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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Data waiving – OECD 416: PFAE aromatic category

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", “information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. In accordance with Section 1.2 of REACH Annex XI, there is sufficient weight of evidence from several independent sources of information leading to the conclusion that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0) does not cause toxicity to reproduction and thus does not have to be classified, because based on an analogue approach.

- in vitro hydrolysis evaluated according to the method described in EFSA Note for Guidance for Food Contact Materials indicates rapid ester hydrolysis of the registered substance in digestive fluid resulting in the formation of 4-hydroxy benzoic acid (excreted via urine) and ultimately C18-C22 fatty acids which will then depending on the energy needs of the body undergo fatty acid ana- or catabolism, thus 4 hydroxy benzoic acid is the main metabolite that should be considered when addressing reproductive toxicity

- no effects on reproductive organs and no influence on sperm parameters and testosterone, LH/FSH blood levels when applied up to 1000 mg/kg bw/d to male rats was observed in a 56 day dietary study in Methylparaben (Oishi, 2004, as cited in Soni et al. 2005)

- no significant effect was seen in the uterotrophic assay with Methylparaben up to 800 mg/kg bw/d (Routledge,J. et al., 1998, as cited in Soni et al., 2005)).

- no influence on reproductive performance was noted in a female dog which had been mated towards the end of a non-rodent subchronic study where it was dosed with 500 mg/kg bw Methylparaben for more than 300 days. The animal delivered a litter of healthy pubs (Matthews et al., 1956)

- in developmental studies in rabbits, rats, hamsters and guinea pigs no maternal or developmental effect was seen with 4-hydroxy benzoic acid esters (FDRL, 1973, FDRL, 1972, as cited in Soni et al. 2005)

It can therefore be concluded with sufficient certainty that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0) will not cause toxicity to reproduction and that testing is not scientifically necessary.

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within the CSR.

Short description of key information:
data waiving

Effects on developmental toxicity

Description of key information

Developmental toxicity study (similar to OECD 414), oral, rabbit: NOEL maternal: ≥300 mg/kg bw/day; NOEL developmental: ≥300 mg/kg bw/day; NOEL teratogenicity: ≥300 mg/kg bw/day,

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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: Well documented study, conducted similar to guideline.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(only 12 animals were tested in the high dose group and body weights were recorded every 6 days only)

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

other: Dutch-belted

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: virgin, adult females
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: tap water, ad libitum

ENVIRONMENTAL CONDITIONS
Temperature and humidity controlled (not further specified)

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: artificial insemination
On Day 0, each doe was given an injection of 0.4 mL human chorionic gonadotropin (400 IU) via the marginal ear vein. 3 hours later, each doe was inseminated artificially with 0.3 mL of diluted semen from a proven donor buck using approximately 20E+6 motile sperm.

Duration of treatment / exposure:

Test item:
Day 6 through Day 18 of gestation

Positive control substance:
on Day 9 of gestation

Frequency of treatment:

Test groups: daily
Positive control group: single gaveage

Duration of test:

29 days

No. of animals per sex per dose:

- Vehicle control: 14 inseminated animals (11 pregnant animals)
- Positive control: 17 inseminated animals (10 pregnant animals)
- Test item 3.0 mg/kg bw/d Methylparaben: 20 inseminated animals (9 pregnant animals)
- Test item 14.0 mg/kg bw/d Methylparaben: 20 inseminated animals (9 pregnant animals)
- Test item 65.0 mg/kg bw/d Methylparaben: 14 inseminated animals (10 pregnant animals)
- Test item 300.0 mg/kg bw/d Methylparaben: 12 inseminated animals (9 pregnant animals)

Control animals:

yes, concurrent vehicle

Details on study design:

Positive control animals were treated with a single gavage of 6-Aminonicotinamide 2.5 mg/kg bw on test Day 9.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on Days 0, 6, 12, 18 and 29 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 29
- Organs examined: Caesarean section; the urogenital tract of each animal was examined in detail for normality.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of dead foetuses: Yes

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
The live fetuses of each litter were then placed in an incubator for 24 hours for the evaluation of the neonatal survival.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
- All pregnant animals (except of 1 female in the control group) survived until scheduled necropsy and no clinical signs were noted
- Body weights were not affected by treatment
- The relevant reproduction parameters (no. of Corpora lutea, implantation sites/dam, resorptions etc.) were not affected by treatment with the test item

Dose descriptor:

NOEL

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOEL

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Sex ratio and fetal body weight were not affected by treatment
- No dose related skeletal findings or soft tissue abnormalities

Dose descriptor:

NOEL

Effect level:

>= 300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

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, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

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	99-76-3
Chemical Name	Benzoic acid, 4-hydroxy-, C18-22-alkyl esters	Methyl 4-hydroxybenzoate
MW	390.60-446.71 g/mol	152.15 g/mol
Developmental Toxicity	RA from CAS 99-76-3	Experimental result: Rabbit: NOEL maternal ≥ 300 mg/kg bw NOEL developmental ≥ 300 mg/kg bw NOEL Teratogenicity ≥ 300 mg/kg bw

 

Discussion

Developmental toxicity

No data are available on the developmental toxicity of Benzoic acid, 4-hydroxy-, C18-22-alkyl esters (CAS 201305-16-0), but there is one reliable study via the oral route from the structurally related substance Methyl 4-hydroxybenzoate (Methylparaben, CAS 99-76-3), which is used for read-across based on an analogue approach.

Oral

In a prenatal developmental toxicity study similar to OECD guideline 414, the effects of Methylparaben (CAS 99-76-3) on inseminated female Dutch-belted rabbits were investigated during Days 6 to 18 of gestation (FDRL, 1973). Groups of 12 to 20 female rabbits received the test substance via gavage at dose levels of 3, 14 and 65 and 300 mg/kg bw/day. A further group of 14 inseminated female rabbits served as vehicle controls. On Day 29 of gestation, does were sacrificed and maternal as well as foetal examinations were performed. All pregnant animals (except of 1 female in the control group) survived until scheduled necropsy and no clinical signs were noted. Body weights and the relevant reproduction parameters (no. of Corpora lutea, implantation sites/dam, resorptions etc.) were not affected by treatment with the test item. The sex ratio and foetal body weights were not affected by treatment and no dose related skeletal findings or soft tissue abnormalities were noted. Thus, there was no evidence at any dose level, that the test substance was teratogenic in rabbits.

Based on the results of the study, the NOEL for developmental toxicity in Dutch-belted rabbits was set at ≥ 300 mg/kg bw/ day. The NOAEL for maternal toxicity in Dutch-belted rabbits was set at ≥ 300 mg/kg bw/ day.

Conclusion on developmental toxicity

In conclusion, the available data on developmental toxicity of the structural analogue substance indicate that Benzoic acid, 4-hydroxy-, C18-22-alkyl esters will not induce developmental or teratogenic effects after repeated oral exposure.

Justification for selection of Effect on developmental toxicity: via oral route:
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 a structurally similar substance, the available data on developmental toxicity do not meet the classification criteria according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Data are lacking for toxicity to reproduction (fertility).