Sodium 1,4-diisodecyl sulphonatosuccinate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 889.1 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

15 868 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral 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:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. 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:

267.86 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

9 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 90-day oral toxicity study 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:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. 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 DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Source information for DNELS:

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

Subacute toxicity was tested with the registered substance in Wistar rats by oral gavage at 0 (propylene glycol), 100, 300 and 1000 mg /kg bw/day in a supporting 14-day dose range finding and at 0 (propylene glycol), 100, 300 and 1000 mg /kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). In summary, the test substance did not result in test item related mortality or adverse clinical signs. Test item related adverse effects were observed on body weight gain parameters and food consumption in High dose (600 mg/kg bw/day) males and moderate effects were observed on body weight and body weight gain in the gestation and lactation period for High dose  females. It is most likely these effects were related to local gastric irritation. There were no adverse changes in animal behaviour, general physical condition or in the reactions to different type of stimuli or in clinical pathology in test item treated groups when compared to control.  There was no test item effect on mortality or survival of the pups. Test item-related effects were observed in the liver (increased relative organ weights in Mid and High dose males and females) associated with centrilobular hepatocellular hypertrophy in the High dose. Hepatic changes were considered to be adaptive and non-adverse. Test item related effect was observed in the organ weight of the heart (decreased absolute and relative organ weight) of the High dose males (not in females) compared to controls. However, there were no histopathological findings which indicates any adversity. Histologically, test item-related changes were observed in the stomach in High and Mid dose animals with squamous hyperplasia, hyperkeratosis and ulcer of the non-glandular gastric mucosa observed at 300 and 600 mg/kg bw/day dose level in females and at 100, 300 and 600 mg/kg bw/day dose level in males, as test item-related adverse local changes. Sporadic cases of noisy respiration in a few animals ascribed to reflux or minor exposure to test item in the region of the upper respiratory tract. Also, centrilobular hepatocellular hypertrophy was observed at 600 mg/kg bw/day dose level as a non-adverse adaptive change (associated with liver weight increase). Minimal to mild multifocal eosinophilic droplets/globules were seen in the renal tubules in the High dose males and were considered as test item-related but non-adverse. The NOAEL for local toxicity of the parental generation was <100 mg/kg bw/day (based on local gastric histological effects in Low, Mid and High dose animals). The NOAEL for systemic toxicity of the parental generation was considered to be 300 mg/kg bw/day. (based on body weight, body weight gain and food consumption changes at 600 mg/kg bw/day, although these effects were probably secondary to local gastric irritation).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. The litter size of control and treated groups were comparable. A slightly lower pup growth/weight at the High dose, while within the historic control range, may be related to maternal toxicity (gastric irritation/food intake); there is no indication of a direct adverse effect of the test item on pup development. Under the experimental conditions of this study and based on the results of thyroid hormone measurement, thyroid weights, nipple retention, anogenital distance and external reproductive organs analysis, histopathology and reproductive performance, there was no evidence for any endocrine effects.  There was no test item effect on mortality or survival of the pups. The litter size of control and treated groups were comparable. A slightly lower pup growth/weight at the High dose, while within the historic control range, may be related to maternal toxicity (gastric irritation/food intake); there is no indication of a direct adverse effect of the test item on pup development. The NOAEL for reproductive effects of the parental generation was considered to be 600 mg/kg bw/day.  The NOAEL for Pup development and survival was considered to be 600 mg/kg bw/day.

Repeated dose toxicity was further tested in various species, including rats, dogs, rabbits and monkeys. The NOAEL of 750 mg/kg bw/day obtained in the subchronic 90-day dietary toxicity study in rats with registered substance was confirmed to be consistent with data from category members in rats and the NOAEL of 1000 mg/kg bw of Docusate sodium  in a 90-day dietary toxicity study. Other data from other species were tested with read-across substance and were of limited reliability and relevance and therefore not taken into account.

Based on the above information, the NOAEL of 300 mg/kg bw/day of the OECD 422 study is considered too conservative. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated irritation, and not relevant for humans as supported by following arguments.

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


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


3. There was a clear  dose-response: it was observed at the highest and mid dose and not at the 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 genotoxicity).


6. It was only observed with gavage dosing; the gavage is giving a bolus dose, which is considered excessive.

In conclusion, 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 750-1000 mg/kg bw from the 90-day dietary toxicity study, DNEL derivation will not be based on the oral gavage study but on the dietary 90-day study with Docusate, waiting new data from the 90-day study with registered substance. A justification for calculation of DNELs is attached.

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:

559.1 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

7 826 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key 28-55 -day (OECD 422) oral 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:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. 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:

160.71 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):

56

Dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

9 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key 28-55 -day (OECD 422) oral toxicity study 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:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. 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 DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.86 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 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 in the various studies, therefore no additional factor is used.

AF for differences in duration of exposure:

1.4

Justification:

The factor for duration is based on subchronic, as 90-day toxicity data are available and will become updated with new studies. 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

Source information for DNELS:

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

Subacute toxicity was tested with the registered substance in Wistar rats by oral gavage at 0 (propylene glycol), 100, 300 and 1000 mg /kg bw/day in a supporting 14-day dose range finding and at 0 (propylene glycol), 100, 300 and 1000 mg /kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). In summary, the test substance did not result in test item related mortality or adverse clinical signs. Test item related adverse effects were observed on body weight gain parameters and food consumption in High dose (600 mg/kg bw/day) males and moderate effects were observed on body weight and body weight gain in the gestation and lactation period for High dose  females. It is most likely these effects were related to local gastric irritation. There were no adverse changes in animal behaviour, general physical condition or in the reactions to different type of stimuli or in clinical pathology in test item treated groups when compared to control.  There was no test item effect on mortality or survival of the pups. Test item-related effects were observed in the liver (increased relative organ weights in Mid and High dose males and females) associated with centrilobular hepatocellular hypertrophy in the High dose. Hepatic changes were considered to be adaptive and nonadverse. Test item related effect was observed in the organ weight of the heart (decreased absolute and relative organ weight) of the High dose males (not in females) compared to controls. However, there were no histopathological findings which indicates any adversity. Histologically, test item-related changes were observed in the stomach in High and Mid dose animals with squamous hyperplasia, hyperkeratosis and ulcer of the non-glandular gastric mucosa observed at 300 and 600 mg/kg bw/day dose level in females and at 100, 300 and 600 mg/kg bw/day dose level in males, as test item-related adverse local changes. Sporadic cases of noisy respiration in a few animals ascribed to reflux or minor exposure to test item in the region of the upper respiratory tract. Also, centrilobular hepatocellular hypertrophy was observed at 600 mg/kg bw/day dose level as a non-adverse adaptive change (associated with liver weight increase). Minimal to mild multifocal eosinophilic droplets/globules were seen in the renal tubules in the High dose males and were considered as test item-related but non-adverse. The NOAEL for local toxicity of the parental generation was <100 mg/kg bw/day (based on local gastric histological effects in Low, Mid and High dose animals). The NOAEL for systemic toxicity of the parental generation was considered to be 300 mg/kg bw/day. (based on body weight, body weight gain and food consumption changes at 600 mg/kg bw/day, although these effects were probably secondary to local gastric irritation).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. The litter size of control and treated groups were comparable. A slightly lower pup growth/weight at the High dose, while within the historic control range, may be related to maternal toxicity (gastric irritation/food intake); there is no indication of a direct adverse effect of the test item on pup development. Under the experimental conditions of this study and based on the results of thyroid hormone measurement, thyroid weights, nipple retention, anogenital distance and external reproductive organs analysis, histopathology and reproductive performance, there was no evidence for any endocrine effects.  There was no test item effect on mortality or survival of the pups. The litter size of control and treated groups were comparable. A slightly lower pup growth/weight at the High dose, while within the historic control range, may be related to maternal toxicity (gastric irritation/food intake); there is no indication of a direct adverse effect of the test item on pup development. The NOAEL for reproductive effects of the parental generation was considered to be 600 mg/kg bw/day.  The NOAEL for Pup development and survival was considered to be 600 mg/kg bw/day.

Repeated dose toxicity was further tested in various species, including rats, dogs, rabbits and monkeys. The NOAEL of 750 mg/kg bw/day obtained in the subchronic 90-day dietary toxicity study in rats with registered substance was confirmed to be consistent with data from category members in rats and the NOAEL of 1000 mg/kg bw of Docusate sodium  in a 90-day dietary toxicity study. Other data from other species were tested with read-across substance and were of limited reliability and relevance and therefore not taken into account.

Based on the above information, the NOAEL of 300 mg/kg bw/day of the OECD 422 study is considered to be too conservative. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated irritation, and not relevant for humans, as supported by following arguments. .

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


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


3. There was a clear  dose-response: it was observed at the highest and mid dose and not at the 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 genotoxicity).


6. It was only observed with gavage dosing; the gavage is giving a bolus dose, which is considered excessive.

In conclusion, 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 750-1000 mg/kg bw from the 90-day dietary toxicity study, tDNEL derivation will not be based on the oral gavage study but on the dietary 90-day study with Docusate, waiting new data from the 90-day study with registered substance. A justification for calculation of DNELs is attached.

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.