Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

31.74 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):

30

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

952 mg/m³

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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 speices; see justification attached.

AF for intraspecies differences:

5

Justification:

ECHA default factor.

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:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22.5 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):

120

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 700 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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 speices; see justification attached.

AF for intraspecies differences:

5

Justification:

ECHA default factor.

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:

1

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 but no further hazard information necessary as no exposure expected

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 key combined repeated dose and reproductive/developmental screening study was performed with registered 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.

- A 90-day study was not available for the registered substance, however read across data were available from read-across substance in the same subgroup, CAS No. 37294-49-8 (disodium C-isodecyl sulphonatosuccinate). This key study for subchronic toxicity was performed in rats with test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975) at 0.25%, 1.00% and 4.00% in the diet (corresponding to mean calculated test article intake of 188, 750 and 3000 mg act.ingr./kg bw/day). At the highest dose levels, it caused a significant difference in body weight gain, most probably related to an effect by the compound during absorption from the gastro-intestinal tract. There was one mortality in the high dosed females. Haematology and serum analysis also indicated toxicity at the high dose, whereas at the medium dose, only some organ-to-body weight changes were observed (e.g. liver weight increases in both sexes). Other organ-to-body weight changes were also observed at the high dose group (e.g. slightly decreased gonad weights in males; decreased gonad weight in females); increased relative kidney weights were observed in all female dose groups. Chronic renal disease (mild) was observed in 1/20 males and 6/20 females of the high dose groups. The high dose was considered to be toxic, whereas the changes of the medium dose may be considered adaptive. Therefore 1% (750 mg/kg bw/day) may be considered as NOAEL and 0.25% (174 mg/kg bw/day) may be considered as NOEL.

- For risk assessment, the lowest NOAEL of 60 mg/kg bw with registered substance tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS. This approach was considered conservative, as the NOAEL with read across substance in subchronic study with dietary administration was much higher. Further justification of assessment factors is explained in the DNEL justification document attached to the endpoint summary.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.83 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):

60

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

470 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key oral OECD 422 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:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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:

10

Justification:

ECHA default factor.

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:

1

Justification:

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

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.25 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):

240

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2 700 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

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

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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 speices; see justification attached.

AF for intraspecies differences:

10

Justification:

ECHA default factor.

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:

1

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 but no further hazard information necessary as no exposure expected

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:

0.25 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):

240

Dose descriptor starting point:

NOAEL

Value:

60 mg/kg bw/day

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:

Different doses were tested, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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:

10

Justification:

ECHA default factor.

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:

1

Justification:

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

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 key combined repeated dose and reproductive/developmental screening study was performed with registered 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.

- A 90-day study was not available for the registered substance, however read across data were available from read-across substance in the same subgroup, CAS No. 37294-49-8 (disodium C-isodecyl sulphonatosuccinate). This key study for subchronic toxicity was performed in rats with test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975) at 0.25%, 1.00% and 4.00% in the diet (corresponding to mean calculated test article intake of 188, 750 and 3000 mg act.ingr./kg bw/day). At the highest dose levels, it caused a significant difference in body weight gain, most probably related to an effect by the compound during absorption from the gastro-intestinal tract. There was one mortality in the high dosed females. Haematology and serum analysis also indicated toxicity at the high dose, whereas at the medium dose, only some organ-to-body weight changes were observed (e.g. liver weight increases in both sexes). Other organ-to-body weight changes were also observed at the high dose group (e.g. slightly decreased gonad weights in males; decreased gonad weight in females); increased relative kidney weights were observed in all female dose groups. Chronic renal disease (mild) was observed in 1/20 males and 6/20 females of the high dose groups. The high dose was considered to be toxic, whereas the changes of the medium dose may be considered adaptive. Therefore 1% (750 mg/kg bw/day) may be considered as NOAEL and 0.25% (174 mg/kg bw/day) may be considered as NOEL.

- For risk assessment, the lowest NOAEL of 60 mg/kg bw with registered substance tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS. This approach was considered conservative, as the NOAEL with read across substance in subchronic study with dietary administration was much higher. Further justification of assessment factors is explained in the DNEL justification document attached to the endpoint summary.