6-tert-butyl-2,4-xylenol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.14 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEC

Value:

10.58 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose the default respiratory volume for the rat corresponding to the daily duration of human exposure is considered in the first step, followed by a correction for the difference between respiratory rates of workers under standard conditions and under light activity in the second step. NAECcorr_inh = oral NOAEL (6  x  1/0.38 m3/kg bw x 6.7 m3/10 m3 = 10.58 mg/m3.  Oral absorption in rats is assumed to be 100%, based on the toxicokinetic evaluation.  For the purposes of risk assessment, absorption in humans is also taken as 100%. Therefore, NAECcorr_inh = 70.5 x 100/100 = 10.58 mg/m3.

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Default assessment factor for extrapolation from subacute to chronic

Justification:

No allometric scaling required for inhalation route.

Justification:

Default assessment factor

Justification:

Default assessment factor of 5 for workers

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.02 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data on skin absorption is available.  The substance is considered to be dermally toxic and a skin irritant on the basis of the results noted in rabbits. Rats are largely unaffected by the substance, whereas rabbits demonstrate a toxic response to the substance when applied dermally.   The studies carry no definitive explanation of this difference of toxicity observed, and it is concluded that this is a species specific effect.   Assessment of the literature, specifically: Skin Permeability In Vivo: Comparison in Rat, Rabbit, Pig and Man; Journal of Investigative Dermatology (1972) 58, 114–123; doi:10.1111/1523-1747.ep12538909 Accepted 26 October 1971.  This paper details that in a comparative percutaneous absorption study undertaken in rats, rabbits, miniature swine and man, the results obtained indicated that skin permeability decreases in the following order: rabbit, rat, pig and man.  It may be therefore that the permeability of rabbit skin is much greater for the substance than it is in the rat, and the toxic response is proliferated by rabbit skin to a greater extent.  As a worst case, assume that oral absorption in rats is 100%  and dermal absorption in humans is considered to be 100%. Therefore dose descriptor after route to route extrapolation is 6 x 100/100 = 6 mg/kg bw/day.  This is considered to give an appropriate assessment factor for long term exposure.  In practise, exposure would be precluded by the acute dermal toxicity labelling of the substance.

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Default assessment factor for extrapolation from subacute to chronic

Justification:

Allometric scaling factor for rat = 4

Justification:

Default assessment factor

Justification:

Default assessment factor of 5 for workers

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

On the basis of the results noted in the rabbit studies, classification under the  CLP Regulation (EC No 1272/2008 is as follows:

 

Acute toxicity, Category 1

H310: Fatal in contact with skin

 

No data on skin absorption is available. The substance is considered to be dermally toxic and a skin irritant on the basis of the results noted in rabbits.Rats are largely unaffected by the substance, whereas rabbits demonstrate a toxic response to the substance when applied dermally.  The studies carry no definitive explanation of this difference of toxicity observed, and it is concluded that this is a species specific effect. 

 

Assessment of the literature, specifically:

 

Skin Permeability In Vivo: Comparison in Rat, Rabbit, Pig and Man;Journal of Investigative Dermatology(1972)58, 114–123; doi:10.1111/1523-1747.ep12538909 Accepted 26 October 1971.

 

This paper details that in a comparative percutaneous absorption study undertaken in rats, rabbits, miniature swine and man, the results obtained indicated that skin permeability decreases in the following order: rabbit, rat, pig and man. It may be therefore that the permeability of rabbit skin is much greater for the substance than it is in the rat, and the toxic response is proliferated by rabbit skin to a greater extent.

 

There is a repeated dose oral toxicity study available for the substance itself (K1) study . A NOAEL of 6 mg/kg bw/day was established in this study and was selected as starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL on the basis of being the lowest dose. Long-term local DNELs (inhalation and dermal) were not derived as it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. Acute toxicity DNEL’s were not derived. Chapter R.8: Characterisation of dose [concentration]-response for human health, APPENDIX R. 8-8 Acute toxicity states that if an acute toxicity hazard (leading to C&L) has been identified, a DNEL for acute toxicity is only established for the effects of peak exposures if these peaks could be significantly higher than the average daily exposure and the long-term DNEL is insufficient to limit them. As high peak exposures are not anticipated during the use of the substance, no derivation of a DNEL is required. The long term DNEL is considered appropriate to address this species specific risk.

 

In practice, occupational protection for workers does not allow a direct exposure of workers to the test item at a concentration causing irritation, due to PPE as standard in the workplace. The RMMs installed to protect workers are sufficient to prevent any hazard from local dermal exposure. It is considered that the derivation from long term systemic effects provides a suitable margin of safety for use.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.035 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEC

Value:

5.22 mg/m³

Explanation for the modification of the dose descriptor starting point:

Modification of the dose descriptors is necessary, because the routes of exposure are different between animals (oral) and humans (inhalation). For this purpose, the oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the rat (1.15 m3/kg for 24 hrs exposure of general public). NAECcorr_inh = oral NOAEL (6)  x  1/1.15 m3/kg bw = 5.22 mg/m3. Oral absorption in rats is assumed to be 100%, based on the toxicokinetic evaluation. For the purposes of risk assessment, absorption in humans is also taken as 100%   Therefore, NAECcorr_inh = 5.22 x 100/100 = 5.22 mg/m3.

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Default assessment factor for extrapolation from subacute to chronic

Justification:

No allometric scaling required for inhalation route.

Justification:

Default assessment factor

Justification:

Default assessment factor of 10 for general population

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

As worst case, assume that oral absorption in rats is 100% and dermal absorption in humans is 100%. Therefore dose descriptor after route to route extrapolation is  6 x 100/100 = 6 mg/kg bw/day.

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEL (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Default assessment factor for extrapolation from subacute to chronic

Justification:

Allometric scaling factor for rat = 4

Justification:

Default assessment factor

Justification:

Default assessment factor for general population

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal to Dermal

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Not applied for dermal; see below

Justification:

Default assessment factor

Justification:

Default assessment factor of 10 for the general public

Justification:

Default assessment factor

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

6 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not required

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC

Justification:

Default assessment factor for extrapolation from subacute to chronic

Justification:

Factor for allometric scaling for rat

Justification:

Default assessment factor

Justification:

Default assessment factor for general population

Justification:

Default assessment factor for good/standard quality of database (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

It is considered that there is sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

36.4 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

910 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Due to the nature of use of the products that contain the substance by consumers, it is considered appropriate to utilise an acute DNEL in place of the longer-term DNEL’s.  The justification for this is that the products containing the substance would only be used sporadically, and as such would need to be assessed on these terms.  Guidance R8 Appendix 8.8 details that if an acute toxicity hazard (leading to C&L) has been identified, a DNEL for acute toxicity can be established for the effects of peak exposures as these peaks can be significantly higher than the average daily exposure and the long-term DNEL may be insufficient to limit them.  High peak exposures are usually assessed for the inhalation route only, however, on a case-by-case basis an ‘acute’ dermal or oral DNEL can be set for comparison with single exposure events.    On the basis of the proposed dermal toxicity, assessment is performed for dermal exposure on a sporadic basis; comparison to acute DNEL’s is considered to be appropriate.  A starting NAEC of 910 mg/kg is assumed as a worst case, as the data set provides for oral absorption in rats is assumed to be 100% and oral absorption in humans is assumed to be 100%. Therefore, NAECcorr_oral = 910 x 100/100 = 910 mg/kg.

Justification:

Default assessment factor when the starting point for the DNEL calculation is a NOAEC (Chapter R.8: Characterisation of dose [concentration]-response for human health)

Justification:

Not applied for oral; see below

Justification:

Default assessment factor

Justification:

Default assessment factor of 10 for the general public

Justification:

Default assessment factor

Justification:

It is considered that there are sufficient safety factors built into the extrapolations utilised to justify omission of this “uncertain” assessment factor.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

On the basis of the results noted in the rabbit studies, classification under the CLP Regulation (EC No 1272/2008 is as follows:

 

Acute toxicity, Category 1

H310: Fatal in contact with skin

 

No data on skin absorption is available. The substance is considered to be dermally toxic and a skin irritant on the basis of the results noted in rabbits.Rats are largely unaffected by the substance, whereas rabbits demonstrate a toxic response to the substance when applied dermally.  The studies carry no definitive explanation of this difference of toxicity observed, and it is concluded that this is a species specific effect. 

 

Assessment of the literature, specifically:

Skin PermeabilityIn Vivo: Comparison in Rat, Rabbit, Pig and Man;Journal of Investigative Dermatology(1972)58, 114–123; doi:10.1111/1523-1747.ep12538909 Accepted 26 October 1971.

 

This paper details that in a comparative percutaneous absorption study undertaken in rats, rabbits, miniature swine and man, the results obtained indicated that skin permeability decreases in the following order: rabbit, rat, pig and man. It may be therefore that the permeability of rabbit skin is much greater for the substance than it is in the rat, and the toxic response is proliferated by rabbit skin to a greater extent.

 

There is a repeated dose oral toxicity study available for the substance itself (K1) study . A NOAEL of 6 mg/kg bw/day was established in this study and was selected as starting point for deriving the long-term systemic inhalation DNEL and the long-term systemic dermal DNEL on the basis of being the lowest dose. Long-term local DNELs (inhalation and dermal) were not derived as it is considered that the derivation from long term systemic effects provides a suitable margin of safety for use. 

Due to the nature of use of the products that contain the substance by consumers, it is considered appropriate to utilise an acute DNEL in place of the longer-term DNEL’s. The justification for this is that the products containing the substance would only be used sporadically, and as such would need to be assessed on these terms.

 

Guidance R8 Appendix 8.8 details thatif an acute toxicity hazard (leading to C&L) has been identified, a DNEL for acute toxicity can be established for the effects of peak exposures as these peaks can be significantly higher than the average daily exposure and the long-term DNEL may be insufficient to limit them. High peak exposures are usually assessed for the inhalation route only, however, on a case-by-case basis an ‘acute’ dermal or oral DNEL can be set for comparison with single exposure events. 

 

On the basis of the proposed dermal toxicity, assessment is performed for dermal exposure on a sporadic basis; comparison to acute DNEL’s is considered to be appropriate.

 

In practice, given the nature of use of the substance, it is unlikely that long term exposure to the substance by the general population is anticipated.