2-hydroxypropyl [(1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl] carbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Value:

2.46 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

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

185.13 mg/m³

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Value:

1.75 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

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

525 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4 (log Pow 3.72). The molecular weight of the substance is above 100 g/mol (MW 258 g/mol). Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 40 % of oral absorption was taken for calculation.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

6

Justification:

extrapolation from sub-acute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

Recommended AF for other interspecies differences.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test substance is performed under consideration of the recommendations of ECHA. In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Workers – Hazard via inhalation route

 

Long term systemic inhalation DNEL, worker

The DNEL long term, systemic (inhalation) is derived by route-to route extrapolation from the repeated dose oral toxicity study.

Step 1: Selection of the relevant dose descriptor (starting point):

The repeated dose oral toxicity study OECD 407 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 150 mg/kg bw/day.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long term inhalation exposure) is derived considering a two times higher absorption via inhalation than oral absorption.

 

Relevant dose descriptor (NOAEL): 150 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m³/kg bw/d

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

 

Corrected inhalatory NOAEC for workers

= 150 mg/kg bw/day* 0.5 * (1 / 0.38 m³/kg bw/day) * (6.7 m³/10 m³) * (7/5)

= 185.13 mg/m³

 

Step 3: Use of assessment factors: 75

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

Remaining uncertainties AF: 1

 

In conclusion, long term systemic inhalation DNEL, workers = 2.46 mg/m3

 

Short term systemic inhalation DNEL, worker

No data for the classification and labelling of the test substance for acute systemic toxicity (inhalation) is available. The substance is not classified for acute oral toxicity and acute dermal toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Thus, no DNEL is required.

 

Short and long term local inhalation DNEL, worker

No data on respiratory irritation is available. However, the test substance is not classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). This implies that no potential damage to mucosal tissue may occur by an inhalation exposure.

 

Workers – Hazard via dermal route

 

Long term systemic dermal DNEL, worker

The DNEL long term, systemic (dermal) is derived by route-to route extrapolation from the repeated dose oral toxicity study (OECD 407).

 

Step 1: Selection of the relevant dose descriptor (starting point):

The repeated dose toxicity study (OECD 407) is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral NOAEL is 150 mg/kg bw/day.

 

Step 2: Modification of the starting point:

There are no relevant experimental data on repeated dermal exposure. Based on physicochemical data dermal absorption is possible. According to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”, especially water solubility is high enough to enable dermal penetration. The log Pow lies in the range between -1 and 4 (log Pow 3.72). The molecular weight of the substance is above 100 g/mol (MW 258 g/mol). Penetration through skin is anticipated to be less extensive than oral absorption and an absorption rate of 40 % of oral absorption was taken for calculation.

 

Relevant dose descriptor (NOAEL): 150 mg/kg bw/day

Frequency of exposure in study: 7 days/week

Frequency of worker exposure: 5 days/week

Oral absorption of the rat / dermal absorption of humans (ABSoral-rat / ABSinh-human): 100/40

 

Corrected dermal NOAEL for workers

150 mg/kg bw/day * (100%/40%) * (7/5) = 525 mg/kg bw/day

 

Step 3: Use of assessment factors: 300

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

Remaining uncertainties AF: 1

 

In conclusion, long term systemic dermal DNEL, workers = 1.75 mg/kg bw/day

 

Short term systemic dermal DNEL, worker

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

 

Long term and short term local dermal DNEL, worker

The test item is not classified for skin sensitization or skin irritation/corrosion according to Regulation (EC) No 1272/2008 (CLP). Thus, no qualitative risk assessment has to be conducted.

   

Worker – Hazard for the eyes

The test item is classified for eye irritation according to Regulation (EC) No 1272/2008 (CLP). Thus, qualitative risk assessment is required. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

With regard to consumer exposure the substance under concern is used only in cosmetic products. Therefore, the derivation of DNELs, assessment of exposure and risk characterization are not required (ECHA guidance on information requirements and chemical safety assessment - Chapter R.8: Characterisation of dose [concentration]-response for human health, Version 2.1, November 2012, ECHA-2010 -G-19 -EN). Furthermore, no indirect exposure assessment is necessary in accordance to ECHA guidance on information requirements and chemical safety assessment - Chapter R.16: Environmental exposure assessment, Version 3.0, February 2016, ECHA-16 -G-03 -EN.