Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
566.73 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4 761 mg/m³
Explanation for the modification of the dose descriptor starting point:
Starting from a key oral subchronic OECD 408 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:
1.4
Justification:
Extrapolation from subchronic 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 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:
401.79 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
13 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Starting from a key oral subchronic OECD 408 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:
1.4
Justification:
Extrapolation from subchronic 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 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:
low hazard (no threshold derived)

Additional information - workers

Source information for DNELs:

- Key data for subchronic toxicity were available from an oral 90-day repeated dose toxicity study with the registered substance at dose levels of 100, 300, or 1000 mg/kg bw given to rats by daily oral administration via gavage for 90 days, followed by a 4-week recovery period. The NOAEL was 300 mg act.ingr./kg bw/day. Test-item related effects were observed at 1000 mg/kg bw, including a slight reduction in mean body weight in male and female animals, increased drinking water consumption in male and the female animals and changes in the forestomach (non-glandular part of the stomach) of almost all in the form of squamous cell hyperplasia, hyperkeratosis and sometimes submucosal mixed inflammatory cell infiltrate. The body weight and drinking water intake of all previously high-dosed animals was in the normal range during the recovery period, and no abnormalities were noted in the stomach after this recovery period. The changes in the stomach were not considered relevant for humans as humans do not have a forestomach, exposure conditions were considered to be extreme (irritating concentration daily given by bolus) and the findings were completely reversible.

- Key data for subacute toxicity were available from an oral (gavage) OECD 422 study in rats with registered substance, at dose levels given by oral gavage of 100, 300 and 1000 mg/kg bw/day. No relevant effects were observed at 100 and 300 mg/kg bw. At the dose of 1000 mg/kg bw, decreased body weight, increased serum ALAT and decreased serum albumin were observed as systemic changes, whereas macroscopic and microscopic stomach changes were observed as local changes, however the latter without relevance to humans. NOAEL for paternal/maternal toxicity was 300 mg/kg bw/day.

- Supporting data for subchronic toxicity were available from an oral (diet) 90-day toxicity study in rats with read-across substance 'Aspartic acid, N-(3-carboxy-1-oxo-sulfopropyl)-N-(C16-C18 (even numbered), C18unsaturated alkyl) tetrasodium salts' dosed at 0.5, 2 and 8 (reduced to 4) g/kg bw.day. The study showed decreased body weight gain, feed consumption and food efficiency at the mid dose and high dose levels and increased SGOT and SGPT (liver enzymes) at the high dose. Further hematuria was seen in the mid and high dose rats, various organ weights were decreased (e.g. decrease in adrenal and gonadal weight in high dose groups; decrease in pituitary weight in females of high dose group) and lower urinary tract pathology was seen in 2 high dosed rats. It thus appeared that the NOEL in the rat was below 0.50 g/kg/day, however 0.5 g act.ingr./kg bw/day can be considered as NOAEL.

- For risk assessment, the lowest NOAEL of 300 mg/kg bw with registered substance tested in the OECD 408 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 another subchronic study with dietary administration was 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:
167.7 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2 348 mg/m³
Explanation for the modification of the dose descriptor starting point:
Starting from a key oral subchronic OECD 408 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:
1.4
Justification:
Extrapolation from subchronic 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 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:
241.07 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
13 500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Starting from a key oral subchronic OECD 408 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:
1.4
Justification:
Extrapolation from subchronic 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 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:
5.36 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Not applicable; starting from a key oral subchronic OECD 408 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:
1.4
Justification:
Extrapolation from subchronic 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 speciees; 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:
low hazard (no threshold derived)

Additional information - General Population

Source information for DNELs:

- Key data for subchronic toxicity were available from an oral 90-day repeated dose toxicity study with the registered substance at dose levels of 100, 300, or 1000 mg/kg bw given to rats by daily oral administration via gavage for 90 days, followed by a 4-week recovery period. The NOAEL was 300 mg act.ingr./kg bw/day. Test-item related effects were observed at 1000 mg/kg bw, including a slight reduction in mean body weight in male and female animals, increased drinking water consumption in male and the female animals and changes in the forestomach (non-glandular part of the stomach) of almost all in the form of squamous cell hyperplasia, hyperkeratosis and sometimes submucosal mixed inflammatory cell infiltrate. The body weight and drinking water intake of all previously high-dosed animals was in the normal range during the recovery period, and no abnormalities were noted in the stomach after this recovery period. The changes in the stomach were not considered relevant for humans as humans do not have a forestomach, exposure conditions were considered to be extreme (irritating concentration daily given by bolus) and the findings were completely reversible.

- Key data for subacute toxicity were available from an oral (gavage) OECD 422 study in rats with registered substance, at dose levels given by oral gavage of 100, 300 and 1000 mg/kg bw/day. No relevant effects were observed at 100 and 300 mg/kg bw. At the dose of 1000 mg/kg bw, decreased body weight, increased serum ALAT and decreased serum albumin were observed as systemic changes, whereas macroscopic and microscopic stomach changes were observed as local changes, however the latter without relevance to humans. NOAEL for paternal/maternal toxicity was 300 mg/kg bw/day.

- Supporting data for subchronic toxicity were available from another oral (diet) 90-day toxicity study in rats with read-aross substance 'Aspartic acid, N-(3-carboxy-1-oxo-sulfopropyl)-N-(C16-C18 (even numbered), C18unsaturated alkyl) tetrasodium salts' dosed at 0.5, 2 and 8 (reduced to 4) g/kg bw.day. The study showed decreased body weight gain, feed consumption and food efficiency at the mid dose and high dose levels and increased SGOT and SGPT (liver enzymes) at the high dose. Further hematuria was seen in the mid and high dose rats, various organ weights were decreased (e.g. decrease in adrenal and gonadal weight in high dose groups; decrease in pituitary weight in females of high dose group) and lower urinary tract pathology was seen in 2 high dosed rats. It thus appeared that the NOEL in the rat was below 0.50 g/kg/day, however 0.5 g act.ingr./kg bw/day can be considered as NOAEL.

- For risk assessment, the lowest NOAEL of 300 mg/kg bw with registered substance tested in the OECD 408 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 another subchronic study with dietary administration was higher. Further justification of assessment factors is explained in the DNEL justification document attached to the endpoint summary.