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Diss Factsheets

Administrative data

Description of key information

Oral: LD50 > 2000 mg/kg bw, OECD 423, EU Method B. 1 tris, Kiss 2012a.
Dermal: LD50 > 2000 mg/kg, OECD 402, EU Method B. 3, EPA OPPTS 870. 1200, Kiss 2012b.

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:
07 March 2012 to 22 March 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: CRL: (WI)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10 to 11 weeks old.
- Weight at study initiation: 220 to 235 g
- Fasting period before study: Animals were fasted the night before treatment, and then returned three hours after treatment.
- Housing: In groups of three, in polypropylene/polycarbonate cages.
- Diet: Complete diet for rats and mice, ad libitum.
- Water: tap water from the municipal supply ad libitum.
- Acclimation period: At least 20 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15 - 20 per hour.
- Photoperiod (hrs dark / hrs light): 12 hours per day, between 06:00 and 18:00 hours.

IN-LIFE DATES: From: 07 March 2012 To: 21/22 March 2012
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Distilled
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: The test amterial was freshly formulated at a concentration of 200 mg/mL in the vehicle, on the day of administration. The formulation container was stirred continuously up to finishing the treatment.

CLASS METHOD
- Rationale for the selection of the starting dose: The initial dose level was selected by the study director to be that which is most likely to produce mortality in some of the dosed animals. In the lack of any preliminary toxicological information, 2000 mg/kg bw was selected to be the starting dose.

DOSING
- Method: A group of three females were tested at the dose level initially, based on the findings a second group was dosed to confirm the results.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Three females per group.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days.
- Frequency of observations and weighing:
> Weighing: Body weights were recorded on the day before treatment (Day -1), on the day of the treatment (Day 0) and weekly thereafter.
> Clinical: Observations were recorded at 30 minutes, 1, 2, 3, 4 and 6 hours after dosing and daily for 14 days thereafter. Individual observations were performed on the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Necropsy of survivors performed: Yes, and macroscopic examination was performed on all animals. After examination of the external appearance, the cranial, thoracic and the abdominal cavities were opened and the organs and the tissues were observed. Macroscopic abnormalities were recorded.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities were observed in either group dosed at 2000 mg/kg bw.
Clinical signs:
other: No treatment related observations were made during the 14 day observation period.
Gross pathology:
No treatment related effects were observed.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, no mortalities or signs of toxicity were observed in animals treated at 2000 mg/kg bw. The LD50 was therefore considered to be greater than 2000 mg/kg bw.
Executive summary:

The acute oral toxicity of the test material was determined in a study conducted under GLP conditions and in line with OECD 423 and EU Method B. 1 tris, according to the acute toxic class method. Two groups of three females were dosed with the test material, formulated in distilled water, at 2000 mg/kg bw via oral gavage. Animals were observed for 14 days post treatment for mortality, clinical signs of toxicity, changes in body weight and macroscopic changes at necropsy.

Under the conditions of the study, no mortalities or signs of toxicity were observed in treated animals. The LD50 was therefore considered to be greater than 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The quality of the dataset is considered to be high.

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:
04 April 2012 to 18 April 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CRL: (WI)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young rats
- Weight at study initiation: 214 - 266g
- Housing: Individually in polypropylene/polycarbonate cages.
- Diet: Complete diet for rats and mice, ad libitum.
- Water: Municipal tap water, ad libitum.
- Acclimation period: 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15 - 20 per hour.
- Photoperiod (hrs dark / hrs light): 12 hours from 06:00 to 18:00 hours daily.

IN-LIFE DATES: From: 04 April 2012 To: 18 April 2012.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: On the back of each animal.
- % coverage: Approximately 10 % of the whole body surface area.
- Type of wrap if used: The test material was placed onto a gauze pad. The gauze pad was fixed with a hypoallergenic plaster and the entire trunk of the animal was then wrapped with semi occlusive plastic wrap.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): With body temperature water.
- Time after start of exposure: 24 hours.

TEST MATERIAL
Sufficient water to damp the material was used to ensure good contact with the skin.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
> Clinical: Observations were performed on the day of treatment at 1 and 5 hours after application of the test material and once each day for 14 days thereafter. Observations included the skin and fur, eyes and mucous membranes, the respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
> Bodyweight: Recorded on Day 0 (before exposure) and on Days 7 and 14.
- Necropsy of survivors performed: Yes, after examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed. All macroscopic changes were recorded.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortalities were observed in either males or females dosed at 2000 mg/kg bw.
Clinical signs:
other: No treatment related systemic or local signs of toxicity observed during the 14 day observation period.
Gross pathology:
No treatment related effects were observed. Bilateral uterine dilatation with clear fluid seen in 2/5 females was regarded as common background.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, no mortalities, systemic or local signs of toxicity were observed in animals treated at 2000 mg/kg bw. The LD50 was therefore considered to be greater than 2000 mg/kg bw.
Executive summary:

The acute dermal toxicity of the test material was determined in a study conducted under GLP conditions and in line with OECD 402, EU Method B. 3 and EPA OPPTS 870.1200, according to the standard acute method. Five male and five female rats were exposed to the test material in a limit test at 2000 mg/kg bw for 24 hours under an occlusive dressing.

Under the conditions of the study, no mortalities or treatment related systemic or local signs of toxicity were observed in animals treated at 2000 mg/kg bw. The LD50 was therefore considered to be greater than 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The quality of the dataset is considered to be high.

Additional information

Oral

Acute toxicity via the oral route is addressed with one key study and two supporting studies.

 

The key study (Kiss 2012a) was conducted under GLP conditions and in line with OECD 423 and EU Method B. 1 tris, according to the acute toxic class method and hence has been awarded a reliability score of 1, in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). Two groups of three females were dosed with the test material, formulated in distilled water, at 2000 mg/kg bw via oral gavage. Animals were observed for 14 days post treatment for mortality, clinical signs of toxicity, changes in body weight and macroscopic changes at necropsy. Under the conditions of the study, no mortalities or signs of toxicity were observed in treated animals. The LD50 was therefore considered to be greater than 2000 mg/kg bw.

 

The supporting study (Ichimura & Kirimura 1969) was performed using read across substance, sodium 5-oxo-DL-prolinate. Read across is considered to be suitable based on structural similarities between the read across substance and the substance. The study was performed following similar or equivalent methodology to the standardised guideline OECD 401. The study has been translated into English, however the full the study report is not available; therefore there is insufficient information to how the study was performed, hence this study has been designated a reliability score of 4, in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). Acute oral toxicity of sodium 5 -oxo-DL-prolinate was assessed using optional test groups of dd-line mice, which consisted of 10 mice in each group. In the case of the control group, solvent alone was administered in accordance with the case of the test groups. The dose levels administered are as follows: 7.02, 8.19, 9.36, 10.8, 12.3 and 14.0 g/kg. These concentrations were administered to each mouse in a constant volume per 10 g of mouse body weight by a stomach tube. The animals were under observation for 7 days and any mortality was recorded. Under the conditions of the study, the LD50 was found to be 10.4 g/kg (95 % confidence limit between 9.08 and 11.8 g/kg).

 

Another supporting study (Ishida 1997) was also performed using read across substance, 5-oxo-L-proline. Read across is considered to be suitable based on the structural similarities between read across substance, 5-oxo-L-proline and substance sodium 5-oxo-L-prolinate. The study was performed following similar or equivalent methodology to the standardised guideline OECD 401. As this study has been used for read across, and performed to standardised guidelines, it was awarded a reliability score of 2 in accordance with the criteria for assessing data quality as set forth by Klimisch et al. (1997). During the study, 5 male and 5 female (ICR) mice received a test material dose of 2000 mg/kg administered in a 0.5 w/v % carboxymethylcellulose sodium solution via gavage. The observation period was 14 days in which external appearance, nutritional value and behaviour were examined. No deaths were observed. Under the conditions of this study, the acute oral LD50 of the test material in male and female (ICR) mice was greater than 2000 mg/kg.

 

Inhalation

In accordance with point 8.5.2, Column 2 (Specific rules for adaptation from Column 1), Annex VIII of Regulation (EC) No. 1907/2006, an acute inhalation study does not need to be performed as use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur. The acute toxicity endpoint has been addressed by assessing the toxicity via the oral and dermal routes, which are more appropriate when considering the use pattern of this substance.

Dermal

The acute dermal toxicity of the test material was determined in a study conducted under GLP conditions and in line with OECD 402, EU Method B. 3 and EPA OPPTS 870.1200, according to the standard acute method. Five male and five female rats were exposed to the test material in a limit test at 2000 mg/kg bw for 24 hours under an occlusive dressing.

Under the conditions of the study, no mortalities or treatment related systemic or local signs of toxicity were observed in animals treated at 2000 mg/kg bw. The LD50 was therefore considered to be greater than 2000 mg/kg bw.

 


Justification for selection of acute toxicity – oral endpoint
This study was performed under GLP conditions and in accordance with standardised guidelines. It was assigned a reliability score of 1 in accordance with the criteria outlined in Klimisch (1997). It was therefore considered suitable to be the key study for this endpoint.

Justification for selection of acute toxicity – inhalation endpoint
A data waiver has been submitted to address acute toxicity via the inhalation route.

Justification for selection of acute toxicity – dermal endpoint
This study was performed under GLP conditions and in accordance with standardised guidelines. It was assigned a reliability score of 1 in accordance with the criteria outlined in Klimisch (1997). It was therefore considered suitable to be the key study for this endpoint.

Justification for classification or non-classification

Acute Oral Toxicity:

In accordance with criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the test material does not require classification as no signs of toxicity were noted during the course of the study.

Acute Dermal Toxicity:

In accordance with criteria for classification as defined in Annex I, Regulation (EC) No. 1272/2008, the test material does not require classification as no signs of toxicity were noted during the course of the study.