Sulfonation products of disodium sulfite with (esterification products of C9-11 (branched and linear) Alkyl Polyglycosides with maleic anhydride)

Endpoint summary

Description of key information

Available literature data regarding the group of alkyl polyglucosides permitted to evaluate the long-term effects produced by "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-) glycosides with maleic anhydride) with disodium sulfite". More in details, an oral subchronic repeated toxicity study, an oral combined repeated dose toxicity study with reproduction/developmental toxicity screening test and a dermal subacute repeated toxicity study were available and permitted to use the effect level values in the derivation of the no-effect levels (see DNEL Section). No inhalation repeated toxicity study is available because the exposure to "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-) glycosides with maleic anhydride) with disodium sulfite" through the inhalation route was considered not significant.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study is cited by CIR, 2011. Decyl Glucoside and Other Alkyl Glucosides as Used in Cosemtics. Final Safety Assessment.

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Main experiment: 10 males and 10 females.
Control: 5 males and 5 females.

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
250 mg/kg bw/day
Basis:
no data

Remarks:

Doses / Concentrations:
500 mg/kg bw/day
Basis:
no data

Remarks:

Doses / Concentrations:
1000 mg/kg bw/day
Basis:
no data

No. of animals per sex per dose:

Main experiment: 10 males and 10 females.
Control: 5 males and 5 females.

Control animals:

yes

Observations and examinations performed and frequency:

Animal were subjected to routine clinical observations. Their body weight and food and water consumption were recorded. Haematologicalm clinicochemical and ophtalmoscopic investigations were performedduring week 7 and 13. At the end of the treatment period, all the animals were subjected to general pathological examination and organ weight analizes. A wide range of tissues was fixed and examineted by microscope.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

2 mortalities.

Mortality:

mortality observed, treatment-related

Description (incidence):

2 mortalities.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

ulcers and oedema confined to the forestomach of the highest dose level.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

slowly reversible, dose-related irritation and ulceration of the mucous membrane of the forestomach of animals in the highest dose group.

Histopathological findings: neoplastic:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Dose descriptor:

other: NOAEC

Effect level:

2.5 other: %

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: irritation and ulcers in the forestomach

Critical effects observed:

not specified

Conclusions:

Systemic toxicity was not observed in any group. The NOAEL for systemic toxicity was 1000 mg/kg bw/day. The NOEC for “local compatibility” (irritation and ulceration of the mucous membrane of the forestomach) was deduced as 2.5% active ingredient.

Executive summary:

Sprague-Dawley rats were dosed by gavage with 0, 250, 500 and 1000 mg/kg bw/day C12/16 APG for 90 days. An additional 5 male and 5 female control and high dose rats were used as a recovery group. There were two fatalities, neither of which was linked to the test material. No treatment-related changes in body weights, organ weights, or biochemistry or hematology parameters were observed. Absolute gonad weights were decreased in all test groups, but the decrease was not considered treatment related by the researchers because of a lack of a dose-response. A dose-dependent, slowly reversible, irritation and ulceration of the forestomach mucosa was observed in animals of the 0.5 and 1 g/kg bw groups. Systemic toxicity was not observed in any group. The NOAEL for systemic toxicity was 1000 mg/kg bw. The NOEC for “local compatibility” (irritation and ulceration of the mucous membrane of the forestomach) was deduced as 2.5% active ingredient.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The combined repeated dose toxicity study with reproduction/developmental toxicity screening test confirms the results of the read-across study.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study cited by: CIR, 2011. Decyl Glucoside and Other Alkyl Glucosides as Used in Cosmetics. Final Safety Assessment.

Qualifier:

no guideline available

Deviations:

not applicable

Principles of method if other than guideline:

Using non-occlusive applications, 2 mL of 0, 0.06, 0.18, or 0.54 g a.i./kg caprylyl/capryl glucoside (60% active) in distilled water (corresponding to concentrations of 0, 3, 9, and 27% a.i., respectively) were applied to the intact skin of the backs of 6 male rabbits/group.

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Sex:

male

Type of coverage:

other: non-occlusive

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 days

Remarks:

Doses / Concentrations:
60 mg/kg bw/day
Basis:
nominal per unit area

Remarks:

Doses / Concentrations:
180 mg/kg bw/day
Basis:
nominal per unit area

Remarks:

Doses / Concentrations:
540 mg/kg bw/day
Basis:
nominal per unit area

No. of animals per sex per dose:

6 males per group

Clinical signs:

not specified

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

slight to moderate

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

decrease

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

not statistically significative decrease in testes weight

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group. No test article-related microscopic changes were observed in the testes or accessory sex glands at any dose.

Dose descriptor:

NOAEL

Effect level:

180 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: Decrease in body and testes weight, not statistically significative.

Dose descriptor:

LOAEL

Effect level:

60 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: Slight to moderate dermal irritation.

Critical effects observed:

not specified

Conclusions:

In the main study, treatment-related signs of toxicity were not observed. Slight dermal irritation was observed in all groups after the initiation of dosing; the irritation became moderate in the high dose group after 3 days of dosing. Microscopically, epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group; these changes were not observed in rabbits of the other test groups. Body weights of rabbits of the high dose group were slightly, but significantly, decreased compared to controls. Absolute testes weights were slightly, but not significantly, decreased in the high dose group. Microscopically, no test article-related microscopic changes were observed in the testes or accessory sex glands at any dose. No treatment-related effects on hematology or clinical chemistry values or organ weights were reported. The NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside.

Executive summary:

In a 14 -day study, using non-occlusive applications, 2 mL of 0, 60, 180, or 540 g active ingredient/kg caprylyl/capryl

glucoside (60% active) in distilled water were applied to the intact skin of the backs of 6 male rabbits/group. Slight dermal irritation was observed in all groups after the initiation of dosing; the irritation became moderate in the high dose group after 3 days of dosing. Microscopically, epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group; these changes were not observed in rabbits of the other test groups. Body weights of rabbits of the high dose group were slightly, but significantly, decreased compared to controls. Absolute testes weights were slightly, but not significantly, decreased in the high dose group. Microscopically, no test article-related changes were observed in the testes or accessory sex glands at any dose.

No treatment-related effects on hematology or clinical chemistry values or organ weights were reported. The NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

180 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study cited by: CIR, 2011. Decyl Glucoside and Other Alkyl Glucosides as Used in Cosmetics. Final Safety Assessment.

Qualifier:

no guideline available

Deviations:

not applicable

Principles of method if other than guideline:

Using non-occlusive applications, 2 mL of 0, 0.06, 0.18, or 0.54 g a.i./kg caprylyl/capryl glucoside (60% active) in distilled water (corresponding to concentrations of 0, 3, 9, and 27% a.i., respectively) were applied to the intact skin of the backs of 6 male rabbits/group.

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Sex:

male

Type of coverage:

other: non-occlusive

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 days

Remarks:

Doses / Concentrations:
60 mg/kg bw/day
Basis:
nominal per unit area

Remarks:

Doses / Concentrations:
180 mg/kg bw/day
Basis:
nominal per unit area

Remarks:

Doses / Concentrations:
540 mg/kg bw/day
Basis:
nominal per unit area

No. of animals per sex per dose:

6 males per group

Clinical signs:

not specified

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

slight to moderate

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

decrease

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

not statistically significative decrease in testes weight

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group. No test article-related microscopic changes were observed in the testes or accessory sex glands at any dose.

Dose descriptor:

NOAEL

Effect level:

180 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: Decrease in body and testes weight, not statistically significative.

Dose descriptor:

LOAEL

Effect level:

60 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: Slight to moderate dermal irritation.

Critical effects observed:

not specified

Conclusions:

In the main study, treatment-related signs of toxicity were not observed. Slight dermal irritation was observed in all groups after the initiation of dosing; the irritation became moderate in the high dose group after 3 days of dosing. Microscopically, epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group; these changes were not observed in rabbits of the other test groups. Body weights of rabbits of the high dose group were slightly, but significantly, decreased compared to controls. Absolute testes weights were slightly, but not significantly, decreased in the high dose group. Microscopically, no test article-related microscopic changes were observed in the testes or accessory sex glands at any dose. No treatment-related effects on hematology or clinical chemistry values or organ weights were reported. The NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside.

Executive summary:

In a 14 -day study, using non-occlusive applications, 2 mL of 0, 60, 180, or 540 g active ingredient/kg caprylyl/capryl

glucoside (60% active) in distilled water were applied to the intact skin of the backs of 6 male rabbits/group. Slight dermal irritation was observed in all groups after the initiation of dosing; the irritation became moderate in the high dose group after 3 days of dosing. Microscopically, epithelial hyperplasia, hyperkeratosis, congestion, and eschar formation were observed in the skin of rabbits of the high dose group; these changes were not observed in rabbits of the other test groups. Body weights of rabbits of the high dose group were slightly, but significantly, decreased compared to controls. Absolute testes weights were slightly, but not significantly, decreased in the high dose group. Microscopically, no test article-related changes were observed in the testes or accessory sex glands at any dose.

No treatment-related effects on hematology or clinical chemistry values or organ weights were reported. The NOEL for systemic toxicity was 0.18 g a.i./kg caprylyl/capryl glucoside.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

1.18 mg/cm²

Study duration:

subacute

Species:

rabbit

Additional information

In the oral repeated toxicity studies, no systemic effects were observed after the administration of the substance, therefore the NOAEL was set at the highest dose tested (1000 mg/kg bw/day). Locally, instead, oedema and ulceration of the forestomach were noted in the highest dose group.

In the dermal repeated toxicity study, no significative systemic effects were observed, with the exception of a slight decrease in body weights. The NOAEL for systemic toxicity was set at 180 mg/kg bw/day. Locally, instead, slight dermal irritation was noted in all dosage groups, but it became moderate in the highest dose-group after 3 days treatment. The LOAEL for local effects was evaluated to be 60 mg/kg bw/day (1.18 mg/cm3).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study refers to the category of alkyl polyglucosides, and "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-)glycosides with maleic anhydride) with disodium sulfite" pertains to this group.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
The study refers to the category of alkyl polyglucosides, and "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-)glycosides with maleic anhydride) with disodium sulfite" pertains to this group.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
The study refers to the category of alkyl polyglucosides, "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-)glycosides with maleic anhydride) with disodium sulfite" pertains to this group.

Justification for classification or non-classification

No severe systemic effects were observed, neither in the oral repeated toxicity study, nor in the dermal repeated toxicity study.

Local effects produced by group of alkyl polyglucosides were coherent with the classification of "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-)glycosides with maleic anhydride) with disodium sulfite" for acute effects. Indeed skin irritation resulted to be slight, while irritation of mucose membrane produced slowly reversible effects, as for acute eye exposure.

Results of repeated toxicity studies did not lead to the classification of "Sulfonation products of (esterification products of C9-11 (branched and linear) alkyl-(mono-, di- and tri-)glycosides with maleic anhydride) with disodium sulfite" for long term effects.

Specific Target Organ Toxicity after Repeated Exposure:

Classification: not required

Signal word: none

Hazard statement: none