2-isopropyl-N-hydroxyethyl 1,3-oxazolidine;methyl carbonato-N-ethyl-2-isopropyl-1,3-oxazolidine;reaction mass of: carbonato-bis-N-ethyl-2-isopropyl-1,3-oxazolidine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.5 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:

185.1 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:

The default extrapolation factor for exposure duration is used: subacute (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:

The default value for interspecies differences is used.

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

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 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:

210 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Due to physico-chemical properties the same absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.

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:

The default extrapolation factor for exposure duration is used: subacute (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:

The default value for interspecies differences is used.

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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Acute/short term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incozol LV is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

Acute/long term, local effects

Skin irritation/corrosion: Based on the available acute skin irritation study Incozol LV is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.

Eye irritation/corrosion: The available eye irritation study on rabbits revealed that the test item causes severe eye damage. Incozol LV is therefore classified as H318 according to Regulation (EC) No 1272/2008.

Skin sensitization: The test item is classified for skin sensitisation, Cat. 1 according to Regulation (EC) No 1272/2008. Thus, a qualitative risk assessment is conducted.

Long term, systemic effects

Occupational exposure to Incozol LV occurs mainly by dermal route, and may also occur by inhalation route. Therefore, two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Exposure by inhalation (worker)

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

The NOAEL of 150 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Covance, 1999) is identified as the relevant dose descriptor and starting point.

Step 2: Modification into a correct starting point:

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

Relevant dose descriptor (NOAEL): 150 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

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker (=1.4)

Corrected inhalatory NOAEC for workers:

= 150 mg/kg bw/day x 0.5 x (1 / 0.38 m3/kg bw/day) x (6.7 m3/10 m³) x 1.4

= 185.1 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.

Intraspecies AF (worker): 5

Interspecies AF, remaining differences: 2.5

Exposure duration AF: 6

In conclusion, long term systemic inhalation DNEL, workers = 2.5 mg/m3 

Dermal exposure (worker)

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

The NOAEL of 150 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Covance, 1999) is identified as the relevant dose descriptor and starting point.

Step 2: Modification of the starting point:

Assuming that dermal absorption is the same as oral absorption, a worker DNEL (long-term dermal exposure) is derived.

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABSderm-human):100%/100%

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEL (dermal) for workers:

= 150 mg/kg bw/day x 1 x 1.4

= 210 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

In conclusion, long term systemic dermal DNEL, workers = 0.7 mg/kg bw/day

 

References

(not included as endpoint study record)

ECHA (2012). 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 (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.43 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):

150

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

65.2 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:

The default extrapolation factor for exposure duration is used: subacute (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:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" 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

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 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):

600

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Due to physico-chemical properties the same absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.

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:

The default extrapolation factor for exposure duration is used: subacute (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:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" 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:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 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):

600

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.

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:

The default extrapolation factor for exposure duration is used: subacute (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:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" 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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012) 

Acute/short term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incozol LV is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

Acute/long term, local effects

Skin irritation/corrosion: Based on the available acute skin irritation study Incozol LV is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.

Eye irritation/corrosion: The available eye irritation study on rabbits revealed that the test item causes severe eye damage. Incozol LV is therefore classified as H318 according to Regulation (EC) No 1272/2008.

Skin sensitization: The test item is classified for skin sensitisation, Cat. 1 according to Regulation (EC) No 1272/2008. Thus, a qualitative risk assessment is conducted.

Long term, systemic effects

Consumer exposure to Incozol LV occurs mainly by dermal route, and may also occur by oral and inhalation route. Therefore long-term DNELs are calculated for the general population. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Exposure by inhalation (general population)

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

The NOAEL of 150 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Covance, 1999) is identified as the relevant dose descriptor and starting point.

Step 2: Modification into a correct starting point:

Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived. 

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

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

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m³/kg bw

 Corrected inhalatory NOAEC for general population

= 150 mg/kg bw/day x 0.5 x (1/1.15 m³/kg bw/day)

= 65.2 mg/m³  

Step 3: Use of assessment factors: 150

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

Intraspecies AF (general population): 10

Exposure duration AF: 6

Interspecies AF, remaining differences: 2.5 

In conclusion, long term systemic inhalation DNEL, general population = 0.43 mg/m³

Dermal exposure (general population)

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

The NOAEL of 150 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Covance, 1999) is identified as the relevant dose descriptor and starting point.

Step 2: Modification of the starting point:

Assuming that dermal absorption is the same as oral absorption, a general population DNEL (long-term dermal exposure) is derived.

Step 3: Use of assessment factors: 600

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

Intraspecies AF (general population): 10

Interspecies AF, remaining differences: 2.5 

Exposure duration AF: 6  

In conclusion, long term systemic dermal DNEL, general population = 0.25 mg/kg bw/day

Oral exposure (general population)

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

The NOAEL of 150 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Covance, 1999) is identified as the relevant dose descriptor and starting point.

Step 2: Use of assessment factors: 600

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

Intraspecies AF (general population): 10

Exposure duration AF: 6

In conclusion, long term systemic oral DNEL, general population = 0.25 mg/kg bw/day

 

References

(not included as endpoint study record)

ECHA (2012). 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 (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016