Sodium 1,2-diisobutoxycarbonylethanesulphonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 889.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA factors in combination with recent scientific literature

Overall assessment factor (AF):

8.4

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

15 868 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key OECD 422 oral toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. See justification attached.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already applied in route-to-route extrapolation.

AF for other interspecies differences:

1

Justification:

No toxicodynamic differences between species; see justification attached.

AF for intraspecies differences:

2.4

Justification:

Refined assessment of population differences; see justification attached.

AF for the quality of the whole database:

1

Justification:

Results were based on key Klimisch 1-2 studies (and possible supporting studies).

AF for remaining uncertainties:

2.5

Justification:

For remaining uncertainties that would result from the above assessment factors.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

267.86 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA factors in combination with recent scientific literature

Overall assessment factor (AF):

33.6

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

9 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 28 -55-day (OECD 422) oral toxicity study available; no repeated dose dermal toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. See justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

No toxicodynamic differences between species; see justification attached.

AF for intraspecies differences:

2.4

Justification:

Refined assessment of population differences; see justification attached.

AF for the quality of the whole database:

1

Justification:

Results were based on key Klimisch 1-2 studies (and possible supporting studies).

AF for remaining uncertainties:

2.5

Justification:

For remaining uncertainties that would result from the above assessment factors.

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 DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

The following source information was taken into account for DNEL calculation:

Subacute toxicity was tested with the registered substance in Wistar rats by oral gavage at 0 (distilled water), 100, 300 and 1000 mg solid/kg bw/day in a supporting 14-day dose range finding and a key combined repeated dose/reproductive toxicity study (OECD No. 422). In the OECD 422 study, the test substance did not result in test item related mortality or adverse clinical signs. One High dose animal died during gestation due to gavage accident. Slightly noisy respiration was observed for two High dose males and three High dose females; however, the finding was transiently or intermittently noted mostly (not longer than consecutive 7 days), and there were no other observations in those animals. This clinical sign might be related to local irritative effect of the test item but was not considered as a test item related adverse effect. The bodyweight, body weight gain, and food consumption of the test item treated groups did not show any test item related effect. At the functional observation battery (FOB) and locomotor activity measurement, there were 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 test item related findings were seen in the clinical pathology parameters. No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. The NOAEL for systemic toxicity of the parental generation was 1000 mg solid/kg bw/day (based on the lack of adverse findings).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14.

There were no test item effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic findings were recorded for F1 pups at necropsy.

No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. Under the experimental conditions of this study and based on the results of thyroid hormone measurement, thyroid weights, nipple retention, anogenital distance and external reproductive organs analysis, histopathology and reproductive performance, there was no evidence for any endocrine effects. Based on the results of this study, the NOAEL for reproductive effects of the parental generation was 1000 mg solid/kg bw/day (based on the lack of adverse findings); the NOAEL for pups’ (F1 generation) development and survival: 1000 mg solid/kg bw/day (based on the lack of adverse findings).

Repeated dose toxicity was further tested in various species, including rats, dogs, rabbits and monkeys. The NOAEL of 750 mg/kg bw/day obtained in the subchronic 90-day dietary toxicity study in rats with registered substance was confirmed to be consistent with data from category members in rats and the NOAEL of 1000 mg/kg bw of Docusate sodium in a 90-day dietary toxicity study. Other data from other species were tested with read-across substance Docusate sodium and were of limited reliability and relevance and therefore not taken into account.

Based on the above information, the NOAEL of 1000 mg/kg bw/day of the OECD 422 study can be considered as most appropriate point of departure for DNEL derivation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

559.01 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA factors in combination with recent scientific literature.

Overall assessment factor (AF):

14

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

7 826 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 28 -55 -day (OECD 422) oral toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. See justification attached.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling is already applied in route-to-route extrapolation.

AF for other interspecies differences:

1

Justification:

No toxicodynamic differences between species; see justification attached.

AF for intraspecies differences:

4

Justification:

Refined assessment of population differences; see justification attached.

AF for the quality of the whole database:

1

Justification:

Results were based on key Klimisch 1-2 studies (and possible supporting studies).

AF for remaining uncertainties:

2.5

Justification:

For remaining uncertainties that would result from the above assessment factors.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

160.71 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA factors in combination with recent scientific literature

Overall assessment factor (AF):

56

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

9 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 28-55-day (OECD 422) oral toxicity study available; no repeated dose dermal toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. See justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

No toxicodynamic differences between species; see justification attached.

AF for intraspecies differences:

4

Justification:

Refined assessment of population differences; see justification attached.

AF for the quality of the whole database:

1

Justification:

Results were based on key Klimisch 1-2 studies (and possible supporting studies).

AF for remaining uncertainties:

2.5

Justification:

For remaining uncertainties that would result from the above assessment factors.

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 DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.86 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA factors in combination with recent scientific literature

Overall assessment factor (AF):

56

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:

Different doses were tested in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. See justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

No toxicodynamic differences between species; see justification attached.

AF for intraspecies differences:

4

Justification:

Refined assessment of population differences; see justification attached.

AF for the quality of the whole database:

1

Justification:

Results were based on key Klimisch 1-2 studies (and possible supporting studies).

AF for remaining uncertainties:

2.5

Justification:

For remaining uncertainties that would result from the above assessment factors.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

The following source information was taken into account for DNEL calculation:

Subacute toxicity was tested with the registered substance in Wistar rats by oral gavage at 0 (distilled water), 100, 300 and 1000 mg solid/kg bw/day in a supporting 14-day dose range finding and a key combined repeated dose/reproductive toxicity study (OECD No. 422). In the OECD 422 study, the test substance did not result in test item related mortality or adverse clinical signs. One High dose animal died during gestation due to gavage accident. Slightly noisy respiration was observed for two High dose males and three High dose females; however, the finding was transiently or intermittently noted mostly (not longer than consecutive 7 days), and there were no other observations in those animals. This clinical sign might be related to local irritative effect of the test item but was not considered as a test item related adverse effect. The bodyweight, body weight gain, and food consumption of the test item treated groups did not show any test item related effect. At the functional observation battery (FOB) and locomotor activity measurement, there were 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 test item related findings were seen in the clinical pathology parameters. No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. The NOAEL for systemic toxicity of the parental generation was 1000 mg solid/kg bw/day (based on the lack of adverse findings).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14.

There were no test item effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic findings were recorded for F1 pups at necropsy.

No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. Under the experimental conditions of this study and based on the results of thyroid hormone measurement, thyroid weights, nipple retention, anogenital distance and external reproductive organs analysis, histopathology and reproductive performance, there was no evidence for any endocrine effects. Based on the results of this study, the NOAEL for reproductive effects of the parental generation was 1000 mg solid/kg bw/day (based on the lack of adverse findings); the NOAEL for pups’ (F1 generation) development and survival: 1000 mg solid/kg bw/day (based on the lack of adverse findings).

Repeated dose toxicity was further tested in various species, including rats, dogs, rabbits and monkeys. The NOAEL of 750 mg/kg bw/day obtained in the subchronic 90-day dietary toxicity study in rats with registered substance was confirmed to be consistent with data from category members in rats and the NOAEL of 1000 mg/kg bw of Docusate sodium in a 90-day dietary toxicity study. Other data from other species were tested with read-across substance Docusate sodium and were of limited reliability and relevance and therefore not taken into account.

Based on the above information, the NOAEL of 1000 mg/kg bw/day of the OECD 422 study can be considered as most appropriate point of departure for DNEL derivation.