Tin disulphide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

1 000 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

503 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 90-day inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90 day study)

AF for interspecies differences (allometric scaling):

1

Justification:

Factor is not applicable to inhalation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

NOAEC

Value:

5 020 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

8 475 mg/m³

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation, but correction for workers respiratory rate and duration of exposure
(see justification & comments)

AF for dose response relationship:

3

Justification:

Safety factor for laboured respiration and respiratory rate increase at limit dose

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applicable to concentrations (ECHA R8 p 26)

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.02 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

other: NOAEC corrected

Value:

101 mg/m³

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90 day study)

AF for interspecies differences (allometric scaling):

1

Justification:

Factor is not applicable to inhalation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

226 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

NOAEC

AF for dose response relationship:

3

Justification:

Safety factor for laboured respiration and respiratory rate increase at limit dose

AF for interspecies differences (allometric scaling):

1

Justification:

Allometiric scaling not applicable to local effects (ECHA R8 p 26)

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral toxicity study available; no repeated dose dermal toxicity study available. In absence
of kinetic data, dermal absorption is considered equal to oral absorption as conservative approach.

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90 day study)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Source information for DNEL derivation:

A key acute inhalation toxicity study was performed in Wistar rats (sighting exposure using 2 males and 2 females, followed by main study 5 males and 5 females) at target dust aerosol concentration of 5 mg/L Tin disulfide (Nagy, 2012). The animals were exposed for 4 hours using a nose-only exposure system, followed by a 14 day observation period. In the main study, the mean achieved atmosphere concentration was 5.02 mg/L. The MMAD was 3.91 µm ± 2.13 (GSD). Significant clinical signs were recorded on the day of exposure including laboured respiration and respiratory rate increase. All animals recovered by Day 2. Normal bodyweight gain was recorded, with the exception of one female where a slight bodyweight loss was recorded during the first three days of the observation period. No gross macroscopic observations were apparent at necropsy. LC50 > 5 mg/L.

 

In a dose escalation inhalation toxcity 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 toxcity 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.

 

A key 90-day inhalation toxicity study in rats with Tin disulfide was available (Krajcs, 2022). 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 key 90- day repeated dose oral gavage toxicity study in rats daily dosed with read-across substance 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 for toxicity was defined at 1000 mg/kg and the NOEL at 300 mg/kg.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

1 000 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

250 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 90-day inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90-day study)

AF for interspecies differences (allometric scaling):

1

Justification:

Factor is not applicable to inhalation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

169 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEC

Value:

5 020 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

12 650 mg/m³

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation, but correction for workers respiratory rate and duration of exposure (see justification & comments)

AF for dose response relationship:

3

Justification:

Safety factor for laboured respiration and respiratory rate increase at limit dose

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applicable to concentrations (ECHA R8 p 26)

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

other: NOAEC corrected

Value:

50 mg/m³

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90-day study)

AF for interspecies differences (allometric scaling):

1

Justification:

Factor is not applicable to inhalation

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

169 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEC

Value:

5 020 mg/m³

AF for dose response relationship:

3

Justification:

Safety factor for laboured respiration and respiratory rate increase at limit dose

AF for interspecies differences (allometric scaling):

1

Justification:

Allometiric scaling not applicable to local effects (ECHA R8 p 26)

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral toxicity study available; no repeated dose dermal toxicity study available. In absence
of kinetic data, dermal absorption is considered equal to oral absorption as conservative approach.       

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90-day study)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

ECHA default

AF for differences in duration of exposure:

2

Justification:

ECHA default (90-day study)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

10

Justification:

ECHA default

AF for the quality of the whole database:

1

Justification:

Based on high reliability study

AF for remaining uncertainties:

1

Justification:

No indication that another factor is needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

Source information for DNEL derivation:

A key acute inhalation toxicity study was performed in Wistar rats (sighting exposure using 2 males and 2 females, followed by main study 5 males and 5 females) at target dust aerosol concentration of 5 mg/L Tin disulfide (Nagy, 2012). The animals were exposed for 4 hours using a nose-only exposure system, followed by a 14 day observation period. In the main study, the mean achieved atmosphere concentration was 5.02 mg/L. The MMAD was 3.91 µm ± 2.13 (GSD). Significant clinical signs were recorded on the day of exposure including laboured respiration and respiratory rate increase. All animals recovered by Day 2. Normal bodyweight gain was recorded, with the exception of one female where a slight bodyweight loss was recorded during the first three days of the observation period. No gross macroscopic observations were apparent at necropsy. LC50 > 5 mg/L.

 

In a dose escalation inhalation toxcity 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 toxcity 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.

 

A key 90-day inhalation toxicity study in rats with Tin disulfide was available (Krajcs, 2022). 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 key 90- day repeated dose oral gavage toxicity study in rats daily dosed with read-across substance 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 for toxicity was defined at 1000 mg/kg and the NOEL at 300 mg/kg.