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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 416.82 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):
3.36
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:
The lowest NOAEL from the Key OECD 422 study (NOAEL 300 mg/kg bw) was used. This is conservative as the findings in the study were mainly related to stomach irritation to the substance by oral gavage administration, whereas in a 90-day oral toxicity study a higher NOAEL was 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:
As there is a 90- day study available with higher NOAEL than the OECD 422 study, the factor for duration is based on subchronic; 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:
1
Justification:
A conservative approach was taken by selecting the lowest NOAEL from the Key OECD 422 study (300 mg/kg bw), which was mainly due to local stomach effects and below the NOAEL (750 mg/kg bw) from a 90-day study. No additional uncertainty factor is needed
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:
200.89 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):
13.44
Dose descriptor starting point:
NOAEL
Value:
300 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:
The lowest NOAEL from the Key OECD 422 study (NOAEL 300 mg/kg bw) was used. This is conservative as the findings in the study were mainly related to stomach irritation to the substance by oral gavage administration, whereas in a 90-day oral toxicity study a higher NOAEL was available.
AF for dose response relationship:
1
Justification:
As there is a 90- day study available with higher NOAEL than the OECD 422 study, the factor for duration is based on subchronic; see justification attached.
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:
1
Justification:
A conservative approach was taken by selecting the lowest NOAEL from the Key OECD 422 study (300 mg/kg bw), which was mainly due to local stomach effects and below the NOAEL (750 mg/kg bw) from a 90-day study. No additional uncertainty factor is needed.
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

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

A key Combined repeated dose toxicity with reproduction/developmental toxicity screening test in Wistar rats was conducted under GLP conditions with the registered substance by oral gavage administration at dose levels at 0, 100, 300 and 1000 mg/kg bw/day (Hargitai, 2021). The study did not result in test item related mortality or clinical signs.Test item related adverse effects were observed on body weight parameters and food consumption in High dose (1000 mg/kg bw/day) males and females (for females during gestation and lactation periods, no effect was seen in the pre-mating period).At the functional observation battery (FOB) and locomotor activity measurement, there were no changes in animal behaviour, general physical condition or in the reactions to different type of stimuli in test item treated groups when compared to control.No test item-related adverse effects were seen in the clinical pathology parameters. Test item related non-adverse changes (increased Alanine aminotransferase activity in the Mid dose males and High dose males and females, as well as increased Alkaline phosphate activity in High dose females) were considered to be linked to the adaptive response seen in the liver during microscopic examination (hepatocellular hypertrophy and vacuolation which was observed only in High dose animals, but not in Mid or Low dose animals). No test item-related effects were observed in the organ weights of the test item treated animals compared to controls. Hyperkeratosis of the non-glandular gastric mucosa of the stomach was identified at the High dose level (1000 mg/kg bw/day), as test item-related adverse change. Mid and Low dose stomach samples of both sexes were also evaluated the get additional information for study interpretation, no test item-related changes were seen in those animals.There were test item-related differences on the offspring body weights or body weight gains in the Mid and High dose groups (300 and 1000 mg/kg bw/day, respectively) when compared to the control values. The difference in the Mid dose group was not considered as an adverse effect of treatment since the values were well within the historic control range, and hence the pup growth was considered to be normal. The measured values of growth and weight were clearly outside the historical control range in case of the High dose group pups, the changes observed in this dose group were considered as a test item related adverse effect (however, significantly lower maternal body weight gain and lower food intake by these lactating dams i.e. maternal toxicity, is considered to be an important factor in, or the direct cause of, the High dose pup effects). No indication of an endocrine disruptor effect was observed in the study based on collected oestrus cycle data, anogenital distance measurement, nipple retention, thyroid hormone measurement, thyroid weight and histopathology and external reproductive organs analysis. Based on the results of this study, the systemic NOAEL for parental toxicity was 300 mg/kg bw/day. The NOAEL for reproductive effects of the parental generation was 1000 mg/kg bw/day (based on the lack of relevant findings). The NOAEL for pups’ (F1 generation) development and survival was 1000 mg/kg bw/day (based on the lack of evidence of a direct effect on the pups at 1000 mg/kg bw/day, where treatment related reduced pup growth and body weight were seen, but were attributed as most probably due to maternal toxicity (~20% lower dam body weight gain and ~20% reduced food intake, associated with local gastric irritation in the lactating dams). No treatment related effect on pup growth was seen at 300 mg/kg/day).

A key 90 -day study was available for the registered substance in which 40 albino rats (20 males, 20 females) were fed with 1% of various test items mixed into the diet. In the same study, various members of the Sulfosuccinates Diester Group were tested (Plank et al, 1969). After 84 days hematological values, blood chemical values, urinalysis values were measured for all animals. Tissues were examined pathologically at the conclusion of the 90-days test period. Organ to body weight and organ to brain weight ratios were calculated. No significant differences in clinical blood chemistry studies and absolute organ weights have been detected, except a slight increase in SGPT (serum glutamic pyruvic transaminase) and SAP (serum alkaline phosphatase). Body weights, organ to body weight ratios, hematologic studies and urinalysis were not different between test and control animals. No deaths or abnormal behavioral reactions occurred; no gross pathological findings were noted. Administration of category members at 1% in the diet (10000 ppm equivalent to ca.750 mg act. ingr./kg body weight/day on average basis) for 90 days in rats did not result in any relevant changes in the subchronic toxicity study. The NOAEL was therefore considered to be worst case 750 mg/kg bw/day. The validity of the study was supported by additional audits on the raw data and histopathological evaluation. Although deficiencies were detected compared to current standards, the study was concluded to be valid and reliable.

 Under consideration of the observations in the OECD 422 study, in particular the reduced body weight and food consumption in High dose (1000 mg/kg bw/day) males and females, the experimental parental NOAEL was 300 mg/kg bw by daily oral gavage administration. The clinical pathology and histopathological changes related to the liver were adaptive, therefore not adverse. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated rritation, and not relevant for humans.

1.     Humans do not have non-glandular stomach (forestomach).

2.     Hyperkeratosis was only seen at 1 site in these animals, no other tissues are involved.

3.     There was a clear  dose-response: it was only observed at the highest dose, not at the mid and low dose, so there is a clear threshold.

4.     This high oral exposure volume is not applicable in humans; and humans do not have the same stomach anatomy (no forestomach in humans).

5.     Genotoxicity studies are negative (Ames, Micronucleus, Mammalian genotoxicty).

6.     It was only observed with gavage dosing. No other routes were tested, but the gavage is giving a bolus dose, which is considered excessive.

The reduced body weight and food consumption in the High dose (1000 mg/kg bw/day) males and females were considered to be due to the stomach lesions. Therefore,the NOAEL of 300 mg/kg bw is rather a local NOAEL for rodents under the oral gavage conditions.As there is a NOAEL of 750 mg/kg bw from the 90-day dietary toxicity study, the NOAEL of 300 mg/kg bw/day is considered as a conservative departure point for systemic DNELs. A justification for calculation of DNELs is attached.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
419.25 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):
5.6
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:
The lowest NOAEL from the Key OECD 422 study (NOAEL 300 mg/kg bw) was used. This is conservative as the findings in the study were mainly related to stomach irritation to the substance by oral gavage administration, whereas in a 90-day oral toxicity study a higher NOAEL was 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:
As there is a 90- day study available with higher NOAEL than the OECD 422 study, the factor for duration is based on subchronic; 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:
1
Justification:
A conservative approach was taken by selecting the lowest NOAEL from the Key OECD 422 study (300 mg/kg bw), which was mainly due to local stomach effects and below the NOAEL (750 mg/kg bw) from a 90-day study. No additional uncertainty factor is needed.
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:
120.54 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):
22.4
Dose descriptor starting point:
NOAEL
Value:
300 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:
The lowest NOAEL from the Key OECD 422 study (NOAEL 300 mg/kg bw) was used. This is conservative as the findings in the study were mainly related to stomach irritation to the substance by oral gavage administration, whereas in a 90-day oral toxicity study a higher NOAEL was 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:
As there is a 90- day study available with higher NOAEL than the OECD 422 study, the factor for duration is based on subchronic; 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:
1
Justification:
A conservative approach was taken by selecting the lowest NOAEL from the Key OECD 422 study (300 mg/kg bw), which was mainly due to local stomach effects and below the NOAEL (750 mg/kg bw) from a 90-day study. No additional uncertainty factor is needed.
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:
13.39 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):
22.4
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. The lowest NOAEL from the Key OECD 422 study (NOAEL 300 mg/kg bw) was used. This is conservative as the finings in the study were mainly related to stomach irritation to the substance by oral gavage administration, whereas in a 90-day oral toxicity study a higher NOAEL was 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:
As there is a 90- day study available with higher NOAEL than the OECD 422 study, the factor for duration is based on subchronic; 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:
1
Justification:
A conservative approach was taken by selecting the lowest NOAEL from the Key OECD 422 study (300 mg/kg bw), which was mainly due to local stomach effects and below the NOAEL (750 mg/kg bw) from a 90-day study. No additional uncertainty factor is needed.
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:

A key Combined repeated dose toxicity with reproduction/developmental toxicity screening test in Wistar rats was conducted under GLP conditions with the registered substance by oral gavage administration at dose levels at 0, 100, 300 and 1000 mg/kg bw/day (Hargitai, 2021). The study did not result in test item related mortality or clinical signs.Test item related adverse effects were observed on body weight parameters and food consumption in High dose (1000 mg/kg bw/day) males and females (for females during gestation and lactation periods, no effect was seen in the pre-mating period).At the functional observation battery (FOB) and locomotor activity measurement, there were no changes in animal behaviour, general physical condition or in the reactions to different type of stimuli in test item treated groups when compared to control.No test item-related adverse effects were seen in the clinical pathology parameters. Test item related non-adverse changes (increased Alanine aminotransferase activity in the Mid dose males and High dose males and females, as well as increased Alkaline phosphate activity in High dose females) were considered to be linked to the adaptive response seen in the liver during microscopic examination (hepatocellular hypertrophy and vacuolation which was observed only in High dose animals, but not in Mid or Low dose animals). No test item-related effects were observed in the organ weights of the test item treated animals compared to controls. Hyperkeratosis of the non-glandular gastric mucosa of the stomach was identified at the High dose level (1000 mg/kg bw/day), as test item-related adverse change. Mid and Low dose stomach samples of both sexes were also evaluated the get additional information for study interpretation, no test item-related changes were seen in those animals.There were test item-related differences on the offspring body weights or body weight gains in the Mid and High dose groups (300 and 1000 mg/kg bw/day, respectively) when compared to the control values. The difference in the Mid dose group was not considered as an adverse effect of treatment since the values were well within the historic control range, and hence the pup growth was considered to be normal. The measured values of growth and weight were clearly outside the historical control range in case of the High dose group pups, the changes observed in this dose group were considered as a test item related adverse effect (however, significantly lower maternal body weight gain and lower food intake by these lactating dams i.e. maternal toxicity, is considered to be an important factor in, or the direct cause of, the High dose pup effects). No indication of an endocrine disruptor effect was observed in the study based on collected oestrus cycle data, anogenital distance measurement, nipple retention, thyroid hormone measurement, thyroid weight and histopathology and external reproductive organs analysis. Based on the results of this study, the systemic NOAEL for parental toxicity was 300 mg/kg bw/day. The NOAEL for reproductive effects of the parental generation was 1000 mg/kg bw/day (based on the lack of relevant findings). The NOAEL for pups’ (F1 generation) development and survival was 1000 mg/kg bw/day (based on the lack of evidence of a direct effect on the pups at 1000 mg/kg bw/day, where treatment related reduced pup growth and body weight were seen, but were attributed as most probably due to maternal toxicity (~20% lower dam body weight gain and ~20% reduced food intake, associated with local gastric irritation in the lactating dams). No treatment related effect on pup growth was seen at 300 mg/kg/day).

A key 90 -day study was available for the registered substance in which 40 albino rats (20 males, 20 females) were fed with 1% of various test items mixed into the diet. In the same study, various members of the Sulfosuccinates Diester Group were tested (Plank et al, 1969). After 84 days hematological values, blood chemical values, urinalysis values were measured for all animals. Tissues were examined pathologically at the conclusion of the 90-days test period. Organ to body weight and organ to brain weight ratios were calculated. No significant differences in clinical blood chemistry studies and absolute organ weights have been detected, except a slight increase in SGPT (serum glutamic pyruvic transaminase) and SAP (serum alkaline phosphatase). Body weights, organ to body weight ratios, hematologic studies and urinalysis were not different between test and control animals. No deaths or abnormal behavioral reactions occurred; no gross pathological findings were noted. Administration of category members at 1% in the diet (10000 ppm equivalent to ca.750 mg act. ingr./kg body weight/day on average basis) for 90 days in rats did not result in any relevant changes in the subchronic toxicity study. The NOAEL was therefore considered to be worst case 750 mg/kg bw/day. The validity of the study was supported by additional audits on the raw data and histopathological evaluation. Although deficiencies were detected compared to current standards, the study was concluded to be valid and reliable.

 Under consideration of the observations in the OECD 422 study, in particular the reduced body weight and food consumption in High dose (1000 mg/kg bw/day) males and females, the experimental parental NOAEL was 300 mg/kg bw by daily oral gavage administration. The clinical pathology and histopathological changes related to the liver were adaptive, therefore not adverse. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated rritation, and not relevant for humans.

1.     Humans do not have non-glandular stomach (forestomach).

2.     Hyperkeratosis was only seen at 1 site in these animals, no other tissues are involved.

3.     There was a clear  dose-response: it was only observed at the highest dose, not at the mid and low dose, so there is a clear threshold.

4.     This high oral exposure volume is not applicable in humans; and humans do not have the same stomach anatomy (no forestomach in humans).

5.     Genotoxicity studies are negative (Ames, Micronucleus, Mammalian genotoxicty).

6.     It was only observed with gavage dosing. No other routes were tested, but the gavage is giving a bolus dose, which is considered excessive.

The reduced body weight and food consumption in the High dose (1000 mg/kg bw/day) males and females were considered to be due to the stomach lesions. Therefore,the NOAEL of 300 mg/kg bw is rather a local NOAEL for rodents under the oral gavage conditions.As there is a NOAEL of 750 mg/kg bw from the 90-day dietary toxicity study, the NOAEL of 300 mg/kg bw/day is considered as a conservative departure point for systemic DNELs. A justification for calculation of DNELs is attached.