3-[(4-aminobenzoyl)amino]propanoic acid

Endpoint summary

Description of key information

The acute oral toxicity study in rats shows that 4-aminobenzoyl-b-alanine is not toxic when administered as a single oral dose of 1000 mg/kg bw. No mortalities, adverse effects or clinical signs were observed during the study and this result is supported by the QSAR prediction performed using the U.S. EPA Toxicity Estimation Software Tool v4.2.1 (T.E.S.T.).

Both 4-aminobenzoyl-b-alanine (ABA) and its N-acetylated metabolite (NABA) are rapidly excreted from the systemic circulation via urine (see separate study summaries for TK (oral and iv)) without any bioaccumulation (based on the rate of excretion and its negative log Pow of -1.19).

Therefore, ABA administered in an acute oral toxicity test would be rapidly removed from the rat, with very low risk of achieving toxic levels in any of the rat’s vital organs and hence highly unlikely to cause mortality especially since the maximum dose is only a factor of 2 higher than the 1000 mg/kg already shown to produce no mortality.

For acute toxicity therefore, it can be reasonably predicted, without the performance of a study, that the LD50 is > 2000 mg/kg.

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Qualifier:

no guideline followed

Principles of method if other than guideline:

No guideline is specified in the report.

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD (SD) BR

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 1% methylcellulose

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg bw

Doses:

1000 mg/kg bw

No. of animals per sex per dose:

3 animals per sex per dose

Control animals:

not specified

Details on study design:

All animals were observed for clinical signs and mortality for 7 days. At the end of the observation period, all animals were sacrificed and subjected to complete necropsy.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 000 mg/kg bw

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality was observed during the test.

Clinical signs:

other: No clinical signs were observed during the test.

Conclusions:

The acute oral non-lethal dose in rats was greater than 1000 mg/kg.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
U.S. EPA Toxicity Estimation Software Tool

2. MODEL (incl. version number)
U.S. EPA Toxicity Estimation Software Tool v4.2.1 (T.E.S.T.)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
Structure, CAS Number

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Acute oral toxicity
- Unambiguous algorithm: No
- Defined domain of applicability: Not specified
- Appropriate measures of goodness-of-fit and robustness and predictivity: The mean absolute error between the experimental and predicted value for the three most similar chemicals in the external test set (0.09) was lower than the value for the entire test set (0.43). This increases the confidence in the predicted value. Critical aspects are that the chemical structures of the most similar compounds in the test and training sets did not show a similarity index >0.8. Moreover, the mean absolute error between the experimental and predicted value for structurally related chemicals in the training set (0.57) was higher than the value for the entire test set (0.34).
- Mechanistic interpretation: Not applicable

5. APPLICABILITY DOMAIN
- Descriptor domain: This Consensus Method value for predicting the acute oral toxicity is the arithmetic mean of three different values obtained by the Hierarchical Clustering, FDA and Nearest Neighbor Method, respectively. To check if β-alanine, N-(4-aminobenzoyl)- falls in the descriptor domain of the QSAR model, the molecular weight and log Ko/w value were compared to the values of the three nearest neighbours and compounds in the cluster, respectively. The query substance showed a slightly higher molecular weight (208 versus 178 - 198) and lower log Ko/w value (0.03 versus 0.87 - 1.59, based on experimental values or KOWWIN v1.67 estimates).
- Structural and mechanistic domains: The slight difference in molecular weight and log Ko/w between the query substance and other compounds means that the result is considered reliable with restrictions.
- Similarity with analogues in the training set: Chemical structures of the most similar compounds in the test and training sets did not show a similarity index >0.8.

6. ADEQUACY OF THE RESULT
The prediction of acute oral toxicity of 4-aminobenzoyl-b-alanine is considered reliable within the constraints of QSAR predictions but is not considered appropriate for the purpose of assigning an acute toxicity classification. This is based on the fact that no mortality was observed at 1000 mg/kg bw in an acute oral toxicity study and that the available toxicokinetic data indicated a lack of accumulation and rapid excretion of 4-aminobenzoyl-b-alanine and its metabolite.

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Software tool used including version: U.S. EPA Toxicity Estimation Software Tool
- Model(s) used: U.S. EPA Toxicity Estimation Software Tool v4.2.1 (T.E.S.T.)
- Model description: see field 'Justification for type of information'
- Justification of QSAR prediction: see field 'Justification for type of information'

GLP compliance:

no

Dose descriptor:

LD50

Effect level:

1 122.23 mg/kg bw

Remarks on result:

other: QSAR predicted value

Conclusions:

The acute oral rat LD50 is predicted to be 1122.23 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 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

Justification for classification or non-classification

No mortalities, adverse effects or clinical signs were observed during the acute oral toxicity study. Based on this result and that 4-aminobenzoyl-b-alanine administered in an acute oral toxicity test would be rapidly removed from the rat, with very low risk of achieving toxic levels in any of the rat’s vital organs and hence mortality, it can be reasonably predicted, that the LD50 for 4-aminobenzoyl-b-alanine is > 2000 mg/kg. Therefore, 4-aminobenzoyl-b-alanine does not require classification for acute effects.