Registration Dossier

Administrative data

Description of key information

In absence of data on 2,5-Xylenol (CAS 95-87-4) an analogue read-across approach from 3,5-Xylenol (CAS 108-68 9) and mixed xylenols was conducted:

- oral:

3,5 -Xylenol (CAS 108-68-9): OECD 407 / GLP, RL1: NOAEL (m/f) = 300 mg/kg bw/day (highest dose tested)

mixed xylenols: OECD 422 / GLP, RL1: NOAEL (m/f) = 100 mg/kg bw/day

- inhalation / dermal: no data

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)
Remarks:
Summary of available short-term toxicity data used for the endpoint assessment of the target substance
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
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Due to clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).
Remarks on result:
other: Source, mixed xylenols, Merisol, 2005, OECD 422
Key result
Critical effects observed:
no

In the result table above the most critical value of the two source substances of the read-across approach is given. The NOAEL of the second source substance 3,5-Xylenol (CAS 108-68-9) was set at 300 mg/kg bw/day (the highest dose tested) in an oral repeated dose toxicity study in rats according to OECD 407 and under GLP due to the lack of adverse effects (BG Chemie, 1993).

Conclusions:
The available subacute repeated dose oral toxicity studies conducted on 3,5-Xylenol (CAS 108-68-9) and mixed xylenols resulted in NOAELs for general systemic toxicity of 300 and 100 mg/kg bw/day, respectively. As detailed in the analogue justification, it is considered that the target and the source substance are unlikely to lead to differences in repeated dose toxicity potential. Therefore, the results can be taken for the hazard assessment of the target substance 2,5-Xylenol (CAS 95-87-4). As a worst-case approach the lower NOAEL of 100 mg/kg bw/day of the mixed xylenols will be taken for risk assessment of the target substance 2,5-Xylenol (CAS 95-87-4).
Executive summary:

In an oral gavage study conducted according to OECD 407 and under GLP the NOAEL for the source substance 3,5-Xylenol (CAS 108-68-9) was set at the highest dose tested, 300 mg/kg bw/day, for male and female rats due to the lack of adverse effects. The sub-acute repeated dose oral toxicity study conducted on mixed xylenols according to OECD 422 and GLP result in a NOAEL of 100 mg/kg bw/day. Increases in liver and kidney weights were reported. No histopathological changes accompanied these increases in organ weights.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable studies (Klimisch Score 1) from reference substances with similar structure and intrinsic properties. Read-across is justified based on similarities in PC/ECO/TOX properties. The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, 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

Additional information

Justification for read-across:

There are no data for repeated dose toxicity available for 2,5-Xylenol (CAS 95-87-4). In order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex XIII, 8.6, read-across from appropriate source substances is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5.

According to 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”.

2,5-Xylenol (CAS 95-87-4) and 3,5-Xylenol (CAS 108-68-9) are considered to be similar on the basis of the structural similar properties and/or activities. The source substance mixed xylenols is a mixture of the target substance 2,5-Xylenol and several other xylenols (3,4-Xylenol, 2,4-Xylenol, 3,5-Xylenol, 2,3-Xylenol and 2,6-Xylenol), which are also considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is thus used to predict the same results for 2,5-Xylenol (CAS 95-87-4). Therefore, the requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6 are fulfiled. A detailed analogue justification is provided in the technical dossier (see IUCLID Section 13).

Short-term toxicity, oral:

To assess the systemic toxicity of the structural analogue substance 3,5-Xylenol (CAS 108-68-9), the test substance was administered by gavage, once daily, to groups of 5 male and 5 female rats for 28 consecutive days at doses of 30, 100 and 300 mg/kg bw/day according to OECD 407 and under GLP (BG Chemie, 1993). The test substance was prepared as suspension in corn oil at concentrations of 0.6, 2 and 6% (w/v). A concurrent control group, consisting of 5 male and 5 female, receiving the vehicle only, was included in addition. Body weights, food consumption and clincial observation were recorded during the study. Blood samples for clinical investigations were taken on Day 27 and all animals were killed and examined macroscopically on Day 29. Specified tissues were subsequently prepared for histological examination. Increased salivation, noted following dosing was frequently seen during the treatment period, commonly accompanied by wet fur, among all rats receiving 300 mg/kg bw/day. Increased salivation was also seen at the lower dosages in all animals, sporadically at 100 mg/kg bw/day (accompanied by wet fur on three occasions for males only). However, post-dose salivation is a common finding in rat orally dosed studies and therefore was considered to be of no toxicological importance. Slightly lower body weight gain (- 14 and -12%) and food consumption (-9 and -7%) was noted for males receiving 300 or 100 mg/kg bw/day. Week 2 measurements of water consumption showed higher than control values for males receiving 300 mg/kg bw/day (+60%) and females receiving 100 or 300 mg/kg bw/day (+88 and +90%). Overall, none of these findings were considered to be toxicological relevant. Changes seen in the other parameteres measured, namely organ weights and clincial, macroscopic and microscopic pathology were considered to be unrelated to treatment. Based on the results of this study the NOAEL for the source substance was set at 300 mg/kg bw/day (the highest dose tested).

Mixed xylenols were tested for oral repeated dose toxicity in Crj: CD(SD) rats for 28 days for male animals and 54 days for females according to OECD 422 and under GLP (Merisol, 2005). Ten rats/sex/dose received daily applications (beginning 14 days prior to cohabitation and continuing until the day before sacrifice) of the test substance in corn oil via gavage at dose levels of 30, 100 and 245 mg/kg bw/day. The general NOAEL was shown to be 100 mg/kg bw/day for male and female animals due to clinical observations which included urine-stained fur, increased kidney, liver and ovarian relative weight.

Conclusion:

The available sub-acute repeated dose oral toxicity studies conducted on 3,5-Xylenol (CAS 108-68-9) and mixed xylenols resulted in NOAELs for general systemic toxicity of 300 and 100 mg/kg bw/day, respectively. As a worst-case approach the lower NOAEL of 100 mg/kg bw/day of the mixed xylenols will be taken for risk assessment of the target substance 2,5-Xylenol (CAS 95-87-4).

Justification for classification or non-classification

Based on the available information (key studies from two source substances), following an analogue read-across approach and in the absence of data on repeated oral dose toxicity of 2,5-Xylenol (CAS 95-87-4), no classification for repeated dose toxicity via the oral route is required for the target substance 2,5-Xylenol (CAS 95-87-4) according to Regulation (EC) 1272/2008.