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Key value for chemical safety assessment

Effects on fertility

Description of key information
No available information
Effect on fertility: via oral route
Dose descriptor:
NOAEL
245 mg/kg bw/day
Additional information

There are no reports of human epidemiological studies which have investigated potential effects of xylenols, ethyl phenols or cresol exposure on fertility or sexual function. Available animal studies reported confirm fertility NOAEL in excess of 450 mg/kg/day for all cresol isomer and >245mg/kg/day for both mixed xylenols and ethyl phenols.


Short description of key information:
7.8.1 Toxicity to Reproduction:
Key study: mixed xylenols (28 day combined repeated dose and reproduction/developmental study). York, 2005. KL.1. NOAEL general tox: 100 mg/kg/day; NOAEL reproduction: >245 mg/kg/day;
Supporting study: mixed ethyl phenols (28 day combined repeated dose and reproduction/developmental study). York, 2005. KL.1. NOAEL general tox: 100 mg/kg/day; NOAEL reproduction: >245 mg/kg/day;
Weight of evidence: m, p, o-cresol (2 generation study). CMA, 1989. KL.3. NOAEL parental: 30 mg/kg/day; NOAEL fertility >450 mg/kg/day;
NOAEL offspring 175 mg/kg/day

Effects on developmental toxicity

Description of key information
7.8.2 Developmental Toxicity / Teratogenicity:
Weight of evidence: m-cresol (rat developmenal study). CMA, 1988. KL.3. NOAEL general tox: 30 mg/kg/day; NOAEL maternal: 175 mg/kg/day;
NOAEL developmental: >450 mg/kg/day;
Weight of evidence: o, p-cresol (rat developmenal study). CMA, 1988. KL.3. NOAEL maternal and developmental: 175 mg/kg/day;
Weight of evidence: m, p-cresols (rabbit, developmental study). CMA, 1988. KL.3. NOAEL maternal: 5 mg/kg/day; NOAEL developmental: 100 mg/kg/day;
Weight of evidence: o-cresols (rabbit, developmental study). CMA, 1988. KL.3. NOAEL maternal:5 mg/kg/day; NOAEL developmental: 50 mg/kg/day;
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
100 mg/kg bw/day
Additional information

For all three cresol isomers the NOAEL for both maternal and developmental toxicity in the rat exceeds 100 mg/kg bw so use of this value as the overall NOAEL is conservative. However, for all three isomers the NOAEL for maternal toxicity in the rabbit is 5 mg/kg bw and the parental NOAEL in the multigeneration study is 30 mg/kg bw. In addition the NOAEL for developmental toxicity in the rabbit was 50 mg/kg bw for o-cresol.

 

Reports of the studies which established these NOAELs are not available to JSC and only summaries can be used to assess whether these NOAELs are robust. These show that the NOAEL for maternal toxicity in the rabbit is based mainly on clinical signs such as audible respiration, hypoactivity and ocular discharge in rabbits receiving 50 mg/kg bw of all three isomers. There may have been some mortality (incidence not reported) in rabbits given 50 mg/kg bw p-cresol but the summary of mortality data for this study is ambiguous and, as no mortality was reported with either of the other two isomers, even if there was a death at 50 mg/kg bw it was probably not treatment related. As the clinical signs of toxicity were not particularly adverse and there was no evidence of developmental effects at any dose level of any isomer, 50 mg/kg bw can be considered a NOEL and the NOAEL in all three developmental toxicity studies of the cresol isomers should be ≥100 mg/kg bw.

 

The parental NOAEL in the multi generation study of all three isomers is based on observations of perioral wetness at 175 mg/kg. There was also a possible increase in still births at this dose level but there was no clear dose response suggesting that it was not treatment related. As the clinical signs of toxicity were mild and there was a considerable spacing between the LOAEL (30 mg/kg bw) and the NOAEL (175 mg/kg bw) it is likely that the true NOAEL for this study is approximately 100 mg/kg bw which is the overall NOAEL for xylenols.

 

o-Cresol is only a very small component of the xylenols and its presence is consequently unlikely to affect the NOAEL for any xylenol, the NOAEL of 50 mg/kg bw for developmental toxicity in the rabbit can therefore be ignored.

 

Cresols constitute <25% of xylenols and so would only affect NOAELs of mixtures in which they were present if they were significantly more toxic than xylenol isomers. Although the reports of reproductive and developmental toxicity studies of cresol isomers are not available, the data discussed above show they are probably of comparable toxicity to xylenol isomers so NOAELs for xylenols can be used to derive DNEL for xylenols containing cresols. This is also to be expected based on the similarity of the structures.

 

Ethyl phenols

As so few studies have been conducted with ethyl phenols a read across approach will be used to justify similar NOAELs to xylenol isomers.

Justification for classification or non-classification