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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 133.46 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:
600 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
9 521 mg/m³
Explanation for the modification of the dose descriptor starting point:
Key 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:
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:
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):
33.6
Dose descriptor starting point:
NOAEL
Value:
600 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Key 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:
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 (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

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 (distilled water), 100, 300 and 1000 mg solid/kg bw/day in a supporting 14-day dose range finding and at 0 (distilled water), 100, 300 and 1000/600 mg solid/kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). On day 28 of the dosing period the high dose was reduced to 600 mg/kg bw/day due to mortalities and increasing incidence and severity of noisy/laboured respiration. In the OECD 422 study, the test substance did result in test item related mortality and clinical signs at 1000 mg/kg bw/day. The initial High dose level of 1000 mg solid/kg bw/day was reduced to 600 mg solid/kg bw/day at 4 weeks due to adverse clinical effects (local irritation) and mortality. The bodyweight, body weight gain, and food consumption of the test item treated groups did not show any test item related effect. At the functional observation battery (FOB) and locomotor activity measurement, there were no test item related changes in animal behaviour, general physical condition, grip strength, motor activity, or in the reactions to different type of stimuli in the control or test groups. No adverse test item-related findings were seen in the clinical pathology parameters. No test item related macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. The NOAEL for local toxicity of the parental generation was 300 mg solid/kg bw/day (based on noisy/laboured respiration at 600 mg solid/kg bw/day); the NOAEL for systemic toxicity of the parental generation was considered to be >=600 mg solid/kg bw/day.
No test item effect on oestrus cycle of parental females was noted. No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD14. There were no adverse effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic finding was recorded for F1 pups at necropsy. No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. No test item related macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. 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. Based on the results of this study, the following No-Observed-Adverse-Effect Levels (NOAELs) were considered: The NOAEL for reproductive effects of the parental generation was considered to be >=600 mg solid/kg bw/day. The NOAEL for pup development and survival was considered to be >=600 mg solid/kg bw/day.

 

Subacute oral toxicity was also tested according to OECD 407 method in male rats at 0.25, 0.5 and 1 % in the diet for 32 days, corresponding with average doses of 240, 510 and 960 mg test material/kg bw.

 

Subchronic oral toxicity was further tested equivalent to OECD 408 method in male and female rats at 1% in the diet for 90 days with registered substance, corresponding with ca. 750 mg act. ingr./kg bw and a NOAEL of 1000 mg/kg bw was obtained for Docusate sodium in a 90-day dietary toxicity study. These studies did not reveal toxicity, therefore 1% in the diet or higher, corresponding with ca. 750 -1000 mg act.ingr./kg bw can be accepted as NOAEL. A justification for calculation of DNELs is attached.

The respiratory problems were considered to be due to small amounts of test item reaching the upper respiratory tract area after gavage dosing and retraction of the gavage needle, which is rather physicochemical than toxicological. Based on the above information, the NOAEL of be >=600 mg solid /kg bw/day of the OECD 422 study can be considered as most appropriate and conservative point of departure for DNEL derivation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
335.4 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:
600 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
4 696 mg/m³
Explanation for the modification of the dose descriptor starting point:
Key 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:
96.43 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:
600 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
5 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Key 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:
10.71 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:
600 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
600 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

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 (distilled water), 100, 300 and 1000 mg solid/kg bw/day in a supporting 14-day dose range finding and at 0 (distilled water), 100, 300 and 1000/600 mg solid/kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). On day 28 of the dosing period the high dose was reduced to 600 mg/kg bw/day due to mortalities and increasing incidence and severity of noisy/laboured respiration. In the OECD 422 study, the test substance did result in test item related mortality and clinical signs at 1000 mg/kg bw/day. The initial High dose level of 1000 mg solid/kg bw/day was reduced to 600 mg solid/kg bw/day at 4 weeks due to adverse clinical effects (local irritation) and mortality. The bodyweight, body weight gain, and food consumption of the test item treated groups did not show any test item related effect. At the functional observation battery (FOB) and locomotor activity measurement, there were no test item related changes in animal behaviour, general physical condition, grip strength, motor activity, or in the reactions to different type of stimuli in the control or test groups. No adverse test item-related findings were seen in the clinical pathology parameters. No test item related macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. The NOAEL for local toxicity of the parental generation was 300 mg solid/kg bw/day (based on noisy/laboured respiration at 600 mg solid/kg bw/day); the NOAEL for systemic toxicity of the parental generation was considered to be >=600 mg solid/kg bw/day.
No test item effect on oestrus cycle of parental females was noted. No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD14. There were no adverse effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic finding was recorded for F1 pups at necropsy. No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. No test item related macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. 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. Based on the results of this study, the following No-Observed-Adverse-Effect Levels (NOAELs) were considered: The NOAEL for reproductive effects of the parental generation was considered to be >=600 mg solid/kg bw/day. The NOAEL for pup development and survival was considered to be >=600 mg solid/kg bw/day.

 

Subacute oral toxicity was also tested according to OECD 407 method in male rats at 0.25, 0.5 and 1 % in the diet for 32 days, corresponding with average doses of 240, 510 and 960 mg test material/kg bw.

 

Subchronic oral toxicity was further tested equivalent to OECD 408 method in male and female rats at 1% in the diet for 90 days with registered substance, corresponding with ca. 750 mg act. ingr./kg bw and a NOAEL of 1000 mg/kg bw was obtained for Docusate sodium in a 90-day dietary toxicity study. These studies did not reveal toxicity, therefore 1% in the diet or higher, corresponding with ca. 750 -1000 mg act.ingr./kg bw can be accepted as NOAEL. A justification for calculation of DNELs is attached.

The respiratory problems were considered to be due to small amounts of test item reaching the upper respiratory tract area after gavage dosing and retraction of the gavage needle, which is rather physicochemical than toxicological. Based on the above information, the NOAEL of be >=600 mg solid /kg bw/day of the OECD 422 study can be considered as most appropriate and conservative point of departure for DNEL derivation.