LBX98

Endpoint summary

Description of key information

Repeat Dose Oral Toxicity: 
Key study: mixed xylenols (28 days combined reproductive / toxicity study). York, 2005. KL.1. NOAEL 100 mg/kg; 
Supporting study: mixed ethylphenols (28 days combined reproductive / toxicity study). York, 2005. KL.1. NOAEL 100 mg/kg; 
Supporting study: m-cresol (28 day). MHWL, 2001. KL.1. NOAEL males: 300 mg/kg/day; females: 100 mg/kg/day; 
Supporting study: p-cresol (28 day). IBTL, 1969. KL.3. NOAEL 45.2 mg/kg/day; 
Weight of evidence: m-cresol (90 day, oral). RTI, 1988. KL.1. NOAEL: 50 mg/kg/day; 
Weight of evidence: o-cresol (90 day, oral). RTI, 1988. KL.1. NOAEL: 50 mg/kg/day; 
Weight of evidence: o-cresol (90 day, diet, rat). RTI, 1988. KL.1. NOAEL males: 247 mg/kg/day; females: 256 mg/kg/day; 
Weight of evidence: o-cresol (90 day, diet, mouse). RTI, 1988. KL.1. NOAEL males: 199 mg/kg/day; females: 237 mg/kg/day; 
Weight of evidence: p-cresol (90 day, oral). RTI, 1988. KL.1. NOAEL 50 mg/kg/day; 
Repeat Dose Dermal Toxicity: 
No key or supporting studies identifed; 
Repeat Dose Inhalation Toxicity: 
No key or supporting studies identifed; 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

Repeat oral dose discussion

 

Sub-acute

The sub acute repeat oral 28 day study conducted on ethyl phenols and xylenols confirms a NOAEL at 100 mg/kg/day for both test materials.

 

Reports of the studies which established m and p cresol NOAELs are not available and only summaries can be used to assess whether these NOAELs are robust. These studies show that the NOAELs are similar to that obtained for the xylenols and ethylphenols (m-cresol 300 and 100 mg/kg/day for males and females respectively; p-cresol 45.2 mg/kg/day [maximum dose tested]), which strengthens the argument that the structural similarities of these compounds provides reliable read-across approach when extrapolating from one material to another.

 

With the exception of the study on p-cresols, increases in liver and/or kidney weights were reported. No histopathological changes accompanied these increases in organ weights (with the exclusion of a dose at 1000 mg/kg/day of m-cresol which reported histopathological changes, but these were not detailed).

 

For the study conducted with p-cresol the NOAEL determined was limited by the maximum dose tested where no signs of toxicity were observed. If higher levels were administered it is conceivable that the NOAEL would be comparable to the values obtained from m-cresol, xylenols or ethylphenols, which all have similar chemical structures.

 

Sub-chronic and Chronic

Studies on cresol isomers (which were not available to JSC) all report similar findings, with NOAEL values which were not only comparable between isomers but also not appreciably different from the NOAEL derived from a 28 day study, irrespective of whether the test material was administered via the diet or orally via gavage.

 

In all cases decreases in food consumption and body weight were reported (which is likely due to lack of palatability of the test materials as they are known irritants). Where changes in organ weights were observed (again liver / kidney, also thymus and testes) no gross histopathological changes accompanied these changes. In the o-cresol dietary study forestomach hyperplasia was noted, which was likely due to the irritant nature of the test material. Furthermore epithelial metaplasia of the trachea was observed in the p-cresol dietary study. These lesions were considered to be an adaptive response due to inhalation exposure resulting from the volatising of the test material from the feed during consumption and not from systemic exposure following oral absorption. Such lesions are commonly observed in NTP (2000) studies on chemicals which are known irritants.

 

The NOAEL established for all three oral gavage studies were 50 mg/kg/day. At these doses clinical signs of toxicity (where reported) were mild. Had the dose spacing been narrower, it is likely that the true NOAEL for this study would be approximately 100 mg/kg/bw.

 

The 2-year carcinogenicity study on m/p-cresol, whilst not specifically designed to set a NOAEL, the data available would imply that NOAEL of 70 mg/kg/day could be set based on the absence of any neoplastic or non-neoplastic findings. Again considerable spacing between doses restricted the NOAEL to the lowest dose tested.

 

In all three duration scenarios the NOAEL does not markedly deviate from a NOAEL of 100 mg/kg/day established in the 28 day study through to a 90 day or 2 year scenario. Whilst no sub-chronic or chronic studies have been conducted with xylenols or ethylphenols, the plethora of sub-chronic and chronic toxicology data available on cresols would indicated (based on similarities in structure and physical properties) that a read-across approach can be used with comparable NOAEL values expected to be obtained.

 

Table 1: NOAEL from sub-acute, sub-chronic and chronic studies

Study duration (study conducted in rat unless otherwise stated)	Test material	Dose levels (mg/kg/day)	LOAEL (mg/kg/day)	NOAEL (mg/kg/day)
SUB-ACUTE
28 day (oral gavage)	Xylenols / Ethyl phenols
28 day (oral gavage)	m-cresol	0, 100, 300, 1000	Male: 100 Female: -	Male: 300 Female: 100
28 day study (diet, rat)	p-cresol	0, 1.9, 14.2, 45.2	-	45.2
SUB-CHRONIC
90 day (oral gavage)	m-cresol	0, 50, 155, 450	-	Male: 50 Female: 150
90 day (oral gavage)	o-cresol	0, 50, 175, 600	-	50
90 day (diet, mouse)	o-cresol	Male: 0, 199, 400, 794, 2723, 2723 Female: 0, 237, 496, 935, 1663, 3205	Male: - Female: -	Male: 199 Female: 237
90 day (diet)	o-cresol	Male: 0, 126, 247, 510, 1017, 2028 Female: 0, 129, 256, 513, 1021, 2024	Male: 126 Female: 129	Male: 247 Female: 256
90 day (oral gavage)	p-cresol	0, 50, 175, 600	-	50
CHRONIC
2 year carcinogenicity	m/p-cresol	70, 230, 720	70	70

 

Repeat dose dermal toxicity

In the published literature there is no valid data available to address the repeat dermal exposure route. In all cases (xylenols, ethylphenols, cresols) these material are known to be highly irriative through to corrosive when in contact with skin. Therefore when setting DNELs for repeated local dermal effects these qualitive effect will be used. In accordance with the guidance from ECHA (2008) route to route extrapolation has been undertaken, extrapolating from the oral route to the dermal route to provide a repeat dose dermal systemic DNEL. Further testing is not justified and therefore a waiver is requested for this endpoint.

Repeat dose inhalaiton toxicity

In the published literature there is no valid data available to address the repeat inhalation exposure route. Cresols are known to be respiratory irritants in both humans and animals following inhalation exposure (ATSDR, 2006) and ethylphenols and xylenols are expected to be exert a similar effect. Therefore when setting DNELs for repeated local inhalation effects this qualitive effect will be used. In accordance with the guidance from ECHA (2008) route to route extrapolation has been undertaken, extrapolating from the oral route to the dermal route fo provide a repeat dose dermal systemic DNEL. Further testing is not justified and therefore a waiver is requested for this endpoint.

References:

ATSDR (Agency for Toxic Substances and Diseae Registry) (2006). Draft toxicological profile for cresols. <http://www.atsdr.cdc.gov/toxprofiles/tp34.pdf>

ECHA (May, 2008). Guidance on information requirements and chemical safety assesment. Chapter R.8: Characterisation of dose [concentration]-response for human health.

NTP (2000). Technical report on the toxicology and carcinogenesis studies of naphthalene (CAS no. 91-20-3) in F344/N rats (Inhalation studies). Technical report series No. 500. NIH Publication No. 01-34434. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, N.C.