p-anisic acid

Endpoint summary

Description of key information

short-term repeated dose toxicity (OECD 422), oral, rat: systemic NOAEL 500 mg/kg bw/day (highest dose tested)

Read-across from anisaldehyde (CAS 123-11-5)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

local effects

Effect level:

20 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

source: 123-11-5; the findings as reported for the rat are considered not to be relevant for humans

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

500 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no systemic adverse effects noted up to and including the high dose of 500 mg/kg bw/day

Remarks on result:

other:

Remarks:

source: 123-11-5; adaptative, non-adverse effects seen in the liver at 500 mg/kg bw/day

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (actual dose received)

System:

gastrointestinal tract

Organ:

stomach

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Conclusions:

The read across approach is justified in the analogue justification (see IUCLID section 13). The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. The oral repeated dose toxicity of the target substance is estimated based on an adequate and reliable combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with the structural analogue surrogate substance anisaldehyde, conducted in rats. The NOAEL for systemic repeated dose toxicity was 500 mg/kg bw/day, while the NOAEL for local effects was 20 mg/kg bw/day. Therefore, a NOAEL for systemic repeated dose toxicity of 500 mg/kg bw/day an a NOAEL for local effects of 20 mg/kg bw/day is expected for the target substance p-anisic acid.

No adverse systemic findings were noted in this OECD 422 study. The findings on local irritation of the forestomach are not considered relevant for humans. Accordingly, the data on the repeated dose toxicity of p-anisic acid are conclusive but not sufficient for classification.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate, reliable (Klimisch 1 and 2) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, of Regulation (EC) No. 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

In the absence of any evidence for species specific effects or modes of action (beside changes in the forestomach) the effects observed in animals and the absence of effects are regarded as relevant for humans.

Additional information

There are no data available on the repeated dose toxicity of p-anisic acid. In order to fulfil the standard information requirements set out in Annex VIII - IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was 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) “to avoid the need to test every substance for every endpoint”. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID section 13).

 

Repeated dose toxicity: oral

CAS 123-11-5

A reliable oral Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with anisaldehyde (CAS 123-11-5) is available and was performed according to OECD 422 (Hatano Research Institute, 2000) and in compliance with GLP.Groups of 13 male and 13 female Sprague-Dawley rats were exposed to the test substance at dose levels of 20, 100 and 500 mg/kg bw/day by oral gavage once daily for 7 days/week for at least 42 (males) and 40 (females) consecutive days. Control animals (13 per sex and dose) received the concurrent vehicle, corn oil, only. Observations and examinations of the animals included clinical signs, body weight, food consumption, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy, organ weights and histopathology. No mortality was observed and except for transient salivation noted in most high dose animals no clinical signs were noted. Body weights and food consumption was marginally increased in mid and high dose males and in high dose females. These findings were not considered adverse. Platelet count was slightly although statistically significantly decreased in high dose males and mid and high dose females. In the absence of any effects on coagulation times this finding was considered to be of no toxicological relevance. Red blood cell count was significantly decreased in mid and high dose males. However, as no significant changes in hematocrit value and hemoglobin content, reticulocyte count and the histopathological examination of bone marrow were seen and the spleen did not show any changes related to hematological changes, these changes were considered to have occurred incidentally. Absolute and relative liver weights were increased in high dose males and females. However, histopathology revealed only very slight to slight centrilobular hypertrophy of hepatocytes, which is considered an adaptive rather than an adverse effect. During necropsy black spots or black deposits in the glandular stomach as well as thickening of the forestomach mucosa were noted in a few high dose males and mid and high dose females. Histopathology revealed no changes in the glandular stomach but squamous cell hyperplasia in the forestomach of all high dose animals and also in the forestomach for 3 male and 5 female mid dose animals. In the absence of adverse systemic effects, a NOAEL of 500 mg/kg bw/day for systemic toxicity was derived, whereas a NOAEL of 20 mg/kg bw/day for local effects was derived based on stomach irritation noted at 100 mg/kg bw/day and above. Histopathological stomach findings were limited to the forestomach, an organ that has no human correlate. Therefore these effects were considered to have no relevance for humans and do not warrant a classification of the test item.

Justification for classification or non-classification

The available data on short-term repeated dose toxicity as available from an OECD 422 study conducted with the source substance ansialdehyde (CAS 123-11-5) do not indicate adverse effects up to and including 500 mg/kg bw/day (the highest dose tested). Therefore, no adverse effects are expected for the target substance at doses up to and including 500 mg/kg bw/day. Therefore and based on read across, classification of p-anisic acid with respect to repeated dose exposure is not warranted according to Regulation (EC) No. 1272/2008.