4-tert-butylcyclohexanol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.76 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

NOAEC

Value:

132.24 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAEC(corr) = NOAEL(oral)*(1/0.38 m³/kg/d)*ABS(oral-rat)/ABS(inh-human)*(6.7 m³ (8h)/10 m³ (8 h)) = 150 mg/kg bw/d*(1/0.38 m³/kg/d)*(0.5*1)*0.67 = 132.24 mg/m³. It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption. ABS(oral-rat)=oral absorption rate in rats, ABS(inh-human)=inhalation absorption rate in humans.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

DNEL is based on an oral 28-day study.

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No further remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

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:

0.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=oral NOAEL*ABS(oral)/ABS(dermal). On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced when performing oral-to-dermal extrapolation.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL.

AF for differences in duration of exposure:

6

Justification:

DNEL is based on an oral 28-day study.

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was the rat.

AF for other interspecies differences:

2.5

Justification:

Default value according to ECHA REACH Guidance.

AF for intraspecies differences:

5

Justification:

Default value for workers according to ECHA REACH Guidance.

AF for the quality of the whole database:

1

Justification:

The data base is adequate and of good quality (taking into account reliability and consistency, across different studies and endpoints).

AF for remaining uncertainties:

1

Justification:

No further remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

In general, the calculation of a DNEL is based on the observed effect level which has to be modified as described in “Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health” (ECHA, November 2012). Dermal and inhalative intakes are the possible exposure routes for workers.

The establishment of a DNEL for acute toxicity for covering effects which occur after a single exposure of a few minutes up to 24 hours is unnecessary for 4-tert-butylcyclohexanol. The substance has a low vapour pressure (6 Pa at 25°C) at room temperature and as a consequence, the inhalation via vapours can be considered negligible. In addition, 4-tert-butylcyclohexanol is described as pasty or viscid and therefore the generation and inhalation of dust is unlikely. Thus, peak exposure significantly higher than the average daily exposure and the long-term DNEL are very unlikely. Thus the assessment of a hazard after short-term exposure is sufficiently covered by derivation of the DNEL for long-term exposure. Based on the available data it is not possible to derive DNELs for local effects. Irritation on eyes is the leading local health effect but does not provide dose-response data. Therefore, a qualitative assessment is conducted and appropriate risk management measures will be identified.

As starting point for derivation of the long-term DNELs, a NOAEL of 150 mg/kg bw/day (for systemic effects) was used which was found in a subacute toxicity study performed according to OECD guideline 407 (98-0184-DGT). In this GLP Guideline study 4-tert-butylcyclohexanol was administered via gavage at concentrations of 50, 150 and 300 mg/kg bw/day for 28 days. A NOAEL of 150 mg/kg bw/day was set based on clinical symptoms, effects on motoractivity and body weight. This NOAEL was selected as relevant dose descriptor.

 

Inhalation

For calculation of the DNEL for long-term inhalative systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation.

It is assumed, that the oral absorption rate is 50% of that of the inhalation absorption.

Besides this, the interspecies difference between rat and human has to be taken into account. Therefore, the no observed adverse effect level has to be corrected by 6.7 / 0.38*10 regarding breathing volume and frequency. Thus, the corrected starting point for workers was 132.24 mg/m³/day for inhalation.

Subsequently assessment factors (AF) are listed, which have to be taken into account for the final DNEL calculation: remaining interspecies-differences (2.5), intraspecies differences (5), duration extrapolation: subacute - chronic (6).

The DNEL is calculated according to the formula DNEL = (corrected starting point) / (overall AF). Thus, the resulting DNEL for long-term inhalative systemic effects is 1.76 mg/m³ for workers.

 

Dermal

For calculation of the DNEL for long-term dermal systemic effects, the dose descriptor has to be converted into a corrected starting point by route-to-route extrapolation. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor is introduced when performing oral-to-dermal extrapolation. This is supported by the skin absorption potential of 0.010 mg/cm²/h for 4-tert-butylcyclohexanol, which is assigned to a high dermal absorption rate of 80% (for details refer to IUCLID chapter 7.1 toxicokinetics, metabolism and distribution). Thus, the corrected starting point for workers was 150 mg/kg bw/day for the dermal route.

Subsequently, following assessment factors are taken into account for the final DNEL calculation: interspecies differences (4), remaining interspecies-differences (2.5), intraspecies differences (5) and duration extrapolation: subacute - chronic (6).

As a consequence, the resulting DNEL for long-term dermal systemic effects is 0.5 mg/kg bw/day for workers.

 

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

4-tert-Butylcyclohexanol is only handled in industrial or professional settings (for details refer to IUCLID section 3.5 or to CSR section 2). Since exposure of the general public is precluded, DNELs for the general population are not relevant and thus not derived.