Disodium (Z)-4-(9-octadecenylamino)-4-oxo-2(or 3)-sulphonatobutyrate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

93.34 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):

20.4

Modified dose descriptor starting point:

NOAEC

Value:

1 904 mg/m³

Explanation for the modification of the dose descriptor starting point:

Start from subacute oral OECD 422 toxicity study; 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:

3.4

Justification:

Extrapolation from subacute to chronic; 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:

66.18 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):

81.6

Modified dose descriptor starting point:

NOAEL

Value:

5 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Start from subacute oral OECD 422 toxicity study; there was no repeated-dose dermal toxicity study.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

3.4

Justification:

Extrapolation from subacute to chronic; 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 hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNELs were based on following source information:

- Key data for repeated dose toxicity were available from read-across substance 'Butanoic acid, 4-amino-4-oxo-2(or 3)-sulfo-, N-(C16-C18 (even numbered), C18 unsaturated alkyl), disodium salts' in a combination repeated dose/reproduction and developmental toxicity screening study according to OECD TG 422 (Key study; Hansen, 2013a). The test item was administered orally by gavage as a test item containing 25.5% active ingredient to rats at dose levels of 60, 120 or 300 mg act.ingr./kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 37 for the male rats and on lactation day 4 or shortly thereafter for the female rats. One of 10 male and one of 10 female animals both at 120 and 300 mg/kg bw/day died prematurely. At 300 mg/kg bw/day clinical signs in form of salivation, pilo-erection and/or breathing sounds were noted in a few male and female animals for 1 or 2 test days. A statistically significant reduction in body weight was noted temporarily in males dosed at 120 mg/kg bw/day and in both sexes at 300 mg/kg bw/day. Accordingly, food consumption and body weight were statistically significantly reduced in both sexes at 300 mg/kg bw/day. Haematology showed statistically significant changes at 300 mg test item/kg bw/day, including increased MCH and decreased aPTT time (male animals) and increased No. white blood cells and lymphocytes (female animals). Changes in the relative or absolute organ weights of several organs were noted for the male animals dosed at 300 mg test item/kg bw/day, most remarkably for the relative liver weight which increased for almost 20%. The macroscopic and microscopic examinations revealed no test item related changes. NOAEL-levels were as follows: 120 mg/kg bw for paternal/maternal toxicity; 120 mg/kg bw for reproductive toxicity (see Section 7.8.1) and 300 mg/kg bw for developmental toxicity (see Section 7.8.2).

- Subchronic data were also available from read-across substance 'Butanoic acid, 4-amino-4-oxosulfo-, N-tallow alkyl derivs., disodium salts' (CAS No. 68988-69-2) given to albino rats in the diet with test item containing 35% active ingredient at doses of 0.5, 2 and 8 g act.ingr./kg bw/day (Tegeris and Underwood, 1976). Due to mortality at 8 g/kg bw/day, dosing was reduced to 4 g/kg feed/day after 6 weeks. Findings included decreased body weight gain and food intake at all levels and gastro-enteritis / acute nephritis within six weeks at 8.00 g/kg/day. After dose reduction, zonal fatty infiltration in the liver was observed. At the lowest dose level, decreases in body weight (gain) and feed intake were minimal (<10%) and were not considered relevant. Decreased organ weights were observed for heart, liver, kidneys, adrenal an thyroid weight at the medium and high doses. From the data presented in this study a NOAEL of 500 mg/kg bw/day could be considered.

- For risk assessment, the lowest NOAEL of 120 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.

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 risk assessment for irritation is performed.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

27.62 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):

34

Modified dose descriptor starting point:

NOAEC

Value:

939 mg/m³

Explanation for the modification of the dose descriptor starting point:

Start from subacute oral OECD 422 toxicity study; there was no repeated-dose inhalation toxicity study.

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:

3.4

Justification:

Extrapolation from subacute to chronic; 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:

39.71 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):

136

Modified dose descriptor starting point:

NOAEL

Value:

5 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Start from subacute oral OECD 422 toxicity study; there was no repeated-dose dermal toxicity study.

AF for dose response relationship:

1

Justification:

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

AF for differences in duration of exposure:

3.4

Justification:

Extrapolation from subacute to chronic; 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 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 factors in combination with recent scientific literature

Overall assessment factor (AF):

136

Modified dose descriptor starting point:

NOAEL

Value:

120 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:

3.4

Justification:

Extrapolation from subacute to chronic; 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:

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 on following source information:

-Key data for repeated dose toxicity were available from read-across substance 'Butanoic acid, 4-amino-4-oxo-2(or 3)-sulfo-, N-(C16-C18 (even numbered), C18 unsaturated alkyl), disodium salts' in a combination repeated dose/reproduction and developmental toxicity screening study according to OECD TG 422 (Key study; Hansen, 2013a).The test item was administered orally by gavage as a test item containing 25.5% active ingredient to rats at dose levels of 60, 120 or 300 mg act.ingr./kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 37 for the male rats and on lactation day 4 or shortly thereafter for the female rats. One of 10 male and one of 10 female animals both at 120 and 300 mg/kg bw/day died prematurely. At 300 mg/kg bw/day clinical signs in form of salivation, pilo-erection and/or breathing sounds were noted in a few male and female animals for 1 or 2 test days. A statistically significant reduction in body weight was noted temporarily in males dosed at 120 mg/kg bw/day and in both sexes at 300 mg/kg bw/day. Accordingly, food consumption and body weight were statistically significantly reduced in both sexes at 300 mg/kg bw/day. Haematology showed statistically significant changes at 300 mg test item/kg bw/day, including increased MCH and decreased aPTT time (male animals) and increased No. white blood cells and lymphocytes (female animals). Changes in the relative or absolute organ weights of several organs were noted for the male animals dosed at 300 mg test item/kg bw/day, most remarkably for the relative liver weight which increased for almost 20%. The macroscopic and microscopic examinations revealed no test item related changes. NOAEL-levels were as follows: 120 mg/kg bw for paternal/maternal toxicity; 120 mg/kg bw for reproductive toxicity (see Section 7.8.1) and 300 mg/kg bw for developmental toxicity (see Section 7.8.2

- Subchronic data were also available from read-across substance 'Butanoic acid, 4-amino-4-oxosulfo-, N-tallow alkyl derivs., disodium salts' (CAS No. 68988-69-2) given to albino rats in the diet with test item containing 35% active ingredient at doses of 0.5, 2 and 8 g act.ingr./kg bw/day (Tegeris and Underwood, 1976). Due to mortality at 8 g/kg bw/day, dosing was reduced to 4 g/kg feed/day after 6 weeks. Findings included decreased body weight gain and food intake at all levels and gastro-enteritis / acute nephritis within six weeks at 8.00 g/kg/day. After dose reduction, zonal fatty infiltration in the liver was observed. At the lowest dose level, decreases in body weight (gain) and feed intake were minimal (<10%) and were not considered relevant. Decreased organ weights were observed for heart, liver, kidneys, adrenal an thyroid weight at the medium and high doses. From the data presented in this study a NOAEL of 500 mg/kg bw/day could be considered.

- For risk assessment, the lowest NOAEL of 120 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.

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 risk assessment for irritation is performed.