[1S-(1α,2β,3α,5α)]-[2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]methylamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.29 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

22.04 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: 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:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.083 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 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 physico-chemical 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:

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:

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:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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

The test substance is classified and labeled for acute systemic toxicity (Cat 3; H301 and corrosivity (Cat. 1B) according to Regulation (EC) No 1272/2008 (CLP).

According to ECHA Guidance E.3.4 (March 2016), substances which are classified as acute toxic (Cat 3), Skin Corr. 1B; H314 and Eye Dam. 1; H318 are allocated in the moderate hazard band. Due to this classification qualitative risk assessment has been performed and OCs and RMMs based on the systemic long-term DNEL values are considered to ensure sufficient protection.

 

Acute/long-term, local

The test substance is classified and labeled as corrosive to skin (category 1B) and serious eye damaging (category 1). Therefore, a qualitative approach for hazard assessment is deemed necessary.

 

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 NOAEC was derived from NOAEL oral value (determined in a 37-d repeated dose toxicity study with rats, according to OECD Guideline 422), as no repeated dose inhalation study was available. Oral NOAEL of 25 mg/kg bw/day was converted to an inhalation NOAEC, 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): 25 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

= 25 mg/kg bw/day × (1 / 0.38 m³/kg bw/day) × 0.5 × (6.7 m³/10 m³)

= 22.04 mg/m³

 

Step 3: Use of assessment factors: 75

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

 

In conclusion, long term systemic inhalation DNEL, workers = 0.29 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 NOAEL was derived from NOAEL oral value (determined in a 37-d repeated dose toxicity study with rats, according to OECD Guideline 422), as no repeated dose dermal study was available. The oral NOAEL of 25 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):

Dermal absorption is supposed to be moderate to high considering the hydrophilic character and the moderate solubility in combination with its liquid state, the test substance will readily cover the skin surface. Dermal uptake of substances < 100 g/mol is favored. The MW of the test substance of 167.29 g/mol limits dermal absorption. According to the solubility (0.51 g/L) a moderate to good dermal uptake can be anticipated. Furthermore, due to the log Pow of 0.5, the penetration into the stratum corneum and hence dermal absorption will be limited. The corrosive properties of the substance have to be considered, since damaging the barrier function of the skin may lead to enhanced penetration and possibly followed by an increased systemic uptake of the test substance.Therefore, the oral NOAEL of 25 mg/kg bw/day was converted to a dermal NOAEL, considering a conservative 100 % absorption through the skin.

In conclusion, dermal NO(A)EL = 25 x (100/100) = 25 mg/kg bw/d.

 

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 = 0.0833 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:

DNEL (Derived No Effect Level)

Value:

0.073 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

10.87 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: 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:

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:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.042 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption 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:

6

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:

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:

medium hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.042 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:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required 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:

Recommended AF for other interspecies differences.

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:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

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

The test substance is classified and labeled for acute systemic toxicity (Cat 3; H301 and corrosivity (Cat. 1B) according to Regulation (EC) No 1272/2008 (CLP).

According to ECHA Guidance E.3.4 (March 2016), substances which are classified as acute toxic (Cat 3), Skin Corr. 1B; H314 and Eye Dam. 1; H318 are allocated in the moderate hazard band. Due to this classification qualitative risk assessment has been performed and OCs and RMMs based on the systemic long-term DNEL values are considered to ensure sufficient protection.

 

Acute/long-term, local

The test substance is classified and labeled for skin corrosin (category 1B) and serious eye damage (category 1). Therefore, a qualitative approach for hazard assessment is deemed necessary.

 

Long term, systemic DNEL

 

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 37-d repeated dose toxicity study with rats, according to OECD Guideline 422), as no repeated dose inhalation study was available. Oral NOAEL of 25 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:

Relevant dose descriptor (NO(A)EL): 25 mg/kg bw/day

Standard respiratory volume of the rat (sRVrat) for 8 hours: 1.15 m³/kg bw/day

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

 

Corrected inhalatory NOAEC for general population

= 25 mg/kg bw/day × (1 / 1.15 m³/kg bw/day) × 0.5

= 10.87 mg/m³

 

Step 3: Use of assessment factors: 150

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic inhalation DNEL, general population = 0.0733 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 NOAEL was derived from NOAEL oral value (determined in a 37-d repeated dose toxicity study with rats, according to OECD Guideline 422), as no repeated dose dermal study was available. The oral NOAEL of 25 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):

Dermal absorption is supposed to be moderate to high considering the hydrophilic character and the moderate solubility in combination with its liquid state, the test substance will readily cover the skin surface. Dermal uptake of substances < 100 g/mol is favored. The MW of the test substance of 167.29 g/mol limits dermal absorption. According to the solubility (0.51 g/L) a moderate to good dermal uptake can be anticipated. Furthermore, due to the log Pow of 0.5, the penetration into the stratum corneum and hence dermal absorption will be limited. The corrosive properties of the substance have to be considered, since damaging the barrier function of the skin may lead to enhanced penetration and possibly followed by an increased systemic uptake of the test substance. Therefore, the oral NOAEL of 25 mg/kg bw/day was converted to a dermal NOAEL, considering a conservative 100 % absorption through the skin.

In conclusion, dermal NO(A)EL = 25 x (100/10) = 25 mg/kg bw/d.

 

Step 3: Use of assessment factors: 600

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, general population = 0.0417 mg/kg bw/day.

 

Oral exposure

 

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

In order to derive a long-term oral DNEL, an oral NOAEL determined in determined in a 37-d repeated dose toxicity study with rats, according to OECD Guideline 422 was identified as the relevant dose descriptor (25 mg/kg bw/day).

 

Step 2: Use of assessment factors: 600

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic oral DNEL, general population = 0.0417 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.