A mixture of: 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate; 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate

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

Modified dose descriptor starting point:

NOAEC

Value:

188.07 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure and its physical state (waxy solid) of the test substance acute exposure hazard via inhalation is unlikely for humans and hence, repeated dose toxicity testing via the inhalation route was not done. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default, NOAEL derived from subacute study, extrapolation to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling should be applied in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default (workers)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

0.36 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

Modified dose descriptor starting point:

NOAEL

Value:

106.67 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term study on dermal toxicity is available and required, so only oral toxicity data can be used.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for allometric scaling (rat to human) as given in ECHA guidance R.8

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

For ‚Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate’, DNELs are needed for chronic exposure by the oral (only for consumers), dermal (for workers and consumers) and inhalation routes of exposure (workers and consumers). Inhalation is not a relevant route of exposure due to the low vapour pressure and the physical state (waxy solid) of the substance. Since ‚Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate‘ does not represent an acute hazard (not classified for acute toxicity), no DNELs for acute systemic toxicity need to be derived.

No DNELs are needed for local effects because there is no dose-response and route-specific information on these endpoints, and no skin irritating effects were observed. Long-term systemic DNELs cover sufficiently local effects.

From all available data for the different human health endpoints it is clear that ‚Reaction mass of 2,2,6,6-tetramethylpiperidin-4-yl-hexadecanoate and 2,2,6,6-tetramethylpiperidin-4-yl-octadecanoate‘ exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the substance, reflecting the routes, duration and frequency of exposure. DNELs are derived for workers and the general population. The general population includes consumers and humans exposed via the environment. There are following annotations for each endpoint:

 

- Since the substance is not acutely toxic by oral route of exposure, no DNEL needs to be derived. This is based on a LD50dermal greater than 5000 mg/kg bw and a LD50oral > 10000 mg/kg bw (as evident from the available studies).

- Acute DNELs for inhalation (systemic and local) are not necessary since there is no acute toxic hazard by inhalation.

- A qualitative approach in hazard assessment for eye and skin irritation/corrosion and skin sensitization is used because no quantitative dose descriptors are available on these endpoints.

- There is no animal data on repeated dermal or inhalation exposure. To cover this endpoint, data from an oral gavage 28 day study in rats (Information from migrated NONS file) has been used to calculate the long-term DNELs.

- No DNELs for reprotoxic effects are derived because no information on toxicity to reproduction is available, as it is based on the available data scientifically not required.

First of all, available dose descriptors were converted into a correct starting point to take into account differences in routes of exposure between experimental animals and humans and differences in human and animal exposure conditions. Consecutively, the assessment factors have been applied to the correct starting point to obtain the endpoint specific DNELs. Assessment factors (AFs) correct uncertainties and variability within and between species in the effect data.

The assessment factors are applied in accordance with R.8 ECHA guidance document.

 

Modification of the relevant dose descriptors to the correct starting point:

 

Bioavailability (absorption)

A dermal absorption rate of 30% is considered for the target substance as outlined in the subchapter “Basic Toxicokinetics”, based on the available physico-chemical and toxicological properties of the substance. The dermal absorption in rats and in humans is assumed to be the same since no experimentally determined values are available for dermal absorption of the target chemical in rats and in humans. In case of oral to inhalation extrapolation, 80% absorption is assumed for oral absorption in rats and 30% absorption for inhalation is assumed in humans.

 

Route-to-route extrapolation:

Oral-to-inhalation extrapolations are performed to assess long-term inhalation effects in humans, as well as oral-to-dermal extrapolations are conducted to assess long-term dermal effects in humans. This is due to the fact that only one oral study is available, because oral exposure in general is the most suitable administration route to assess systemic toxicity.

 

Exposure conditions:

Exposure time differs in workers and in the 28 day oral study in rats. Rats were exposed to the test substance once daily via gavage, while workers are exposed 8h daily (5days/week). However, the dose descriptor (the NOAEL of 40 mg/kg bw) was not adjusted to 8h exposure because exposure time is not really relevant for the systemic dose resulting from only dermal exposure.

 

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the 28 day gavage study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

 

Applying of assessment factors:

 

Interspecies differences:

No allometric scaling factor is applied in case of oral-to-inhalation extrapolation.

An additional assessment factor of 2.5 is applied for remaining interspecies differences in toxicodynamics between rats and humans.

 

Intraspecies differences:

An assessment factor of 5 is applied for workers for all endpoints and for all exposure routes. The factor of 10 is used in the process of DNEL-calculation for general population due to the greater intra-species variations.

 

Extrapolation of duration:

An assessment factor of 6 was applied in case of the 28 day oral repeated dose toxicity study. This is a default assessment factor for subacute to chronic extrapolation according to ECHA’s guidance R.8 and no reason for deviation was identified.

 

Quality of whole data base:

An assessment factor for uncertainties in the quality of the data base is regarded to be 1, because no concern was indicated upon the quality of the provided data.

 

Issues related to dose response:

An assessment factor of 1 was used because there were no indications for deviation from the default value, as already the available NOAEL was derived taking into account safety considerations.

 

Remaining uncertainties:

An assessment factor of 1 was applied here because no remaining uncertainties were identified.

 

Calculation of endpoint-specific DNELs for workers

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 40 mg/kg bw was converted into the dermal NOAEL:
Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 40 mg/kg bw x (80%/30%) = 106.67 mg/kg bw.

DNEL = 106.67 mg/kg bw/(1 x 6 x 4 x 2.5 x 5 x 1 x 1) = 0.36 mg/kg bw.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 5 – intraspecies (workers), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 40 mg/kg bw was converted into the inhalation NOAEC:

Inhalation NOAEC = dermal NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 40 mg/kg bw x (1/0.38 m³/kg/day) x (80%/30%) x (6.7/10) = 188.07 mg/m³

DNEL = 188.07 mg/m³/(1 x 6 x 1 x 2.5 x 5 x 1 x 1) = 2.50 mg/m³.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 1 – interspecies, no allometric scaling required for oral to inhalation exposure, 2.5 – remaining interspecies differences, 5 – intraspecies (workers), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.62 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

Modified dose descriptor starting point:

NOAEC

Value:

92.75 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure and its physical state (waxy solid) of the test substance acute exposure hazard via inhalation is unlikely for humans and hence, repeated dose toxicity testing via the inhalation route was not done. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default, NOAEL derived from subacute study, extrapolation to chronic

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling should be applied in case of oral-to-inhalation extrapolation

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

0.18 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

Modified dose descriptor starting point:

NOAEL

Value:

106.67 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term study on dermal toxicity is available and required, so only oral toxicity data can be used.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for allometric scaling (rat to human) as given in ECHA guidance R.8

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

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:

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:

DNEL (Derived No Effect Level)

Value:

0.07 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

Modified dose descriptor starting point:

NOAEL

Value:

40 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Not applicable - NOAEL from oral study

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

6

Justification:

default, subacute to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

default factor for allometric scaling (rat to human) as given in ECHA guidance R.8

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

1

Justification:

no remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:

 

Modification of the starting point:

 

Bioavailability (absorption)

The oral absorption in rats and in humans is assumed to be the same since no information for oral absorption for target chemical in rats and in humans is available.

 

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert oral NOAEL into inhalation NOAEC.

 

Applying of assessment factors:

A higher assessment factor of 10 (instead of 5 for workers) for intraspecies variation/differences of human population was used.

 

Calculation of endpoint-specific DNEL for general population

 

Long-term exposure - systemic effects (oral)

The oral NOAEL of 40 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available:
Oral NOAEL rat = oral NOAEL human = 40 mg/kg bw.

DNEL = 40 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 0.07 mg/kg bw.

Assessment factors are:1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (dermal)

The oral NOAEL of 40 mg/kg bw was converted into the dermal NOAEL:
Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 40 mg/kg bw x (80%/30%) = 106.67 mg/kg bw.

DNEL = 106.67 mg/kg bw/(1 x 6 x 4 x 2.5 x 10 x 1 x 1) = 0.18 mg/kg bw.

Assessment factors are: 1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 4 – interspecies, allometric scaling, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).

 

Long-term exposure - systemic effects (inhalation)

The oral NOAEL of 40 mg/kg bw was converted into the inhalation NOAEC:

Corrected inhalation NOAEC = oral rat NOAEL x (1/1.15 m³/kg bw/day) x (ABS oral-rat/ABS inhal-human), where 1.15 m³/kg bw is standard respiratory volume of rats during 24 h, ABS is absorption (values are the same as described for workers).

Corrected Inhalation NOAEC = 40 mg/kg bw x (1/1.15 m³/kg/day) x (80%/30%) = 92.75 mg/m³

DNEL = 92.75 mg/m³/(1 x 6 x 1 x 2.5 x 10 x 1 x 1) = 0.62 mg/m³.

Assessment factors are:1 – dose response (clear dose response), 6 – study duration (subacute to chronic), 1 – interspecies, no allometric scaling required for oral to inhalation exposure, 2.5 – remaining interspecies differences, 10 – intraspecies (general population), 1 – quality of data base, 1 – remaining uncertainties (none remaining).