Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In absence of experimental data on 2,5 -Xylenol (CAS 95 -87 -4) an analogue read-across approach was conducted:

Key - mixed xylenols (RL1; according to OECD 422 and GLP, rat): NOAEL (general toxicity): 100 mg/kg bw/day; NOAEL (reproduction) >=245 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
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:
general toxicity, rat
Effect level:
ca. 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).
Key result
Dose descriptor:
NOAEL
Remarks:
Reproductive, rat
Effect level:
>= 245 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Whilst a reduced mating frequency was observed, this was within the laboratory's historical control range, therefore not considered biologically relevant.
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Remarks:
rat
Generation:
F1
Effect level:
>= 245 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects observed up to highest dose
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
A combined repeated dose toxicity study with the reproduction/developmental toxicity screening with the source substance mixed xylenols is available in rats. Treatment with the source substance resulted in a NOAEL of 100 mg/kg bw/day for general toxicity as toxic effects were observed at the highest dose. No relevant reproductive or developmental effects were observed. Therefore, a NOAEL of 245 mg/kg bw/day was derived for reproduction and developmental effects.
Executive summary:

For the source substance mixed xylenols, a combined repeated dose toxicity study with the reproduction/developmental toxicity screening in rats showed that general toxicity was dominating over the reproductive/developmental toxicity, a NOAEL of 100 mg/kg bw/day for general toxicity was derived. No reproductive or developmental parameters were affected by the treatment in either the parental or offspring animals resulting in a NOAEL of 245 mg/kg bw/day for reproduction and development. Whilst no studies on toxicity to reproduction have been conducted with 2,5-Xylenol the experimental data available on the source substances are considered to be suitable and meaningful to predict toxicity to reproduction (fertility) of the target substance.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
245 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch Score 1) from a reference substance with similar structure and intrinsic properties.Read-across is justified based on similarities in PC/ECO/TOX properties. 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 fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read-across

There are no data for fertility available for 2,5-Xylenol (CAS 95-87-4) to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7. Therefore, read-across from an appropriate source substance 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”.

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 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, 8.7 are fulfiled. A detailed analogue justification is provided in the technical dossier (see IUCLID Section 13).

Mixed xylenols

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening according to OECD 422 in rats is available with mixed xylenols (Merisol, 2005c). Mixed xylenol was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg bw/day. As described under repeated dose toxicity the NOAEL for general toxicity was 100 mg/kg bw/day. Decreased mating and fertility indices were reported at the highest dose level (245 mg/kg bw/day). The number of female rats that mated was reduced from 100% in the control group (10/10) to 80% at 245 mg/kg bw/day (8/10) but the difference was not significantly different. It is clear from the historical control data that fertility in the mixed xylenols study was within the historical control range in several years during the period from 1992-1997 which corresponds to the time when the mixed xylenols study was conducted. As the reduced fertility at 245 mg/kg bw/day was not statistically significant and was within the historical control range, this effect is considered not to be related to treatment and the NOAEL for fertility in this study should therefore be ≥ 245 mg/kg bw/day.

Conclusion:

Based on the available information (key study of an adequate source substance), following an analogue read-across approach, 2,5-Xylenol (CAS 95-87-4) is not considered to be toxic to reproduction.

 

Effects on developmental toxicity

Description of key information

In absence of experimental data on 2,5 -Xylenol (CAS 95 -87 -4) an analogue read-across approach was conducted:

Key - mixed xylenols (RL1; according to OECD 422 and GLP, rat): NOAEL (general toxicity): 100 mg/kg bw/day; NOAEL (developmental toxicity) >=245 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
245 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch Score 1) from a reference substance with similar structure and intrinsic properties.Read-across is justified based on similarities in PC/ECO/TOX properties. 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 read-across

There are no data for developmental toxicity available for 2,5-Xylenol (CAS 95-87-4) to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.7. Therefore, read-across from an appropriate source substance 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”.

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 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, 8.7 are fulfiled. A detailed analogue justification is provided in the technical dossier (see IUCLID Section 13).

Mixed xylenols:

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening according to OECD 422 in rats is available with mixed xylenols (Merisol, 2005c). Mixed xylenol was administered to rats by oral gavage at 0, 30, 100 and 245 mg/kg bw/day. As described under repeated dose toxicity the NOAEL for general toxicity was 100 mg/kg bw/day. There were no effects on developmental toxicity, therefore the NOAEL for developmental toxicity in this study should therefore be ≥ 245 mg/kg bw/day.

Conclusion:

Based on the available information (key study of an adequate source substance), following an analogue read-across approach, it is considered that 2,5-Xylenol (CAS 95-87-4) will also not show developmental toxicity.

Justification for classification or non-classification

Based on the available information (key study from one source substance), following an analogue read-across approach and in the absence of data on reproduction toxicity of 2,5-Xylenol (CAS 95-87-4), there is no indication for reproduction toxicity. However, no final decision on classification for reproductive toxicity according to Regulation (EC) 1272/2008 can be made, as this information is only based on one screening study.

Additional information