Butanedioic acid, sulfo-, C-C16-18-alkyl esters, disodium salt

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA and ERASM factors

Overall assessment factor (AF):

10.2

Modified dose descriptor starting point:

NOAEC

Value:

317 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key OECD 422 oral toxicity study with a read-across substance is available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

3.4

Justification:

ERASM extrapolation factor from subacute (starting point) to chronic (end point); see also 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:

ERASM default factor for other interspecies differences.

AF for intraspecies differences:

3

Justification:

ERASM default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No further assessment factors are required.

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:

66.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA and ERASM factors

Overall assessment factor (AF):

40.8

Modified dose descriptor starting point:

NOAEL

Value:

2 700 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A key oral OECD 422 toxicity study is available with a read-across substance; there was no repeated-dose dermal toxicity study.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

3.4

Justification:

ERASM extrapolation factor from subacute (starting point) to chronic (end point); see also justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

ERASM default factor for other interspecies differences.

AF for intraspecies differences:

3

Justification:

ERASM default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No further assessment factors are required.

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:

medium hazard (no threshold derived)

Additional information - workers

DNELs were based upon following source information:

- A combined repeated dose and reproductive/developmental screening study was performed with a read-across substance according to OECD guideline 422 (Hansen, 2013). The test item was a solid formulation (containing >93% active ingredient) which was administered as a watery solution orally by gavage to rats at dose levels of 60, 120 and 300 mg act. ingr./kg bw/day for at least 28 days in male rats up to 54 days in female rats. One of 10 male and one of 10 female animals at 300 mg/kg b.w./day died prematurely on test day 33 or on gestation day 9. Slight to moderate salivation was noted in a few male and female animals at 120 mg/kg bw/ day; at 300 mg/kg bw/day, piloerection and a slight to extreme salivation was noted for several to all male and female animals on several days. Reduced body weight was noted for the male animals at 120 mg/kg bw/day and for both sexes at 300 mg/kg bw/day. Increases in ALAT, aP and ASAT and decreases in globulin, cholesterol, chloride and potassium concentrations were noted for the male and/or female animals of the intermediate and/or the high dose group (120 and/or 300 mg/kg bw/day).Several organ weights were seen in males and females dosed at120 and 300 mg/kg bw/day, most remarkably for the thymus and liver weights of the animals of the high dose group. Macroscopic inspection revealed changes in the stomach of male animals dosed at 300 mg/kg bw/day and female animals dosed at 120 and 300 mg/kg bw/day. Histopathological examination revealed changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals dosed at 300 mg/kg bw/day. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable.

NOAEL-levels were as follows: 60 mg/kg bw for paternal/maternal toxicity, 120 mg/kg bw for reproductive toxicity (based on reduced gestation index, birth index, live birth index and increased post implantation loss at the high dose levels) and 120 mg/kg bw for developmental toxicity (based on a reduced viability index at the high dose levels).The reproductive and developmental changes were seen at paternal/maternal toxic doses, and were considered to be secondary to that toxicity.

- For risk assessment, the NOAEL of 60 mg/kg bw with the read-across substance C12-18 sulfosuccinate tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS.

Only systemic long term exposure values for worker and general population were calculated, because no concrete values (like NOAEL, LOAEL etc) are available from acute or irritation studies. The study design of the test conducted assessing the acute and local toxicity does not allow in general the derivation of local or acute DNEL, as most of the tests were, for example, conducted as limit tests due to animal welfare. Therefore a qualitative riskassessment for irritiation is performed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.21 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA and ERASM factors

Overall assessment factor (AF):

17

Modified dose descriptor starting point:

NOAEC

Value:

157 mg/m³

Explanation for the modification of the dose descriptor starting point:

A key oral OECD 422 toxicity study is available for a rea-across substance; there was no repeated-dose inhalation toxicity study.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

3.4

Justification:

ERASM extrapolation factor from subacute (starting point) to chronic (end point); see also 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:

ERASM default factor for other interspecies differences.

AF for intraspecies differences:

5

Justification:

ERASM default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No further assessment factors are required.

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:

39.7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA and ERASM factors

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Value:

2 700 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A key oral OECD 422 toxicity study is available for a read-across substance; there was no repeated-dose dermal toxicity study.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

3.4

Justification:

ERASM extrapolation factor from subacute (starting point) to chronic (end point); see also justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

ERASM default factor for other interspecies differences.

AF for intraspecies differences:

5

Justification:

ERASM default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No further assessment factors are required.

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:

0.88 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA and ERASM factors

Overall assessment factor (AF):

68

Modified dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

3.4

Justification:

ERASM extrapolation factor from subacute (starting point) to chronic (end point); see also justification attached.

AF for interspecies differences (allometric scaling):

4

Justification:

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

AF for other interspecies differences:

1

Justification:

ERASM default factor for other interspecies differences.

AF for intraspecies differences:

5

Justification:

ERASM default factor for intraspecies differences.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

DNELs were based upon following source information:

- A combined repeated dose and reproductive/developmental screening study was performed with a read-across substance according to OECD guideline 422 (Hansen, 2013). The test item was a solid formulation (containing >93% active ingredient) which was administered as a watery solution orally by gavage to rats at dose levels of 60, 120 and 300 mg act. ingr./kg bw/day for at least 28 days in male rats up to 54 days in female rats. One of 10 male and one of 10 female animals at300 mg/kg b.w./day died prematurely on test day 33 or on gestation day 9. Slight to moderate salivation was noted in a few male and female animals at 120 mg/kg bw/ day; at 300 mg/kg bw/day, piloerection and a slight to extreme salivation was noted for several to all male and female animals on several days. Reduced body weight was noted for the male animals at 120 mg/kg bw/day and for both sexes at 300 mg/kg bw/day. Increases in ALAT, aP and ASAT and decreases in globulin, cholesterol, chloride and potassium concentrations were noted for the male and/or female animals of the intermediate and/or the high dose group (120 and/or 300 mg/kg bw/day).Several organ weights were seen in males and females dosed at120 and 300 mg/kg bw/day, most remarkably for the thymus and liver weights of the animals of the high dose group. Macroscopic inspection revealed changes in the stomach of male animals dosed at 300 mg/kg bw/day and female animals dosed at 120 and 300 mg/kg bw/day. Histopathological examination revealed changes in the liver (hepatocellular hypertrophy and macrovesicular vacuolation) and the non-glandular stomach (squamous cell hyperplasia) of male and female animals dosed at 300 mg/kg bw/day. These latter changes are considered to be related to a local activity of the test item. As humans lack a forestomach, the relevance of these changes for humans is questionable.

NOAEL-levels were as follows: 60 mg/kg bw for paternal/maternal toxicity, 120 mg/kg bw for reproductive toxicity (based on reduced gestation index, birth index, live birth index and increased post implantation loss at the high dose levels) and 120 mg/kg bw for developmental toxicity (based on a reduced viability index at the high dose levels).The reproductive and developmental changes were seen at paternal/maternal toxic doses, and were considered to be secondary to that toxicity.

For risk assessment, the NOAEL of 60 mg/kg bw with the read-across substance tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS.

Only systemic long term exposure values for worker and general population were calculated, because no concrete values (like NOAEL, LOAEL etc) are available from acute or irritation studies. The study design of the test conducted assessing the acute and local toxicity does not allow in general the derivation of local or acute DNEL, as most of the tests were, for example, conducted as limit tests due to animal welfare. Therefore a qualitative riskassessment for irritiation is performed.