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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:
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:
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:
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:
80.36 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):
33.6
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:
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:
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 (vehicle), 100, 300 and 1000 mg/kg bw/day in a supporting 14-day dose range finding and100, 300 and 1000 reduced to 600 mg/kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). The vehicle was distilled water in the 14-day dose range finding and propylene glycol in the OECD 422 study. In the OECD 422 study, the test item at a dose level of 100 mg solid/kg bw/day (Low dose group) did not result in test item related mortality or clinical signs. In the Mid dose group (300 mg solid/kg bw/day), most animals had minor/transient symptoms of respiratory local effects, related to reflux or by small amounts of test item reaching the upper respiratory tract area in animals; but with no indications of systemic effects of the test item. One Mid dose animal died, related to local effects of the test item. In the High dose group, the initial dose level of 1000 mg solid/kg bw/day was found to be too high despite very careful gavage procedures to ensure minimal local respiratory effects, so the dose was reduced to 600 mg solid/kg bw/day after three days of treatment. A relatively high rate of deaths or euthanasia occurred at the High dose level due to the local effects of the test item; necropsy showed local gastric irritation and respiratory effects. Test item related adverse effects were observed on body weight parameters and food consumption in High dose males and females, this was largely transient, in the first week. In High dose females there was a lower weight gain during gestation (~20% less gain than controls). 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 test item-related adverse effects were seen in the clinical pathology parameters. No test item effect on oestrus cycle of parental females was noted. No adverse test item related systemic macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. Local toxicity was observed as gastric irritation in the High and Mid dose groups (with minimal incidence at the Low dose).Gastric reflux resulted in irritation, sometimes severe, in the upper respiratory tract, which was lethal in approximately 50% of the High dose and in one animal in the Mid dose animals.In animals with respiratory distress, secondary stress effects were recorded (such as organ weight and histological changes in thymus and adrenals).There was an increase in the hepatic weight (12-14%) in both sexes of the High dose group, indicating an adaptive hypertrophy, but below the level that is detectable histologically. Based on the results of this study, the NOAEL for local toxicity of the parental generation was 100 mg solid/kg bw/day (based on local gastric effects). The NOAEL for systemic toxicity of the parental generation was 300 mg solid/kg bw/day (Although body weight/food consumed and mortality in the High dose group were ascribed to secondary effects of the test item from the direct local effects; there could theoretically also be a potential systemic effect. Taking a conservative approach 300 mg solid/kg bw/day was applied here).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. There were no test item effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic findings were recorded for F1 pups at necropsy. No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. 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 NOAEL for reproductive effects of the parental generation was 600 mg solid/kg bw/day (based on no significant findings); the NOAEL for pups’ (F1 generation) development and survival was 600 mg solid/kg bw/day (based on no significant findings).

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 can be considered as most appropriate point of departure for DNEL derivation. The increased liver weights at the high dose were considered to be adaptive, but not adverse. 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. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated irritation, and not relevant for humans.

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

2.    Gastric irritation was 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, 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:
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:
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:
48.21 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:
2 700 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:
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
Modified dose descriptor starting point:
NOAEL
Value:
300 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 (vehicle), 100, 300 and 1000 mg/kg bw/day in a supporting 14-day dose range finding and100, 300 and 1000 reduced to 600 mg/kg bw/day in a key combined repeated dose/reproductive toxicity study (OECD No. 422). The vehicle was distilled water in the 14-day dose range finding and propylene glycol in the OECD 422 study. In the OECD 422 study, the test item at a dose level of 100 mg solid/kg bw/day (Low dose group) did not result in test item related mortality or clinical signs. In the Mid dose group (300 mg solid/kg bw/day), most animals had minor/transient symptoms of respiratory local effects, related to reflux or by small amounts of test item reaching the upper respiratory tract area in animals; but with no indications of systemic effects of the test item. One Mid dose animal died, related to local effects of the test item. In the High dose group, the initial dose level of 1000 mg solid/kg bw/day was found to be too high despite very careful gavage procedures to ensure minimal local respiratory effects, so the dose was reduced to 600 mg solid/kg bw/day after three days of treatment. A relatively high rate of deaths or euthanasia occurred at the High dose level due to the local effects of the test item; necropsy showed local gastric irritation and respiratory effects. Test item related adverse effects were observed on body weight parameters and food consumption in High dose males and females, this was largely transient, in the first week. In High dose females there was a lower weight gain during gestation (~20% less gain than controls). 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 test item-related adverse effects were seen in the clinical pathology parameters. No test item effect on oestrus cycle of parental females was noted. No adverse test item related systemic macroscopic or microscopic changes were recorded at necropsy or at histopathology evaluation of routine organs/tissues or in any reproductive organs. Local toxicity was observed as gastric irritation in the High and Mid dose groups (with minimal incidence at the Low dose).Gastric reflux resulted in irritation, sometimes severe, in the upper respiratory tract, which was lethal in approximately 50% of the High dose and in one animal in the Mid dose animals.In animals with respiratory distress, secondary stress effects were recorded (such as organ weight and histological changes in thymus and adrenals).There was an increase in the hepatic weight (12-14%) in both sexes of the High dose group, indicating an adaptive hypertrophy, but below the level that is detectable histologically. Based on the results of this study, the NOAEL for local toxicity of the parental generation was 100 mg solid/kg bw/day (based on local gastric effects). The NOAEL for systemic toxicity of the parental generation was 300 mg solid/kg bw/day (Although body weight/food consumed and mortality in the High dose group were ascribed to secondary effects of the test item from the direct local effects; there could theoretically also be a potential systemic effect. Taking a conservative approach 300 mg solid/kg bw/day was applied here).

No test item related changes were noted in the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD 14. There were no test item effects on the F1 offspring viability, clinical signs, physical or sexual development. No test item related macroscopic findings were recorded for F1 pups at necropsy. No test item-related macroscopic and microscopic findings were observed in evaluated males and females from the High dose group. 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 NOAEL for reproductive effects of the parental generation was 600 mg solid/kg bw/day (based on no significant findings); the NOAEL for pups’ (F1 generation) development and survival was 600 mg solid/kg bw/day (based on no significant findings).

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 can be considered as most appropriate point of departure for DNEL derivation. The increased liver weights at the high dose were considered to be adaptive, but not adverse. 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. The gross and histological changes in the non-glandular stomach (forestomach) are considered to be due to repeated irritation, and not relevant for humans.

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

2.    Gastric irritation was 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, 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.