Dl-Proline, 5-oxo-, compd. with N2-coco acyl-l-arginine Et ester

Endpoint summary

Description of key information

QSAR Predictions

Toxicity of the target test material component 1 was predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2742 mg/kg bw.

Toxicity of the target test material component 2 predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2106 mg/kg bw.

The LD50 of both components was therefore predicted to be 2106 mg/kg bw.

Supporting Study (Mihara, 2008)

Under the conditions of the study, the LD50 was estimated to be greater than 3.0 g/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

12 November 1987 to 21 December 1987

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was conducted in accordance with generally accepted scientific principles, possibly with incomplete reporting or methodological deficiences which do not affect the quality of the relevant results. This study has been awarded a reliability score of 4, in accordance with the criteria set out in Klimisch, 1997. The study report has been translated into English; however, the full translation of the study report is not available. Therefore there is simply not enough information regarding how the study was performed to be able to give the study a higher reliability score.

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

ICR

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4 weeks old
- Weight at study initiation: 23.5 to 27.4 g
- Fasting period before study: 8 hours before administration
- Housing: 5 animals per cage in polycarbonate cages
- Diet: ad libitum to solid rodent feed
- Water: ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 3 °C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 12 times per hour
- Photoperiod (hrs dark / hrs light): 12 hours of lighting (from 7 a.m. to 7 p.m.)

Route of administration:

oral: unspecified

Vehicle:

olive oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 2.5 and 7.5 %
- Amount of vehicle (if gavage): 0.4 mL/10g

Doses:

1.0 g/kg and 3.0 g/kg

No. of animals per sex per dose:

10 mice.

Control animals:

no

Details on study design:

- Frequency of observations and weighing: The number of deaths was observed once daily in the morning. Acute toxicity symptoms were observed until 2 hours after administration (Day 1). Clinical signs of all surviving animals were observed on Day 1 before treatment, and thereafter once daily in the morning (from Day 2 to Day 7). Animal bodyweights were measured on Days 1, 2 and 7.

Sex:

male

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study period.

Clinical signs:

Decrease in locomotor activity, irregular respiration, eyelid closure, smug of the genital region, crouching position, prone position, slow respiration, unkept fur, and gasping were observed during the observation period as acute toxicity symptoms (until 2 hours after administration). These signs disappeared on the next day. There were no other abnormal clinical signs during the study period.

Body weight:

One animal of 1.0 g/kg test material treatment showed a loss of body weight at day 2. Other animals showed body weight gain during the study period.

Gross pathology:

All animals showed no abnormal findings at necropsy.

Table 1: Clinical signs of individual animals

DOSE (mg/kg)	SEX	Animal No.	Day
			1		2	3	4	5	6	7
			a)	b)	-	-	-	-	-	-
1.0	Male	1	-	A, E, F, G, H	-	-	-	-	-	-
		2	-	A, D, E	-	-	-	-	-	-
		3	-	A, D, E	-	-	-	-	-	-
		4	-	A, B, C, E, F	-	-	-	-	-	-
		5	-	A, E	-	-	-	-	-	-
3.0	Male	1	-	A, D, E	-	-	-	-	-	-
		2	-	A, D, E	-	-	-	-	-	-
		3	-	A, D, E	-	-	-	-	-	-
		4	-	A, I, D, E	-	-	-	-	-	-
		5	-	A, D, E	-	-	-	-	-	-

-: No abnormal findings, A: Decrease of locomotor activity, B: Irregular respiration, C: Eyelid closure, D: Smug of the genital region, E: Crouching position, F: Prone position, G: Slow respiration, H: Unkept fur, I: Gasping

a) Before administration

b) Observation period for acute toxicity symptoms (until 2 hours after administration)

 

Interpretation of results:

other: Not classified according to EU criteria.

Conclusions:

Under the conditions of the study, the LD50 was estimated to be greater than 3.0 g/kg body weight.

Executive summary:

This study has been awarded a reliability score of 4, in accordance with the criteria set out in Klimisch, 1997. The study report has been translated into English; however, the full translation of the study report is not available. Therefore there is simply not enough information regarding how the study was performed to be able to give the study a higher reliability score.

The test material was administered once to mice at the dosage of 1.0 and 3.0 g/kg body weight. No abnormalities were observed after administration, and under the conditions of the study, the LD50 was estimated to be greater than 3.0 g/kg body weight.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

T.E.S.T. (Toxicity Estimation Software Tool, US EPA 2015) estimates the toxicity values and physical properties of organic chemicals based on the molecular structure of the organic chemical entered by the user. It allows the estimation of toxicity values using several different advanced Quantitative Structure Activity Relationship (QSAR) methodologies (Martin et al. 2008):
- Hierarchical method: The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster.
- FDA method: The prediction for each test chemical is made using a new model that is fitted to the chemicals that are most similar to the test compound.
- Single model method: Predictions are made using a multi-linear regression model that is fitted to the training set (using molecular descriptors as independent variables) using a genetic algorithm based approach.
- Group contribution method: Predictions are made using a multi-linear regression model that is fitted to the training set (using molecular fragment counts as independent variables).
- Nearest neighbour method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical.
- Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains) and was shown to achieve the best prediction results during external validation.

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6. May/July 2006

Deviations:

not specified

Principles of method if other than guideline:

T.E.S.T. (Toxicity Estimation Software Tool, US EPA 2015) estimates the toxicity values and physical properties of organic chemicals based on the molecular structure of the organic chemical entered by the user. It allows the estimation of toxicity values using several different advanced Quantitative Structure Activity Relationship (QSAR) methodologies.

GLP compliance:

no

Remarks:

As no laboratory work took place, compliance with GLP is not required.

Specific details on test material used for the study:

Component 1

Species:

rat

Sex:

not specified

Dose descriptor:

LD50

Effect level:

ca. 2 742 mg/kg bw

Toxicity of the target chemical (LD50 2742 mg/kg) is predicted by QSAR. The current prediction has no applicability domain.

Conclusions:

Toxicity of the target chemical was predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2742 mg/kg bw.

Executive summary:

The potential of the test material to cause acute oral toxicity to rats was modelled using the Consensus method in T.E.S.T.

Toxicity of the target chemical was predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2742 mg/kg bw.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source

Justification for type of information:

T.E.S.T. (Toxicity Estimation Software Tool, US EPA 2015) estimates the toxicity values and physical properties of organic chemicals based on the molecular structure of the organic chemical entered by the user. It allows the estimation of toxicity values using several different advanced Quantitative Structure Activity Relationship (QSAR) methodologies (Martin et al. 2008):
- Hierarchical method: The toxicity for a given query compound is estimated using the weighted average of the predictions from several different models. The different models are obtained by using Ward’s method to divide the training set into a series of structurally similar clusters. A genetic algorithm based technique is used to generate models for each cluster.
- FDA method: The prediction for each test chemical is made using a new model that is fitted to the chemicals that are most similar to the test compound.
- Single model method: Predictions are made using a multi-linear regression model that is fitted to the training set (using molecular descriptors as independent variables) using a genetic algorithm based approach.
- Group contribution method: Predictions are made using a multi-linear regression model that is fitted to the training set (using molecular fragment counts as independent variables).
- Nearest neighbour method: The predicted toxicity is estimated by taking an average of the 3 chemicals in the training set that are most similar to the test chemical.
- Consensus method: The predicted toxicity is estimated by taking an average of the predicted toxicities from the above QSAR methods (provided the predictions are within the respective applicability domains) and was shown to achieve the best prediction results during external validation.

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.6. May/July 2006

Deviations:

not specified

Principles of method if other than guideline:

T.E.S.T. (Toxicity Estimation Software Tool, US EPA 2015) estimates the toxicity values and physical properties of organic chemicals based on the molecular structure of the organic chemical entered by the user. It allows the estimation of toxicity values using several different advanced Quantitative Structure Activity Relationship (QSAR) methodologies.

GLP compliance:

no

Remarks:

As no laboratory work took place, compliance with GLP is not required.

Specific details on test material used for the study:

Component 2

Species:

rat

Sex:

not specified

Dose descriptor:

LD50

Effect level:

ca. 2 106 mg/kg bw

Toxicity of the target chemical (LD50 2106 mg/kg) is predicted by QSAR. The current prediction has no applicability domain.

Conclusions:

Toxicity of the target chemical was predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2106 mg/kg bw.

Executive summary:

The potential of the test material to cause acute oral toxicity to rats was modelled using the Consensus method in T.E.S.T.

Toxicity of the target chemical was predicted by T.E.S.T. using the Consensus method. The target chemical was predicted to have an LD50 of 2106 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 106 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

QSAR Predictions

The potential of the test material to cause acute oral toxicity to rats was modelled using the Consensus method in T.E.S.T. Toxicity of component 1 of the target chemical was predicted to have an LD50 of 2742 mg/kg bw.

The potential of the test material to cause acute oral toxicity to rats was modelled using the Consensus method in T.E.S.T. Toxicity of component 2 of the target chemical was predicted to have an LD50 of 2106 mg/kg bw.

The overall LD50 of the test material was predicted to be 2106 mg/kg bw.

Supporting Study (Mihara, 2008)

This study has been awarded a reliability score of 4, in accordance with the criteria set out in Klimisch, 1997. The study report has been translated into English; however, the full translation of the study report is not available. Therefore there is simply not enough information regarding how the study was performed to be able to give the study a higher reliability score.

The test material was administered once to mice at the dosage of 1.0 and 3.0 g/kg body weight. No abnormalities were observed after administration, and under the conditions of the study, the LD50 was estimated to be greater than 3.0 g/kg body weight.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the oral route.