α,α,α-trifluoro-4-nitro-m-cresol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.72 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):

25

Dose descriptor starting point:

NOAEL

Value:

162 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

142.9 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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

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:

DNEL (Derived No Effect Level)

Value:

17.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.62 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):

100

Dose descriptor starting point:

NOAEL

Value:

162 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

162 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure available. Taken into account the physicochemical and toxicokinetic properties of the substance, dermal absorption is anticipated to be 100 % of oral absorption.

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:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

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:

DNEL (Derived No Effect Level)

Value:

4.86 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012). Regarding the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered each to a value of 1, and are not shown in the calculations presented below.

 

Acute, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two acute DNELs are calculated for workers.

Exposure by inhalation

According to the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (ECHA, 2012), the short term inhalatory DNEL was calculated, based on the DNEL for oral long-term exposure, modified by a factor of 3, considering conservatively the differences between route and length of exposure.

long term systemic inhalation DNEL, workers * 3 = 5.72 mg/m³ * 3

In conclusion, the short term inhalatory DNEL, workers = 17.2 mg/m³

Dermal exposure

According to the Guidance on information requirements and chemical safety assessment Chapter R.8: Characterisation of dose [concentration]-response for human health (ECHA, 2012), the short term dermal DNEL was calculated, based on the DNEL for oral long-term exposure, modified by a factor of 3, considering conservatively the differences between route and length of exposure.

long term systemic dermal DNEL, workers * 3 = 1.62 mg/kg bw/day * 3

In conclusion, the short term dermal DNEL, workers = 4.86 mg/kg bw

Acute/long-term, local

The test substance is classified and labeled as severely eye damaging (category 1) and corrosive to the skin (category 1C).

Conclusion: According to the Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation (ECHA, 2016)

- the local acute/long term inhalatory hazard is low.

- the local acute/long term hazard for skin and eye is moderate.

 

Long term, systemic DNEL

Occupational exposure to the test substance occurs mainly by dermal route, and may also occur by inhalation exposure. Therefore two long-term DNELs are calculated for workers.

 

Exposure by inhalation

 

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

In order to derive a long-term inhalation DNEL, an inhalation NOEC was derived from NOAEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose inhalation study was available. Oral NOAEL of 162 mg/kg bw/day was converted to an inhalation NOEC, assuming 100 % absorption via the lung and 50 % absorption via the oral route.

 

Step 2: Modification into a correct starting point:

The oral NO(A)EL was converted into an inhalation NO(A)EC according to the following formula assuming a daily exposure period of 8 hours during light activity:

 

Relevant dose descriptor (NO(A)EL): 162 mg/kg bw/day

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

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

 

Corrected inhalatory NOAEC for workers

= 162 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 0.5 × (6.7 m³/10 m³)

= 142.9 mg/m³

 

Step 3: Use of assessment factors: 25

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2

 

In conclusion, long term systemic inhalation DNEL, workers = 5.72 mg/m³

 

 

Dermal exposure

 

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

In order to derive a long-term dermal DNEL, a dermal NOEL was derived from NOAEL oral value (determined in a 90-d repeated dose toxicity study with rats), as no repeated dose dermal study was available. The oral NOAEL of 162 mg/kg bw/day was used as starting point.

 

Step 2: Modification into a correct starting point:

Correction for dermal absorption rates of the test substance (based on Guidance on information requirements and chemical safety assessment, R. 7C, 2014, Chapter R 7.12):

Application of the test substance onto the skin of rabbits induced corrosion, which in turn could impair the natural barrier function of the skin against environmental influences and favor direct absorption into systemic circulation. The physico-chemical properties of the test substance additionally favour dermal uptake, regarding the molecular weight of 207.1 g/mol and the water solubility (15 g/L). The barrier function of the skin for ionic substances decreases the penetration of the test substance. However, the log Pow of 3.6 indicates a moderate transition capacity into the stratum corneum and hence dermal absorption. In addition, the results of the acute dermal toxicity study supports absorption via dermal route. Therefore, oral NOAEL of 162 mg/kg bw/day was converted to a dermal NOEL, considering a conservative 100 % absorption through the skin.

In conclusion, dermal NO(A)EL = 162.0 x (100/100) = 162.0 mg/kg bw/d.

 Step 3: Use of assessment factors: 100

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2

 

In conclusion, long term systemic dermal DNEL, workers = 1.62 mg/kg bw/day.

 

References

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health.

- ECHA (2014). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Only professional use and no consumer use is intended for the test substance. No exposure to the test substance can be assumed for the general population. Therefore, no further hazard assessment has to be performed for the general population. In addition, secondary poisoning via the environment can be excluded for the test substance.