Benzoic acid, 4-hydroxy-, C18-22-alkyl esters

Endpoint summary

Description of key information

LD50 oral: > 2000 mg/kg bw
LD50 dermal: > 2000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties along with data, which each alone are regarded insufficient for assessment (Klimisch score 4). Read-across is justified based on common functional groups, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details). However, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Basic data given.

Principles of method if other than guideline:

The study was conducted before test guidelines were established.
Six rabbits were treated with the test item in a limit test under occlusive conditions. Half of the animals were dosed on abraded skin, the remaining animals were dosed on intact skin.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

No information given in the study report.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Concentration (if solution): neat
- Constant volume or concentration used: yes

Duration of exposure:

no data

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
No further details are given in the study report.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The animals were tested on both abraded and intact skin.

Mortality:

1/3 males died; no further mortalities occurred throughout the study period.
No further information is given in the study report.

Clinical signs:

other: No details given in the study report.

Gross pathology:

No details given in the study report.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch score 2) study from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional groups, common precursors/breakdown products and similarities in physicochemical and toxicological properties (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Justification for grouping of substances and read-across

No data are available on the acute toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0). In order to fulfil the standard information requirements set out in Annex VIII in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substances depicted in the table below are selected as source substances for assessment.

The read-across is based on the identified structural similarities and the likelihood of common breakdown products by biological processes (metabolism). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

CAS	201305-16-0 TARGET SUBSTANCE	68411-27-8	99-76-3	120-47-8	94-13-3	94-26-8
Chemical Name	Benzoic acid, 4-hydroxy-, C18-22-alkyl esters	Benzoic acid,C12-15-alkyl esters	Methyl 4-hydroxybenzoate	Ethyl 4-hydroxybenzoate	Propyl 4-hydroxybenzoate	Butyl 4-hydroxybenzoate
MW	390.60-446.71 g/mol	311 g/mol	152.15 g/mol	166.18 g/mol	180.2 g/mol	194.23 g/mol
Acute toxicity oral	RA woe: CAS 16958-92-2, 99-76-3, 120-47-8, 94-13-3, 94-26-8	Experimental result: LD50 (rat) = 34500 mg/kg bw	Experimental result: LD50 (mouse) > 8000 mg/kg bw	Experimental result: LD50 (mouse) = 6008 mg/kg bw	Experimental result: LD50 (mouse) = 6332 mg/kg bw	Experimental result: LD50 (mouse) = 13200 mg/kg bw
Acute toxicity inhalation	RA: CAS 68411-27-8	LC50 (rat) > 50 mg/L	--	--	--	--
Acute toxicity dermal	RA: CAS 68411-27-8	Experimental result: LD50 (rabbit) > 2000 mg/kg bw	--	--	--	--

Lack of data is indicated by --

Acute oral toxicity

No data are available for the acute oral toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0). To sufficiently cover this endpoint, data from structurally related substances, i.e. Benzoic acid, C12-15-alkyl esters; Methyl 4-hydroxybenzoate; Ethyl 4-hydroxybenzoate; Propyl 4-hydroxybenzoate; Butyl 4-hydroxybenzoate are used for read-across based on an analogue approach.

In a non-GLP study conducted similarly to OECD Guideline 401, the acute oral toxicity of Benzoic acid, C12-15-alkyl esters was studied in male and female albino rats (Brown, 1979). Three animals of each sex were treated with the undiluted test item at doses of 30000, 33000, 37000 and 40000 mg/kg bw via gavage and were observed for a period of 14 days. Dose groups were based on a preliminary range-finding study and the maximum dose volume applied was 40 mL/kg bw. During the main study no mortality was observed at the lowest dose group. However, 4/6, 5/6 and 4/6 animals died at dose groups of 33000, 37000 and 40000 mg/kg bw, respectively. No further details were given. The LD50 was reported to be 34500 mg/kg bw.

Further data are available as short abstracts only for Ethyl 4-hydroxybenzoate (Sado, 1973), Propyl 4-hydroxybenzoate and Butyl 4-hydroxybenzoate. The acute oral toxicity of each substance was assessed according to a standard acute method similar to OECD Guideline 401 (1981). Male mouse were treated with the test item via gavage with a maximum dose volume of 1 mL/animal. No dose levels were reported. Olive oil was used as vehicle. The LD50 were reported to be 6008, 6332 and 13200 mg/kg bw for Ethyl 4-hydroxybenzoate; Propyl 4-hydroxybenzoate and Butyl 4-hydroxybenzoate, respectively .

A further study performed with Propyl 4-hydroxybenzoate was performed similarly to OECD Guideline 401 in albino mice (Matthews, 1956). Animals were fasted 12 h prior to gavage of unreported doses of test item. The maximum dose volume was 10 mL/kg bw but was increased at higher dose levels. The observation period was 7 days. There was a rapid onset of ataxia and deep depression resembling anaesthesia. In case of mortality this was observed within 1 h after treatment. Clinical signs of toxicity comprised increased motor activity seldom lasting beyond 30 min. The LD50 was reported to be > 8000 mg/kg bw.

The acute oral toxicity of Methyl 4-hydroxybenzoate was assessed under the same conditions as described for the previous study (Matthews, 1956). Under these conditions the LD50 was reported to be > 8000 mg/kg bw.

Although the quality of some studies was not assessable and reporting of details was often limited, the available data on acute oral toxicity draw a coherent picture for the structurally related substances. The oral LD50 of the target substance can be anticipated to be greater than 2000 mg/kg bw.

Acute inhalation toxicity

No data are available for the acute inhalation toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0). To sufficiently cover this endpoint, data from the structurally related substance, i.e. Benzoic acid, C12-15-alkyl esters was used for read-across based on an analogue approach.

The study with Benzoic acid, C12-15-alkyl esters did not follow any Guideline but the study was performed before testing guidelines were available. Albino rats in groups of 10 ( 5 males and 5 females) were exposed to a concentration of 200 mg/L for 1 h, followed by a post-exposure observation period of 2 weeks (Brown, 1979b). One male died within the study period. No further details were reported. The LC50 was reported to be greater than 200 mg/L air. Corrected for the differences of exposure duration according to the Guidance on the Application of the CLP Criteria (Version 3.0, Nov 2012), Section 3.1.2.2, Table 3.1.1 Note (b) the LC50 after 4 h exposure period is estimated to be greater than 50 mg/L air.

Based on this data no classification for acute inhalation toxicity is needed. However, the reliability of the study was not assessable as only a study summary with limited information was available. Further inhalation toxicity testing with Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0) is however not needed. According to Regulation (EC) No 1907/2006, Annex VIII, Section 8.5, Column 2, in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for the relevant route. The target substance is used in liquid media and due to its very low vapour pressure (< 0.0001 Pa at 20°C) inhalation is not viewed as a significant route of exposure. Inhalation of the target substance may occur by inhalation of aerosols generated by spray applications. However, spray applications are not an identified use of the target substance and therefore exposure to the target substance via the inhalation route is unlikely. Taken into account that the acute toxicity of the target substance is generally low no further information on acute toxicity is expected by testing for acute inhalation toxicity. As information under 8.5.3 (dermal route) is provided, the requirement of Regulation (EC) No 1907/2006, Annex VIII, is fulfilled by using the most appropriate route of exposure.

Acute dermal toxicity

No data are available for the acute dermal toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0). To sufficiently cover this endpoint, data from the structurally related substance, i.e. Benzoic acid, C12-15-alkyl esters were used for read-across based on an analogue approach. The study with Benzoic acid, C12-15-alkyl esters did not follow any guideline as the study was performed before testing guidelines were available. Three male and three female rabbits were treated with the undiluted test item in a limit test under occlusive conditions (Brown, 1979c). Half of the animals were dosed on abraded skin and the remaining animals were dosed on intact skin. The observation period lasted 14 days following administration. One male rabbit died during the study period. No further information is given in the study report. The LD50 was reported to be > 2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
Hazard assessment is conducted by means of read-across from structural analogues and based on the weight of evidence from all available studies.

Justification for selection of acute toxicity – dermal endpoint
Hazard assessment is conducted by means of read-across from a structural analogue/surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the structurally similar substances, the available data on oral, inhalation and dermal toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.