Butanedioic acid, 2-sulfo-, mono(C16-18 and C18-unsatd. alkyl) esters, ammonium sodium salts

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.93 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):

30

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

238 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key ral OECD 422 toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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:

5

Justification:

ECHA default factor.

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:

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:

5.63 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):

120

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

675 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key oral OECD 422 toxicity study available; no repeated dose dermal toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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 toxicodyanmic differences between speices; see justification attached.

AF for intraspecies differences:

5

Justification:

ECHA default factor.

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:

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 hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNELs were based upon following source information:

- A key subacute OECD No. 422 study was conducted with the registered substance in Wistar rats (12/sex/group) by oral gavage at 0 (distilled water), 15, 45 and 90 mg/kg bw/day (Szaloki, 2022). Parameters measured during the study included twice a day mortality checking, daily routine and weekly detailed observation of clinical signs, weekly body weight and food consumption measurements and clinical pathology evaluation (including haematology, coagulation, clinical chemistry and urinalysis). Neurological assessment (Functional Observation Battery (FOB) including measurements of the landing foot splay, grip strength as well as locomotor activity measurement) was performed during the last week of the treatment for each sex. Reproductive performance is reported under Section 7.8. At termination (Day 28 for males, PPD (Post-partum Day) 14 for females), necropsy with macroscopic examination was performed. Weights of selected organs were recorded, and representative tissues/organs were sampled and preserved in appropriate fixatives from the adult animals or F1 animals. The thyroxine (T4) levels in the PND (Post-natal Day) 13 pups and parental males were also determined. For the adult animals, a detailed histological examination was performed on the selected list of retained organs of 5 animals/sex in the Control and High dose groups, the retained reproductive organs of all Control and High dose animals, liver from all animals and prostate and seminal vesicle of all males, the found dead animal or all organs with relevant macroscopic changes, and the male / female mating pair where no liveborn pups were achieved. In addition, the study was extended with a Mammalian Erythrocyte Micronucleus Test on bone marrow samples of all groups. Dosing formulations were analysed for concentration and/or homogeneity on three occasions during the study. Overall, the formulations were considered adequate for the study. In summary, Butanedioic acid, sulfo-, mono (C16-18 and C18-unsatd. alkyl) esters, ammonium sodium salts by oral gavage to Wistar rats at dose levels of 15, 45 or 90 mg/kg bw/day (Low, Mid and High dose groups, respectively) did not result in test item related mortality or clinical signs in the majority of animals. One High dose male had clinical signs of weakness and general poor condition, it was terminated early, but there was no pathology found that could indicate the aetiology of the test item effects; however the early termination is ascribed to treatment. Test item related adverse effect was observed on body weight, body weight gain parameters and food consumption in High dose (90 mg/kg bw/day) males and females. Test item related adverse effect was observed on body weight, body weight gain parameters and food consumption in Mid dose (45 mg/kg bw/day) females. In males, the High dose animals lost ~8.5% body weight in the first week of the study but gained weight thereafter; lower food intake in the High dose female group during lactation would have resulted in lower milk production (associated with loss of all pups in this group). 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. Statistically significant haematological changes comprised decreased reticulocytes (%) in the High dose female group with the value was outside of the historical control range, which was considered a test item related effect. Statistically significant clinical chemistry changes included increased alanine aminotransferase, ALT/GPT ratio and bile acid concentration in case of the High dose males were considered as test item related but none were of a magnitude to be considered clearly adverse. These changes were probably related to the low food intakes and/or the histopathology findings in the liver. No test item-related changes were observed in the urinalysis parameters in male and female animals of any dose groups when compared to control. Eleven females in the High dose group were pregnant. However, one female had no live born pups and four pregnant females had no delivery (100% of the embryos was resorbed). High dose pups who were live born were dead in three days after birth the latest. It was considered as test item related adverse effect. There were severe test item related effects on pup mortality or survival of the pups (F1 generation) in the High dose groups; slight but similar tendency was observed in the Mid dose group which was considered to be adverse. In summary for the reproductive effects, the changes in High dose males were most probably secondary to significant body weight loss during the study. However, in females a significant reduction in implantations was not associated with body weight or food intake effect and as such is probably a reprotoxic effect at the High dose. Death/resorption of embryos/foetuses at the High dose were treatment related, reduced numbers of pups born, relatively high numbers of pups born dead and the death of all High dose pups by Day 3, were considered as treatment related. During gestation, the lower body weight gain at the High dose was probably a reflection of the presence of fewer foetuses. It is not considered likely that the lower body weight of the dams caused to foetal losses. During gestation all High dose pups died, and the dams had a food intake similar to females with no litter; it is not possible to be sure if the low food intake caused low milk production and pup death, or if the lack of pups resulted in less milk production hence a lower food intake, although this was clearly a treatment related effect. In the Mid dose, there were statistically significant differences suggesting a similar trend to the High dose, a dose response could be observed from the data on these parameters. Test item-related pale discoloration of the liver were observed in 3/11 High dose males and in 7/7 High dose females. The prostate and seminal vesicles were small in 1/11 High dose male, considered as test item-related; seminal vesicles were also small in 1/12 Low dose males, of uncertain relationship with treatment.Test item-related changes were observed in the parental organ weights of the liver of Mid (~14%) and High dose male animals (~35%). Multifocal/diffuse hepatocellular vacuolation at 90 mg/kg bw/day dose level both in males and females were observed, ascribed to test item, but not considered as adverse. Reduced weights of the prostate and seminal vesicles in High dose males, compared to controls, was probably secondary to the ~8.5% body weight loss in the first week of the study. No adverse test item related changes were observed in the female animal organ weights. In the parameters measured in adults and pups, there was no evidence for any neurotoxicity and no effects on thyroids or other endocrine systems, and no evidence for immunological effects in immunocompetent organs or tissues.       
No test item-related effect, thus no evidence of genotoxic activity was seen in the Mammalian Erythrocyte Micronucleus Test.    
The NOAEL for systemic toxicity of the parental generation was considered to be 15 mg/kg bw/day  (based on a strong effect on body weight and food consumption in the High dose animals, and a slight but statistically significant effect in the Mid dose group).    
The NOAEL for reproductive effects of the parental generation: 45 mg/kg bw/day (based on marked adverse findings on pregnancy seen only in the High dose group, whereas statistical differences in the Mid dose were consistent with historical control ranges).    
The NOAEL for pups’ (F1 generation) development and survival: 15 mg/kg bw/day (based on the death of all High dose pups and based on Mid dose group statistically significant mortality data).

- A 90-day study was not available for the registered substance, however read across data were available from read-across substance in the same subgroup, CAS No. 37294-49-8 (disodium C-isodecyl sulphonatosuccinate). This key study for subchronic toxicity was performed in rats with test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975) at 0.25%, 1.00% and 4.00% in the diet (corresponding to mean calculated test article intake of 188, 750 and 3000 mg act.ingr./kg bw/day). At the highest dose levels, it caused a significant difference in body weight gain, most probably related to an effect by the compound during absorption from the gastro-intestinal tract. There was one mortality in the high dosed females. Haematology and serum analysis also indicated toxicity at the high dose, whereas at the medium dose, only some organ-to-body weight changes were observed (e.g. liver weight increases in both sexes). Other organ-to-body weight changes were also observed at the high dose group (e.g. slightly decreased gonad weights in males; decreased gonad weight in females); increased relative kidney weights were observed in all female dose groups. Chronic renal disease (mild) was observed in 1/20 males and 6/20 females of the high dose groups. The high dose was considered to be toxic, whereas the changes of the medium dose may be considered adaptive. Therefore 1% (750 mg/kg bw/day) may be considered as NOAEL and 0.25% (174 mg/kg bw/day) as NOEL.

- Subchronic toxicity testing with CAS No. 147993-66-6 is planned and will be updated later when results are available (currently waived in the dossier).

- For risk assessment, the lowest NOAEL of 15 mg/kg bw with registered substance tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS. This approach was considered conservative, as the NOAEL with read across substance in subchronic study with dietary administration was much higher. Further justification of assessment factors is explained in the DNEL justification document attached to the endpoint summary.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.96 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):

60

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

117 mg/m³

Explanation for the modification of the dose descriptor starting point:

Key ral OECD 422 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:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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:

10

Justification:

ECHA default factor.

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:

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:

2.81 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):

240

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

675 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Key ral OECD 422 toxicity study available; no repeated dose inhalation toxicity study available.

AF for dose response relationship:

1

Justification:

Different doses were tested, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. The factor for duration will become updated with new studies in near future. 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:

10

Justification:

ECHA default factor.

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:

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 hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.06 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):

240

Dose descriptor starting point:

NOAEL

Value:

15 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

15 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, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

ECHA default factor. Extrapolation from subacute 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:

10

Justification:

ECHA default factor.

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:

For remaining uncertainties that would result from the above assessment factors.

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

DNELs were based upon following source information:

- A key subacute OECD No. 422 study was conducted with the registered substance in Wistar rats (12/sex/group) by oral gavage at 0 (distilled water), 15, 45 and 90 mg/kg bw/day (Szaloki, 2022). Parameters measured during the study included twice a day mortality checking, daily routine and weekly detailed observation of clinical signs, weekly body weight and food consumption measurements and clinical pathology evaluation (including haematology, coagulation, clinical chemistry and urinalysis). Neurological assessment (Functional Observation Battery (FOB) including measurements of the landing foot splay, grip strength as well as locomotor activity measurement) was performed during the last week of the treatment for each sex. Reproductive performance is reported under Section 7.8. At termination (Day 28 for males, PPD (Post-partum Day) 14 for females), necropsy with macroscopic examination was performed. Weights of selected organs were recorded, and representative tissues/organs were sampled and preserved in appropriate fixatives from the adult animals or F1 animals. The thyroxine (T4) levels in the PND (Post-natal Day) 13 pups and parental males were also determined. For the adult animals, a detailed histological examination was performed on the selected list of retained organs of 5 animals/sex in the Control and High dose groups, the retained reproductive organs of all Control and High dose animals, liver from all animals and prostate and seminal vesicle of all males, the found dead animal or all organs with relevant macroscopic changes, and the male / female mating pair where no liveborn pups were achieved. In addition, the study was extended with a Mammalian Erythrocyte Micronucleus Test on bone marrow samples of all groups. Dosing formulations were analysed for concentration and/or homogeneity on three occasions during the study. Overall, the formulations were considered adequate for the study. In summary, Butanedioic acid, sulfo-, mono (C16-18 and C18-unsatd. alkyl) esters, ammonium sodium salts by oral gavage to Wistar rats at dose levels of 15, 45 or 90 mg/kg bw/day (Low, Mid and High dose groups, respectively) did not result in test item related mortality or clinical signs in the majority of animals. One High dose male had clinical signs of weakness and general poor condition, it was terminated early, but there was no pathology found that could indicate the aetiology of the test item effects; however the early termination is ascribed to treatment. Test item related adverse effect was observed on body weight, body weight gain parameters and food consumption in High dose (90 mg/kg bw/day) males and females. Test item related adverse effect was observed on body weight, body weight gain parameters and food consumption in Mid dose (45 mg/kg bw/day) females. In males, the High dose animals lost ~8.5% body weight in the first week of the study but gained weight thereafter; lower food intake in the High dose female group during lactation would have resulted in lower milk production (associated with loss of all pups in this group). 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. Statistically significant haematological changes comprised decreased reticulocytes (%) in the High dose female group with the value was outside of the historical control range, which was considered a test item related effect. Statistically significant clinical chemistry changes included increased alanine aminotransferase, ALT/GPT ratio and bile acid concentration in case of the High dose males were considered as test item related but none were of a magnitude to be considered clearly adverse. These changes were probably related to the low food intakes and/or the histopathology findings in the liver. No test item-related changes were observed in the urinalysis parameters in male and female animals of any dose groups when compared to control. Eleven females in the High dose group were pregnant. However, one female had no live born pups and four pregnant females had no delivery (100% of the embryos was resorbed). High dose pups who were live born were dead in three days after birth the latest. It was considered as test item related adverse effect. There were severe test item related effects on pup mortality or survival of the pups (F1 generation) in the High dose groups; slight but similar tendency was observed in the Mid dose group which was considered to be adverse. In summary for the reproductive effects, the changes in High dose males were most probably secondary to significant body weight loss during the study. However, in females a significant reduction in implantations was not associated with body weight or food intake effect and as such is probably a reprotoxic effect at the High dose. Death/resorption of embryos/foetuses at the High dose were treatment related, reduced numbers of pups born, relatively high numbers of pups born dead and the death of all High dose pups by Day 3, were considered as treatment related. During gestation, the lower body weight gain at the High dose was probably a reflection of the presence of fewer foetuses. It is not considered likely that the lower body weight of the dams caused to foetal losses. During gestation all High dose pups died, and the dams had a food intake similar to females with no litter; it is not possible to be sure if the low food intake caused low milk production and pup death, or if the lack of pups resulted in less milk production hence a lower food intake, although this was clearly a treatment related effect. In the Mid dose, there were statistically significant differences suggesting a similar trend to the High dose, a dose response could be observed from the data on these parameters. Test item-related pale discoloration of the liver were observed in 3/11 High dose males and in 7/7 High dose females. The prostate and seminal vesicles were small in 1/11 High dose male, considered as test item-related; seminal vesicles were also small in 1/12 Low dose males, of uncertain relationship with treatment.Test item-related changes were observed in the parental organ weights of the liver of Mid (~14%) and High dose male animals (~35%). Multifocal/diffuse hepatocellular vacuolation at 90 mg/kg bw/day dose level both in males and females were observed, ascribed to test item, but not considered as adverse. Reduced weights of the prostate and seminal vesicles in High dose males, compared to controls, was probably secondary to the ~8.5% body weight loss in the first week of the study. No adverse test item related changes were observed in the female animal organ weights. In the parameters measured in adults and pups, there was no evidence for any neurotoxicity and no effects on thyroids or other endocrine systems, and no evidence for immunological effects in immunocompetent organs or tissues.       
No test item-related effect, thus no evidence of genotoxic activity was seen in the Mammalian Erythrocyte Micronucleus Test.    
The NOAEL for systemic toxicity of the parental generation was considered to be 15 mg/kg bw/day  (based on a strong effect on body weight and food consumption in the High dose animals, and a slight but statistically significant effect in the Mid dose group).    
The NOAEL for reproductive effects of the parental generation: 45 mg/kg bw/day (based on marked adverse findings on pregnancy seen only in the High dose group, whereas statistical differences in the Mid dose were consistent with historical control ranges).    
The NOAEL for pups’ (F1 generation) development and survival: 15 mg/kg bw/day (based on the death of all High dose pups and based on Mid dose group statistically significant mortality data).

- A 90-day study was not available for the registered substance, however read across data were available from read-across substance in the same subgroup, CAS No. 37294-49-8 (disodium C-isodecyl sulphonatosuccinate). This key study for subchronic toxicity was performed in rats with test item containing ca. 50% active ingredient (Tegeris and Underwood, 1975) at 0.25%, 1.00% and 4.00% in the diet (corresponding to mean calculated test article intake of 188, 750 and 3000 mg act.ingr./kg bw/day). At the highest dose levels, it caused a significant difference in body weight gain, most probably related to an effect by the compound during absorption from the gastro-intestinal tract. There was one mortality in the high dosed females. Haematology and serum analysis also indicated toxicity at the high dose, whereas at the medium dose, only some organ-to-body weight changes were observed (e.g. liver weight increases in both sexes). Other organ-to-body weight changes were also observed at the high dose group (e.g. slightly decreased gonad weights in males; decreased gonad weight in females); increased relative kidney weights were observed in all female dose groups. Chronic renal disease (mild) was observed in 1/20 males and 6/20 females of the high dose groups. The high dose was considered to be toxic, whereas the changes of the medium dose may be considered adaptive. Therefore 1% (750 mg/kg bw/day) may be considered as NOAEL and 0.25% (174 mg/kg bw/day) as NOEL.

- Subchronic toxicity testing with CAS No. 147993-66-6 is  planned and will be updated later when results are available (currently waived in the dossier).

- For risk assessment, the lowest NOAEL of 15 mg/kg bw with registered substance tested in the OECD 422 study was selected as dose descriptor for calculation of long term systemic DNELS. This approach was considered conservative, as the NOAEL with read across substance in subchronic study with dietary administration was much higher. Further justification of assessment factors is explained in the DNEL justification document attached to the endpoint summary.