Registration Dossier

Administrative data

Description of key information

Key studies for oral and dermal acute toxicity were performed, demonstrating LD50 >2000 mg/kg bw after both routes. Inhalation toxicity testing was waived based upon the fact that acute inhalation exposure as such is very unlikely for sulphosuccinates due to their substance properties and the risk management measures that are already implemented.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to GLP and valid methods, therefore the study is considered relevant, adequate and reliable for classification.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: CD/Crl:CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: At start of administration: approx. 8 weeks
- Weight at study initiation: At start of administration: 169 - 184 g
- Fasting period before study: Approx. 16 hours before administration (only tap water was then available ad libitum)
- Housing: During the 14-day observation period the animals were kept in groups of 3 animals in MAKROLON cages ( type III plus) . Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet (e.g. ad libitum): Commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (e.g. ad libitum): Drinking water in bottles was offered ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C (maximum range)
- Humidity (%): 55% ± 15% (maximum range)
- Air changes (per hr): 12 to 18-fold air change per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: July 18, 2012 To: August 7, 2012
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 4.22 mL/kg bw

DOSAGE PREPARATION (if unusual):
Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts was used as supplied. The administration volume was 4.22 mL/kg bw for a dose of 2000 mg/kg bw as the density of the test item was 1.14 g/mL and a correction factor of 2.41 was employed in order to correct for a content of the solid material of 41.5% only.
The pH value of the supplied test item was 6.4.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The dose used is selected from a series of defined dose levels. Due to the small number of animals used with this method, there is no need to perform a range finding test.

Doses:
1 dose group (Limit test): 2000 mg/kg bw (dose level refers to the solids ingredients of the test item)
No. of animals per sex per dose:
6
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration. All surviving animals were observed for a period of 14 days. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study. Changes in weight were calculated and recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (changes of skin and fur, eyes and mucous membranes, respiratory and the circulatory, autonomic and central nervous system and somatomotor activity as well as behaviour pattern; tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma), body weight, gross pathology
Statistics:
No statistical analysis could be performed (the method used is not intended to allow a calculation of a precise LD50 value).
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: actual ingested (gavage)
Mortality:
No death was recorded within the test period.
Clinical signs:
Under the present test conditions, a single oral administration of 2000 mg Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)¬alkyl))¬amino]ethyl]esters, disodium salts/kg bw did not reveal any signs of toxicity.
Body weight:
All animals gained the expected weight throughout the whole study period.
Gross pathology:
No pathological changes were observed at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
According to the EC-Commission directive 67/548/EEC and its subsequent amendments on the approximation of the laws, regulations and administrative provision relating to the classification, packaging and labelling of dangerous substances and the results obtained under the present test conditions, Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts requires no classification (as LD50 > 2000 mg/kg).
Also, according to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute oral toxicity.
Executive summary:

In this experiment Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts was examined for acute toxicity after a single oral administration to 6 female CD/Crl:CD(SD)rats. The test substance dosed by oral gavage at 2000 mg active ingredient/kg bw did not reveal any signs of toxicity. No death was recorded within the 14 days observation period. All animals gained the expected weight throughout the whole study period. No pathological changes were observed at necropsy. The LD50 value was ranked exceeding 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High quality

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to GLP and valid methods, therefore the study is considered relevant, adequate and reliable for classification.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CD/Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: At dosing: Males: approx. 8 weeks; Females: Approx. 9 weeks
- Weight at study initiation: At dosing: Males: 215 - 237 g; Females: 217 – 239 g
- Fasting period before study: Approx. 16 hours before administration (only tap water was then available ad libitum)
- Housing: During the 14-day observation period the animals were kept in groups of 3 animals in MAKROLON cages ( type III plus) . Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany)
- Diet (e.g. ad libitum): Commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (e.g. ad libitum): Drinking water in bottles was offered ad libitum.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C (maximum range)
- Humidity (%): 55% ± 15% (maximum range)
- Air changes (per hr): Not provided
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: July 18, 2012 To: August 6, 2012
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: The shaved intact dorsal skin, between the fore and hind extremities
- % coverage: 5 cm x 6 cm, approx. 1/10 of body surface
- Type of wrap if used: The test item was held in contact with the skin with 8 layers of gauze. The gauze was covered with a plastic sheet and secured with adhesive plaster strips (Omniplast (P. HARTMANN AG, 89522 Heidenheim, Germany) on the application site for 24 hours

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

TEST MATERIAL
- Amount(s) applied (volume or weight with unit) 4.22 mL/kg bw
- Constant volume or concentration used: yes



Duration of exposure:
24 hours
Doses:
1 dose group (Limit test): 2000 mg/kg bw (dose level refers to the solids ingredients of the test item)
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations were performed before and immediately, 5, 15, 30 and 60 min, as well as 3, 6 and 24 hours after administration. All animals were observed for a period of 14 days. Individual body weights were recorded before administration of the test item and thereafter in weekly intervals up to the end of the study. Changes in weight were calculated and recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (changes of skin and fur, eyes and mucous membranes, respiratory and the circulatory, autonomic and central nervous system and somatomotor activity as well as behaviour pattern; tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma), body weight, gross pathology
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
None of the animals died prematurely.
Clinical signs:
Under the present test conditions, a single dermal administration of 2000 mg Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts/kg bw to rats revealed no signs of toxicity.
Body weight:
All animals gained the expected body weight throughout the whole experimental period.
Gross pathology:
No macroscopic findings were observed at necropsy.
Interpretation of results:
GHS criteria not met
Conclusions:
According to the EC-Commission directive 67/548/EEC and its subsequent amendments on the approximation of the laws, regulations and administrative provision relating to the classification, packaging and labelling of dangerous substances and the results obtained under the present test conditions,Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts requires no labeling (as LD50 > 2000 mg/kg).
Also, according to the EC Regulation 1272/2008 and subsequent regulations, the test material is not classified for acute dermal toxicity.
Executive summary:

In this experiment, Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1- oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts was examined for acute toxicity after a single dermal application to rats. One dose level of 2000 mg/kg bw was administered on the shaved intact dorsal skin, between the fore and hind extremities of 5 male and 5 female CD/Crl:CD(SD) rats. The test item was held in contact with the skin with 8 layers of gauze. The gauze was covered with a plastic sheet and secured with adhesive plaster strips on the application site for 24 hours. All animals were observed for a period of 14 days. Under the present test conditions, a single dermal administration of 2000 mg active ingredient/kg bw to rats revealed no signs of toxicity and no deaths. All animals gained the expected body weight throughout the whole experimental period. No macroscopic findings were observed at necropsy.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
High quality

Additional information

Acute oral toxicity

In a key oral acute toxicity study, the registered substance was examined for acute toxicity after a single oral administration to 6 female rats with a test item containing 41.5% active ingredient (Haferkorn, 2013a). The test item dosed by oral gavage at 2000 mg active ingredient/kg bw did not reveal any signs of toxicity. No death was recorded within the 14 days observation period. All animals gained the expected weight throughout the whole study period. No pathological changes were observed at necropsy. The LD50 value was ranked exceeding 2000 mg/kg bw. In conclusion there was no hazard for acute oral toxicity.

 

Acute dermal toxicity

In a key dermal toxicity study, the registered substance was examined for acute toxicity after a single dermal application to rats of test item containing 41.5% active ingredient (Haferkorn, 2013b). One dose level of 2000 mg active ingredient/kg bw was administered on the shaved intact dorsal skin, between the fore and hind extremities of 5 male and 5 female CD/Crl:CD(SD) rats. The test item was held in contact with the skin under occlusive dressing for 24 hours. All animals were observed for a period of 14 days. The test item revealed no signs of toxicity and no deaths. All animals gained the expected body weight throughout the whole experimental period. No macroscopic findings were observed at necropsy. In conclusion, LD50 exceeded 2000 mg/kg bw and there was no hazard for acute dermal toxicity;

 

Acute inhalation toxicity

Inhalation is very unlikely due to large particle size, low vapour pressure and high hydrophilic properties of the substance. Based on these and other physicochemical properties, the inhalation route is not appropriate; the oral and dermal route of administration are therefore applied as first and second relevant routes (ECHA R7a Guidance p 342). Additional inhalation testing would therefore neither lead to a better risk assessment, nor improve the safety of applications. On the basis of the argumentation summarized above an acute inhalation toxicity study is waived.

 

Conclusion

- The substance did not demonstrate any hazard for acute oral and dermal toxicity.

- Inhalation toxicity testing was waived based upon the fact that acute inhalation exposure as such is very unlikely.

 

Justification for selection of acute toxicity – oral endpoint key study 

Justification for selection of acute toxicity – dermal endpoint key study

Justification for classification or non-classification

Based on these results and according to the CLP Guidance (No. 1272/2008 of 16 December 2008), the test substance does not have to be classified and has no obligatory labelling requirement for acute oral and dermal toxicity.