Dipotassium disulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

3 006 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 886 mg/kg was derived from a 13-week subchronic oral toxicity study with ammonium sulphate in F344 rats. This study was selected over a chronic bioassay in which a slight increase was observed in kidney weights and chronic progressive nephropathy (in male rats without clear dose response) was reported at ammonium sulphate dietary doses of 1.5 and 3%. Chronic nephropathy in male rats is likely a degenerative response of limited relevance for humans, thus the true NOAEL is likely higher than 1.5%. In the 13-week study, diarrhoea was observed in male rats at a dietary level 3%, corresponding to 1792 mg/kg; the NOAEL was 1.5% (886 mg/kg). Although diarrhoea was not observed at any dose in the chronic bioassay, it was considered to be the key effect for deriving a DNEL. No changes in body weights, organ weights, haematological, serum biochemical or histopathological parameters were observed so the 13-week study NOAEL is a conservative estimate of systemic toxicity. Diarrhoea is likely a direct response of the change of isotonicity in intestinal tract contents. Sulphate anion may have reduced osmotic pressure in the intestinal lumen, causing a net water influx, resulting in osmotic diarrhoea. The starting point from the 13-week study was modified for the appropriate dose descriptors, i.e., molecular weight differences between ammonium sulphate and the notified substance (254/132 or 1.92), allometric scaling for rodent to worker respiration (1/0.38 m3/kg bw), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2. As described above, the expected systemic toxicity is likely to be of secondary importance compared to the local effects. Thus, the more conservative inhalation local, long term DNEL for sulphuric acid of 0.13 mg/m3 should be utilized for purposes of risk assessment.

AF for dose response relationship:

1

Justification:

The dose descriptor is a conservative NOAEL from a 13-week dietary exposure study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for differences in duration of exposure:

2

Justification:

The observed adverse outcome in a 13-week dietary exposure study was limited to diarrhoea, an outcome likely associated with osmotic imbalance due to high exposure levels of the notified substance. While diarrhoea was not observed in a chronic bioassay with ammonium sulphate in either male or female F344 rats at the same dose levels, diarrhoea was considered to represent an adverse effect. Data were not available to assess the relationship of the key effect with exposure duration. Accordingly, an assessment factor of 2 is a conservative value for study duration per REACH guidance R8.4.3.2.1.

AF for interspecies differences (allometric scaling):

1

Justification:

Since the conversion of the starting point by the respiratory rate scaling factor between rats and humans was utilized (i.e., 1/0.38 m3/kg), no further assessment factor for allometric scaling is necessary for oral to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.

AF for other interspecies differences:

1

Justification:

No overt systemic toxicity was observed from clinical chemical, body or organ weight, or pathological endpoints in the key study. Diahhrea is likely a direct response of the change in isotonicity of intestinal tract contents. Unabsorbed or excessive sulphate anion may reduce the osmotic pressure in the intestinal lumen, causing a net water flow into the lumen, resulting in osmotic diarrhea. This is likely a local effect, associated with high local concentrations of sulphate anion in the luminal contents. Accordingly, an assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for intraspecies differences:

5

Justification:

A default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1; data were not located to support a different value from the default.

AF for the quality of the whole database:

1

Justification:

A robust database exists for the substance. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

3 006 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 886 mg/kg was derived from a 13-week subchronic oral toxicity study with ammonium sulphate in F344 rats. This study was selected over a chronic bioassay in which a slight increase was observed in kidney weights and chronic progressive nephropathy (in male rats without clear dose response) was reported at ammonium sulphate dietary doses of 1.5 and 3%. Chronic nephropathy in male rats is likely a degenerative response of limited relevance for humans, thus the true NOAEL is likely higher than 1.5%. In the 13-week study, diarrhoea was observed in male rats at a dietary level 3%, corresponding to 1792 mg/kg; the NOAEL was 1.5% (886 mg/kg). Although diarrhoea was not observed at any dose in the chronic bioassay, it was considered to be the key effect for deriving a DNEL. No changes in body weights, organ weights, haematological, serum biochemical or histopathological parameters were observed so the 13-week study NOAEL is a conservative estimate of systemic toxicity. Diarrhoea is likely a direct response of the change of isotonicity in intestinal tract contents. Sulphate anion may have reduced osmotic pressure in the intestinal lumen, causing a net water influx, resulting in osmotic diarrhoea. The starting point from the 13-week study was modified for the appropriate dose descriptors, i.e., molecular weight differences between ammonium sulphate and the notified substance (254/132 or 1.92), allometric scaling for rodent to worker respiration (1/0.38 m3/kg bw), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2. As described above, the expected systemic toxicity is likely to be of secondary importance compared to the local effects. Thus, the more conservative inhalation local, long term DNEL for sulphuric acid of 0.13 mg/m3 should be utilized for purposes of risk assessment.

AF for dose response relationship:

1

Justification:

The dose descriptor is a conservative NOAEL from a 13-week dietary exposure study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for interspecies differences (allometric scaling):

1

Justification:

Since the conversion of the starting point by the respiratory rate scaling factor between rats and humans was utilized (i.e., 1/0.38 m3/kg), no further assessment factor for allometric scaling is necessary for oral to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.

AF for other interspecies differences:

1

Justification:

No overt systemic toxicity was observed from clinical chemical, body or organ weight, or pathological endpoints in the key study. Diahhrea is likely a direct response of the change in isotonicity of intestinal tract contents. Unabsorbed or excessive sulphate anion may reduce the osmotic pressure in the intestinal lumen, causing a net water flow into the lumen, resulting in osmotic diarrhea. This is likely a local effect, associated with high local concentrations of sulphate anion in the luminal contents. Accordingly, an assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for intraspecies differences:

5

Justification:

A default factor of 5 for workers is appropriate according to REACH guidance in R.8.4.3.1; data were not located to support a different value from the default.

AF for the quality of the whole database:

1

Justification:

A robust database exists for the substance . An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for remaining uncertainties:

2

Justification:

The observed adverse outcome in a 13-week dietary exposure study was limited to diarrhoea, an outcome likely associated with osmotic imbalance due to high exposure levels of the notified substance. While diarrhoea was not observed in a chronic bioassay with ammonium sulphate in either male or female F344 rats at the same dose levels, diarrhoea was considered to represent an adverse effect. Data were not available to assess the relationship of the key effect with exposure duration. Accordingly, an assessment factor of 2 is a conservative value for study duration per REACH guidance R8.4.3.2.1.

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.065 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

1 482 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 886 mg/kg was derived from a 13-week subchronic oral toxicity study with ammonium sulphate in F344 rats. This study was selected over a chronic bioassay in which a slight increase was observed in kidney weights and chronic progressive nephropathy (in male rats without clear dose response) was reported at ammonium sulphate dietary doses of 1.5 and 3%. Chronic nephropathy in male rats is likely a degenerative response of limited relevance for humans, thus the true NOAEL is likely higher than 1.5%. In the 13-week study, diarrhoea was observed in male rats at a dietary level 3%, corresponding to 1792 mg/kg; the NOAEL was 1.5% (886 mg/kg). Although diarrhoea was not observed at any dose in the chronic bioassay, it was considered to be the key effect for deriving a DNEL. No changes in body weights, organ weights, haematological, serum biochemical or histopathological parameters were observed so the 13-week study NOAEL is a conservative estimate of systemic toxicity. Diarrhoea is likely a direct response of the change of isotonicity in intestinal tract contents. Sulphate anion may have reduced osmotic pressure in the intestinal lumen, causing a net water influx, resulting in osmotic diarrhoea. The starting point from the 13-week study was modified for the appropriate dose descriptors, i.e., molecular weight differences between ammonium sulphate and the notified substance (254/132 or 1.92), allometric scaling for rodent to general population respiration (1/1.15 m3/kg bw), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2. As described above, the expected systemic toxicity is likely to be of secondary importance compared to the local effects. Thus, the more conservative inhalation local, long term DNEL for sulphuric acid of 0.13 mg/m3 should be utilized for purposes of risk assessment.

AF for dose response relationship:

1

Justification:

The dose descriptor is a conservative NOAEL from a 13-week dietary exposure study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for differences in duration of exposure:

2

Justification:

The observed adverse outcome in a 13-week dietary exposure study was limited to diarrhoea, an outcome likely associated with osmotic imbalance due to high exposure levels of the notified substance. While diarrhoea was not observed in a chronic bioassay with ammonium sulphate in either male or female F344 rats at the same dose levels, diarrhoea was considered to represent an adverse effect. Data were not available to assess the relationship of the key effect with exposure duration. Accordingly, an assessment factor of 2 is a conservative value for study duration per REACH guidance R8.4.3.2.1.

AF for interspecies differences (allometric scaling):

1

Justification:

Since the conversion of the starting point by the respiratory rate scaling factor between rats and humans was utilized (i.e., 1/1.15 m3/kg), no further assessment factor for allometric scaling is necessary for oral to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.

AF for other interspecies differences:

1

Justification:

No overt systemic toxicity was observed from clinical chemical, body or organ weight, or pathological endpoints in the key study. Diarrhoea is likely a direct response of the change in isotonicity of intestinal tract contents. Unabsorbed or excessive sulphate anion may reduce the osmotic pressure in the intestinal lumen, causing a net water flow into the lumen, resulting in osmotic diarrhoea. This is likely a local effect, associated with high local concentrations of sulphate anion in the luminal contents. Accordingly, an assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for intraspecies differences:

10

Justification:

A default factor of 10 is appropriate for the general population according to REACH guidance in R.8.4.3.1; data were not located to support a different value from the default.

AF for the quality of the whole database:

1

Justification:

A robust database exists for the substance . An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 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):

20

DNEL extrapolated from long term DNEL

Modified dose descriptor starting point:

NOAEC

Value:

1 482 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 886 mg/kg was derived from a 13-week subchronic oral toxicity study with ammonium sulphate in F344 rats. This study was selected over a chronic bioassay in which a slight increase was observed in kidney weights and chronic progressive nephropathy (in male rats without clear dose response) was reported at ammonium sulphate dietary doses of 1.5 and 3%. Chronic nephropathy in male rats is likely a degenerative response of limited relevance for humans, thus the true NOAEL is likely higher than 1.5%. In the 13-week study, diarrhoea was observed in male rats at a dietary level 3%, corresponding to 1792 mg/kg; the NOAEL was 1.5% (886 mg/kg). Although diarrhoea was not observed at any dose in the chronic bioassay, it was considered to be the key effect for deriving a DNEL. No changes in body weights, organ weights, haematological, serum biochemical or histopathological parameters were observed so the 13-week study NOAEL is a conservative estimate of systemic toxicity. Diarrhoea is likely a direct response of the change of isotonicity in intestinal tract contents. Sulphate anion may have reduced osmotic pressure in the intestinal lumen, causing a net water influx, resulting in osmotic diarrhoea. The starting point from the 13-week study was modified for the appropriate dose descriptors, i.e., molecular weight differences between ammonium sulphate and the notified substance (254/132 or 1.92), allometric scaling for rodent to general population respiration (1/1.15 m3/kg bw), and normal human to worker respiratory volume correction for light activity (6.7 m3/10 m3) per REACH guidance R.8.4.2. As described above, the expected systemic toxicity is likely to be of secondary importance compared to the local effects. Thus, the more conservative inhalation local, long term DNEL for sulphuric acid of 0.13 mg/m3 should be utilized for purposes of risk assessment.

AF for dose response relationship:

1

Justification:

The dose descriptor is a conservative NOAEL from a 13-week dietary exposure study in rats. An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for interspecies differences (allometric scaling):

1

Justification:

Since the conversion of the starting point by the respiratory rate scaling factor between rats and humans was utilized (i.e., 1/1.15 m3/kg), no further assessment factor for allometric scaling is necessary for oral to inhalation route of exposure extrapolation per REACH guidance R.8.4.3.1.

AF for other interspecies differences:

1

Justification:

No overt systemic toxicity was observed from clinical chemical, body or organ weight, or pathological endpoints in the key study. Diarrhoea is likely a direct response of the change in isotonicity of intestinal tract contents. Unabsorbed or excessive sulphate anion may reduce the osmotic pressure in the intestinal lumen, causing a net water flow into the lumen, resulting in osmotic diarrhoea. This is likely a local effect, associated with high local concentrations of sulphate anion in the luminal contents. Accordingly, an assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for intraspecies differences:

10

Justification:

A default factor of 10 is appropriate for the general population according to REACH guidance in R.8.4.3.1; data were not located to support a different value from the default.

AF for the quality of the whole database:

1

Justification:

A robust database exists for the substance . An assessment factor of 1 is appropriate per REACH guidance R.8.4.3.1.

AF for remaining uncertainties:

2

Justification:

The observed adverse outcome in a 13-week dietary exposure study was limited to diarrhoea, an outcome likely associated with osmotic imbalance due to high exposure levels of the notified substance. While diarrhoea was not observed in a chronic bioassay with ammonium sulphate in either male or female F344 rats at the same dose levels, diarrhoea was considered to represent an adverse effect. Data were not available to assess the relationship of the key effect with exposure duration. Accordingly, an assessment factor of 2 is a conservative value for study duration per REACH guidance R8.4.3.2.1.

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.065 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.13 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

Acute/short term exposure

Hazard assessment conclusion:

other toxicological threshold

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

other toxicological threshold

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)