3,4 XYL

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.34 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.75 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEL

Additional information - workers

Acute toxicity - systemic

Available dose-descriptors per endpoint as a result of hazard assessment
Endpoint		Quantitative dose-descriptor	Associated Effect	Remarks on Study
		Systemic Effect
Acute toxicity	Oral	NOAEL 175 mg/kg	Reduced food consumption	Rat
	Derm.	No data	-	-
	Inhal.	No data	-	-

 

Dose descriptor selection

The lowest, reliable NOAEL observed was selected from an acute rat oral study on mixed xylenols. A further study on mixed ethyl phenols returned the same NOAEL value. The available data for all three cresol isomers was already provided (therefore reports were not available to enable complete evaluation and suitability for the LD50 / LOAEL values set). These studies are in excess of 40 years old and consequently not conducted to any guideline, with data absent. The LOAEL determined have been dictated by the dose levels set, with clinical signs of toxicity observed at the LOAEL similar to that observed at higher doses in both the guideline compliant studies on ethylphenols and xylenols. Comparable signs of toxicity were reported compared to the xylenols and ethyl phenols, furthermore, based on structural similarities, if these studies were performed to modern guideline requirements it is reasonable to assume that comparable NOAEL would be obtained.

 

Assessment of mode of action

The identified endpoint of and the observed effects have a threshold.

 

Acute Dermal - systemic

Dose description modification

Guidance [1. Appendix R8-1] was followed for route to route extrapolation as no relevant dose descriptor were available for dermal exposure. As noted in [1.] R.8.4.2, as no information regarding dermal absorption is available, a worse case scenario that 100% of the dose will be absorbed dermally has been assumed.

 

NOAELcorr = NOAEL / Allometric scaling*(ABS oral rat / ABS derm rat) * (ABS derm rat / ABS derm human)

 

NOAELcorr (general) = 175mg/kg bw / 4 * (50% (default) / 100% (default)) * (100% (default) / 100% (default)) = 21.88 mg/kg bw

 

Assessment factors

Default assessment factors [1. R-8.4.3.3.] were applied.

Assessment factor = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

Assessment factor (general) = 2.5 * 5 * 1 * 1 * 1 = 12.5

 

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 21.88 mg/kg bw/day / 12.5 = 1.75 mg/kg bw/day

 

Acute Inhalation - systemic

Dose description modification

Guidance [1. Appendix R8 -1] was followed for route to route extrapolation as no relevant dose descriptor were available for inhalation exposure. As noted in R.8.4.2, as no information regarding inhalation absorption is available, a worse case scenario that 100% of the dose will be absorbed via the inhalation route. The dose descriptor was modified to take into account an 8 hour exposure and the respiratory volume corrected for light work.

 

NOAECcorr = NOAEL *1 / rat resp. volume * oral / inhalation absorption * human resting resp. volume / worker resp. volume

 

NOAECcorr(general) = 175 mg/kg/bw *(1 / 0.38) * (50% (default) / 100%(default)) * 6.7 m³ (8hr) / 10 m³ (8hr) = 154.28 mg/m³

 

Assessment factors

Default assessment factors [1. R-8.4.3.3.] were applied.

Assessment factor = Interspecies * Intraspecies * Exposure duration * Dose-response * Quality of whole database

Assessment factor (general) = 2.5 * 5 * 1 * 1 * 1 = 12.5

 

DNEL derivation

DNEL = NOAELcorr / Assessment factor

DNEL = 154.28 mg/m³/ 12.5 = 12.34 mg/m³

 

Endpoint Specific DNELs for Workers
Endpoint		Corrected dose-descriptor	Overall AF	Endpoint Specific DNEL
		Systemic		Systemic
Acute toxicity	Oral	N/A		N/A
	Derm.	21.88 mg/kg	12.5	1.75 mg/kg
	Inhal.	154.28 mg/m^3	12.5	12.34 mg/m^3

 

Acute / repeat– dermal, local

Cresols and xylenols are classified under Directive 67/548/EEC as irritant/corrosive. Available animal studies show concordance with this classification. As such, a qualitative approach [[1]. R.8.5.3. Page 51-53]] has been taken, with the mixture considered to be corrosive when in contact with skin.

 

Acute / repeat– inhalation, local

None of the components of the mixture are classified for endpoints relating to short term inhalation toxicity, local effects. However cresols are reported to cause local irritation to nose and throat when inhaled [2] and therefore it is reasonable to assume that both xylenols and ethyl phenols are expected to cause a similar effect. As such, a qualitative approach has been taken, with the mixture considered to be irritant when inhaled.

 

Long term exposure

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, where as sub-chronic and chronic studies on cresol isomers 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 respect of the reproductive data available on cresols, for all three 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.

Therefore, the oral sub-acute study has been used to derive dermal and inhalation DNEL. As the duration of the study does not appreciably alter the NOAEL, there is no need to take into account an additional assessment factor for duration extrapolation [[1.] pg 35]].

Available dose-descriptors per endpoint as a result of hazard assessment
Endpoint		Quantitative dose-descriptor	Associated Effect	Remarks on Study
		Systemic Effect
Repeat toxicity (sub-acute)	Oral	NOAEL 100 mg/kg	Adverse clinical observations (urine-stained fur, increased kidney, liver and ovarian relative weight).	Rat
	Derm.	No data	-	-
	Inhal.	No data	-	-

 

Long term exposure –dermal systemic

Guidance [1. Appendix R8-1] was followed for route to route extrapolation as no relevant dose descriptor was available for dermal exposure. As noted in R.8.4.2, as no information regarding dermal absorption is available, a worse case scenario that 100% of the dose will be absorbed dermally has been assumed.

 

NOAELcorr = NOAEL/Allometric scaling*(ABS oral rat / ABS derm rat) * (ABS derm rat / ABS derm human)

 

NOAELcorr (general) = 100mg/kg bw/4 * (50% (default) / 100% (default)) * (100% (default) / 100% (default)) = 12.5 mg/kg bw

 

Assessment factors

Default assessment factors [1. R-8.4.3.3.] were applied.

Assessment factor = Interspecies * Intraspecies * Exposure duration * Dose-response * Quality of whole database

Assessment factor (general) = 2.5 * 5 * 1 * 1 * 1 = 12.5

 

DNEL derivation

DNEL = NOAELcorr / Assessment factor

 

DNEL = 12.5 mg/kg bw/day / 12.5 = 1.00 mg/kg bw/day

 

Long term exposure – inhalation systemic

Dose description modification

Guidance [1. Appendix R8-1] was followed for route to route extrapolation as no relevant dose descriptor were available for inhalation exposure. As noted in R.8.4.2, as no information regarding inhalation absorption is available, a worse case scenario that 100% of the dose will be absorbed via the inhalation route. The dose descriptor was modified to take into account an 8 hour exposure and the respiratory volume corrected for light work.

 

NOAECcorr = NOAEL *1 / rat resp. volume * oral / inhalation absorption * human resting resp. volume / worker resp. volume

 

NOAECcorr(general) = 100 mg/kg/bw *(1 / 0.38) * (50% (default) / 100%(default)) * 6.7 m³ (8hr) / 10 m³ (8hr) = 88.16 mg/m³

 

Assessment factors

Default assessment factors [1. R-8.4.3.3.] were applied.

 

Assessment factor = Interspecies * Intraspecies * Exposure duration * Dose-response * Quality of whole database

Assessment factor (general) = 2.5 * 5 * 1 * 1 * 1 = 12.5

 

DNEL derivation

DNEL = NOAELcorr / Assessment factor

 

DNEL = 88.16 mg/kg bw/day / 12.5 = 7.05 mg/kg bw/day

 

Endpoint Specific DNELs for Workers
Endpoint		Corrected dose-descriptor	Overall AF	Endpoint Specific DNEL
		Systemic		Systemic
Repeat toxicity	Oral	N/A	N/A	N/A
	Derm.	12.5 mg/kg	12.5	1.00 mg/kg
	Inhal.	88.16 mg/m^3	12.5	7.05 mg/m^3

 

References:

1. ECHA, (May, 2008). Guidance on information requirements and chemical safety assessment. Chapter, R.8. – Dose [concentration]-response regarding human health.

2. New Jersey Department of Health and Senior Services. Cresols (mixed isomers) hazardous substance fact sheet.http://nj.gov/health/eoh/rtkweb/documents/fs/0537.pdf

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

No exposure to general population, therefore no requirement to establish DNEL for the general population.