trans-1-(1-oxohexadecyl)-4-[(1-oxohexadecyl)oxy]-L-proline

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.63 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):

100

Modified dose descriptor starting point:

NOAEC

Value:

1 763.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

In a combined repeated dose toxicity study with the Reproduction/Developmental toxicity screening test, groups of ten rats were exposed daily to 100; 300 and 1000 mg/kg bw per day. The NOAEL for the systemic toxicity was 1000 mg/kg bw per day in this study. No treatment-related change was observed at any dose levels For route-to-route extrapolation, the calculation approach follows the Guidelines predefined (see R:8-2). Step 1) Relevant dose-descriptor: NOEL, rat = 1000 mg/kg bw per day Step 2) Modification of starting point - Conversion into inhalation NOAEC (in mg/m³) by using an 8-hour respiratory volume for the rat: 0.38 m³/kg bw - Correction for activity driven differences of respiratory volumes in workers compared to workers in rest: 6.7 m³/10 m³ - Correction for inhalation to oral absorption: no factor is added. Justification: the test substance has a low volatility (boiling point above 150°C, vapour pressure of less than 0.5 kPa). - No difference in oral and inhalation absorption is expected between rats and human. NOAEC corrected = 1000*1/0.38*6.7/10 = 1763.2 mg/m³

AF for dose response relationship:

1

Justification:

NOAEL available

AF for differences in duration of exposure:

4

Justification:

subacute (28 days) to chronic = 4

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

2

Justification:

screening data

AF for remaining uncertainties:

1

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:

2.5 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):

400

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

In a combined repeated dose toxicity study with the Reproduction/Developmental toxicity screening test, groups of ten rats were exposed daily to 100; 300 and 1000 mg/kg bw per day. The NOAEL for the systemic toxicity was 1000 mg/kg bw per day in this study. No treatment-related change was observed at any dose levels. Step 1) Relevant dose-descriptor: NOAEL, rat = 1000 mg/kg bw per day Step 2) Modification of starting point: Correcting for dermal to oral absorption: factor of 1 is used. The known surfactant properties may exert an unknown influence on its uptake and adsorption. Furthermore, the test substance is poorly soluble in water (< 1 mg/l). As no dermal penetration study is available, 100% absorption will be considered as a worst case. No difference in oral and dermal absorption is expected between rats and human. Corrected dermal NOAEL: 1000 mg/kg-day x 100%/100% = 1000 mg/kg-day.

AF for dose response relationship:

1

Justification:

NOAEL available

AF for differences in duration of exposure:

4

Justification:

subacute (about 54 days) to chronic = 4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

5

Justification:

workers

AF for the quality of the whole database:

2

Justification:

screening data

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

No DNEL is required for oral exposure of workers since no significant exposure occurs by this route for trained workers (who do not smoke, eat or drink when manipulating chemicals).

No DNELs are required for acute toxic effects, sensitization, irritation and mutagenic effects because long-term DNELs are sufficient to cover systemic effects, as a worst-case. Furthermore most of these DNELs can not be calculated with the available qualitative or single-dose data.

For the long-term exposure, because of the absence of data for repeated dose, DNELs can not be calculated.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.35 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):

200

Modified dose descriptor starting point:

NOAEC

Value:

869.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

In a combined repeated dose toxicity study with the Reproduction/Developmental toxicity screening test, groups of ten rats were exposed daily to 100; 300 and 1000 mg/kg bw per day. The NOAEL for the systemic toxicity was 1000 mg/kg bw per day in this study. No treatment-related change was observed at any dose levels For route-to-route extrapolation, the calculation approach follows the Guidelines predefined (see R:8-2). Step 1) Relevant dose-descriptor: NOEL, rat = 1000 mg/kg bw per day Step 2) Modification of starting point - Conversion into inhalation NOAEC (in mg/m³) by using an 24-hour respiratory volume for the rat: 1.15 m³/kg bw - Correction for inhalation to oral absorption: no factor is added. Justification: the test substance has a low volatility (boiling point above 150°C, vapour pressure of less than 0.5 kPa). - No difference in oral and inhalation absorption is expected between rats and human. NOAEC corrected = 1000*1/1.15 = 869.6 mg/m³

AF for dose response relationship:

1

Justification:

NOAEL available

AF for differences in duration of exposure:

4

Justification:

subacute (about 54 days) to chronic = 4

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

2

Justification:

screening data

AF for remaining uncertainties:

1

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 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):

800

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

In a combined repeated dose toxicity study with the Reproduction/Developmental toxicity screening test, groups of ten rats were exposed daily to 100; 300 and 1000 mg/kg bw per day. The NOAEL for the systemic toxicity was 1000 mg/kg bw per day in this study. No treatment-related change was observed at any dose levels. Step 1) Relevant dose-descriptor: NOAEL, rat = 1000 mg/kg bw per day Step 2) Modification of starting point: Correcting for dermal to oral absorption: factor of 1 is used. The known surfactant properties may exert an unknown influence on its uptake and adsorption. Furthermore, the test substance is poorly soluble in water (< 1 mg/l). As no dermal penetration study is available, 100% absorption will be considered as a worst case. No difference in oral and dermal absorption is expected between rats and human. Corrected dermal NOAEL: 1000 mg/kg-day x 100%/100% = 1000 mg/kg-day.

AF for dose response relationship:

1

Justification:

NOAEL available

AF for differences in duration of exposure:

4

Justification:

subacute (about 54 days) to chronic = 4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

2

Justification:

screening data

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.25 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):

800

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route-to-route extrapolation

AF for dose response relationship:

1

Justification:

NOAEL available

AF for differences in duration of exposure:

4

Justification:

subacute (about 54 days) to chronic = 4

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

Justification:

general population

AF for the quality of the whole database:

2

Justification:

screening data

AF for remaining uncertainties:

1

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

No assessment and notably no DNEL is required for the general public, as the latter is only exposed to the substances via the use of final cosmetic products. Assessment of human health effects for such exposure is not required by REACH.