dose Concentration, respectively) for 5 days/week. The MMAD varied from 2.01-3.91 µm ± 2.13 (GSD 2.01-2.05). The main animals were sacrificed on the day following the last exposure on Day 91 (histopathology evaluation and BALF analysis were performed). Additionally, 5 females per group were treated and allowed to recover for 6 weeks and sacrificed on Day 132 (histopathology evaluation and BALF analysis were performed) and 15 males per group were treated and allowed to recover and sacrificed on Day 91, Day 132 (6-week recovery) and Day 174 (approximately 3-month recovery) for histopathology and/or lung burden evaluation. Start of the exposure for all 4 groups was Day 1. The treatment was performed in 4 parallel inhalation towers, one tower for each treatment or control group.

No mortality occurred during the study. The exposure to the test item Tin disulphide to Hannover Wistar rats for 90 days at dose levels was measured at 0.020 mg/L (Low Dose), 0.21 mg/L (Mid Dose) and 1.03 mg/L (High Dose).The exposure did not cause any test item-related adverse clinical signs or change in body weight/weight gain or food consumption. The functional observation battery (FOB) and neuromuscular observations showed no changes in animal behaviour, general physical condition, grip strength, motor activity, or in the reactions to different type of stimuli in the control or test groups. No treatment-related changes were noted on ophthalmoscopy examination. No test-item related changes in haematology, clinical chemistry or urine parameters were noted. There were no test item-related observations in the oestrus cycle. All treated groups showed respiratory related changes due to test item. But there were no significant test item-related macroscopic or microscopic changes in any organs or tissues outside the respiratory system. Results of lung burden determination showed ~2.5, ~14 and ~30 mg test item per gram of lung at 91 days. A continuous clearance was observed from the lung over time in all dose groups, however clearance at the High dose was slow and limited. At the 91 day necropsy, yellow discoloration (test item) and enlargement of the lungs and mediastinal lymph node were seen with a dose relationship in all dosed groups, as were lung weights. In the BAL, a dose-dependent increase of LDH and albumin values, and live and dead cell numbers were seen in both males and females after 91 days. At histology, there was a massive, dose-related presence of brown pigment (test item) in the alveolar/bronchiolar lumen, bronchio-alveolar macrophages and in the regional lymphoid tissues. Despite the amount of test item present, there were no evident toxic effects (no degenerative or inflammatory changes). Pigmented macrophages were also seen in nasal mucosa and trachea subserosa, without degenerative or inflammatory changes. An exacerbation of eosinophil droplets in the respiratory epithelium of the nasal cavity was correlated with treatment (dust), but is not considered to be a degenerative change or a specific toxic effect of the test item. All changes seen in the respiratory tract and related tissues were considered to be a response to inhaled dust. Test concentrations higher than 1 mg/L would be above the maximum tolerated dose.

There were no significant changes outside the respiratory system. All the changes observed in the respiratory tract or associated lymph system were considered to be related to the presence of test item or normal physiological responses to the presence of dust. However, the High dose level involved a lung burden that was higher than the clearance systems could process, with little or no recovery of lung weights or of histological changes (although there was no evidence of any degeneration, inflammatory changes or progression after 13 weeks of recovery). In the Mid and Low dose groups, there was good evidence of progress towards a recovery. In conclusion, under the conditions of this study, the No Observed Effect Concentration (NOEC) for systemic effects was the High dose level of 1 mg/L. Local changes in the respiratory tract were seen in all groups treated with test item. Recovery was significant in the Low and Mid dose groups, hence the No Adverse Observed Effect Concentration (NOAEC, based on local effects) for the study was the Mid dose (0.2 mg/L).

 

A key 90-day repeated dose toxicity oral gavage study in rats daily dosed with Tin sulfide was available (Slais, 2010). Four groups of rats (male/female Wistar rats) were daily administered with the test item suspension in 0.5% Carboxymethylcellulose (CMC) orally by gavage for 90 days. Three treated groups were administered with doses of 100, 300 and 1000 mg/kg bw per day. Dosing resulted in 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 indicative of a toxic effect. 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 1000 mg/kg and the NOEL at 300 mg/kg.

Based on the similar structural and physicochemical properties of Tin disulfide (target chemical) and tin sulfide (source chemical), as well as the comparable and low toxicological profiles for acute toxicity, local tolerance and genetic toxicity, the results of the 90-day repeated dose toxicity study with Tin sulfide are considered valid as read-across to Tin disulfide. Therefore no new study has been conducted and current study is considered key study for repeated dose toxicity of Tin disulfide. Further argumentation is provided in a separate document on read-across argumentation under Section 13.

Argumentation on the adequacy of read across between target and source chemical has been documented in a separate document (see Section 13).

Justification for classification or non-classification

No classification and labelling is needed for repeated dose toxicity for Tin disulfide according to CLP regulation (No. 1272/2008 of 16 December 2008).