Dimethylamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.854 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

92.26 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

46.36 mg/m³

Explanation for the modification of the dose descriptor starting point:

Use systemic NOAEC of 50 ppm corresponding to 92.26 mg/m³ (Buckley, 1985) for derivation of DNEL systemic long-term

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6 h/8 h)* (6.7 m³/10 m³ ) = 46.36 mg/m³

These 2 adjustments take into consideration the interspecies differences in exposure conditions and the differences in respiratory volume depending on the activity level.

Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics has been shown to be similar in rats and humans.

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for differences in duration of exposure:

2

Justification:

default (for extrapolation of subchronic to chronic exposure durations)

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

5

Justification:

A factor of 5 is included for intraspecies differences for workers (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28.56 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Value:

184.85 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

357.244 mg/m³

Explanation for the modification of the dose descriptor starting point:

Use of systemic short-term NOAEL of 100 ppm = 184.85 mg/m³ (14 day DRF) for derivation of DNEL systemic acute.

 

Modified Habers Law: c³ * t = k

184.85E3 (exponent of 3 is a default values derived of R8) * 6 = 37897417.4

Then: CE3 = 37897417.4/0.25 = CE3 = 151589669.6, and C = 533.2

This value needs to be further corrected for factor of 0.67 = 357.244 mg/m³

The last adjustment take into consideration the differences in respiratory volume depending on the activity level. Adjustments for absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics has been shown to be similar in rats and humans. No further assessment factors are required for database quality or study duration. 

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

5

Justification:

A factor of 5 is included for intraspecies differences for workers (default value)

AF for the quality of the whole database:

1

Justification:

default (GLP guideline study of high quality)

AF for remaining uncertainties:

1

Justification:

default (no remaining uncertainties are identified)

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.824 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

15

Dose descriptor:

LOAEC

Value:

18.45 mg/m³

AF for dose response relationship:

3

Justification:

An AF or 3 was used for LOAEL to NOAEL extrapolation.

AF for differences in duration of exposure:

1

Justification:

The default AF of 2 for study duration differences normally applicable was omitted in this case, as it does not apply in this case, as here local effects occur at the immediate port of entry.

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

1

Justification:

The default AF of 2.5 for other interspecies differences normally applicable was omitted in this case, as it does not apply in this case, as here local effects at the immediate port of entry are expected. There no differences in deposition, airflow patterns or clearance rate are in this case expected between rat and human.

AF for intraspecies differences:

5

Justification:

A factor of 5 is included for intraspecies differences for workers (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.263 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEC

Value:

92.26 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

26.29 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Use the new inhalation NOAEC of 50 ppm (corresponding to 92.26 mg/m³) for systemic effects is used to assess dermal systemic effects in humans

 

corrected NOAEC = 92.26 mg/m³ * 6 h/8 h * (100 %/100 %)*(100 %/100 %)*0.38 m3/kg bw/day)= 26.29 mg/kg bw/day

This adjustment take into consideration the different route-of exposure of human (dermal) versus rat (inhalation).

Additional adjustments for species differences in absorption and metabolism are not required, and since the metabolism and kinetics has been shown to be similar in rats and humans.

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for differences in duration of exposure:

2

Justification:

default (for extrapolation of subchronic to chronic exposure durations)

AF for interspecies differences (allometric scaling):

4

Justification:

The factor 4 is used for interspecies differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

5

Justification:

A factor of 5 is included for intraspecies differences for workers (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

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)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

The REACH regulation defines the Derived No-Effect Level (DNEL) as the level of exposure above which humans should not be exposed. The calculation of the DNELs is done in accordance to the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”

Available dose descriptors:

From all available data for the different human health endpoints it is clear that dimethylamine 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 from the available toxicity data of dimethylamine (DMA), 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:

o  DNELs for acute toxicity are established because dimethylamine is considered to be of low acute toxicity (Acute Tox 4 according to GHS).

o  A qualitative approach for the risk assessment of skin, eye and respiratory tract irritation/corrosion and skin sensitization is used because no dose descriptors are available on these endpoints.

o  For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived because a No-Effect Level could not be established from the relevant studies. Hence the hazard characterization is based on a qualitative approach.

o  In case of repeated dose toxicity experimental data is incomplete regarding each possible exposure route (oral, dermal). In this case a route-to-route extrapolation was performed.

In order to address the differences between toxicological effect data obtained in animal studies and the real human situation, assessment factors are applied. First of all, available dose descriptors were converted into a correct starting point to take account of differences in routes of exposure between experimental animals and humans, differences in human and animal exposure conditions and possible differences in absorption between routes and between experimental animals and humans. 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 ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

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

Bioavailability

o  Bioavailability for experimental animals and humans for all exposure routes was assumed to be the same since no species-specific information is available.

Route-to-route extrapolation:

o  No assessment factor (factor of 1) is applied when oral-to-dermal extrapolation is performed in accordance with Section R.8.4.2 (p.25), assuming that dermal absorption will not be higher than oral absorption.

o  A default factor of 2 is applied when oral-to-inhalation extrapolation is performed.

Exposure conditions:

o  Exposure times differed in the acute inhalation and repeated dose inhalation studies. The dose descriptors were corrected as described in the Appendix R.8-2. The derived acute DNELs were not corrected for the exposure duration, since the substance acts in a concentration-dependent manner.

o  No Haber’s law was used to calculate the starting point for the acute toxicity inhalation because the test substance acts in a concentration- dependent manner.

Absorption:

o  The differences in the respiratory volumes between experimental animals and humans were taken into account when an inhalatory NOAEC or a inhalatory LOAEC from a rat study or rat study was used to assess inhalation exposure in humans.

o  100 % oral, dermal and inhalation absorption is assumed in a worst case approach in the absence of specific toxicokinetic study results.

 

Applying of assessment factors (AF):

Interspecies differences:

o  The species-specific default AF for allometric scaling from Table R.8-3 is applied in case of repeated dermal exposures.

o  No species-specific default AF for allometric scaling is applied in case of inhalation exposure routes in animals which were taken to assess human inhalatory exposure.

o  Inhalatory dose descriptors are modified into a correct starting point taken into account only the differences of exposure conditions between experimental animals and humans as well as differences in the respiratory volumes between experimental animals and humans.

o  No additional AFs are applied for inhalation route and for local effects to obtain a corrected starting point (Table R8-4, Appendix R.8-2, part 2, example A.2).

o  An additional AF of 2.5 is applied for remaining interspecies differences, except in the case of the inhalation local long--term DNEL, as no interspecies differences in disposition patterns, metabolism are expected in case of DMA. For DMA immediate effects at the port of entry are expected and there no interspecies differences are likely.

 

Intraspecies differences (worker): 

o  AFs of 5 are applied for workers, respectively, for all endpoints and all exposure routes.

 

Extrapolation of duration:

o  The relevant default AFs from Table R.8-5 are applied if relevant.

 

Issues related to dose response:

o  An AF of 3 was applied if an identified LOAEC was used as a starting point (in case of acute toxicity for systemic and for local effects and in case of repeated dose toxicity for systemic and local effects).

Quality of whole data base:

o  The assessment factor for uncertainties to the quality of the data base is regarded to be 1.

Since DMA is classified as low acute toxic substance, DNELs were derived also for short-term exposure via inhalation. These short-term DNELs are more relevant for workers exposed to high peak concentrations (for instance when sampling or connecting/disconnecting vessels), but may in some cases also to be relevant for consumers. The ECHA Guidance Document R.8 outlines only how to set acute toxicity DNELs for the inhalation route. For dermal and oral exposure routes, a qualitative hazard conclusion was derived.

 

Irritation/corrosivity (skin): there are no dose descriptors available, therefore only a qualitative approach is conducted.

Qualitative approach:

An irritation specific DNEL for the local effects could be derived from dermal acute, sub-acute or sub-chronic studies in animals (Appendix R.8-9). In the available acute dermal studies on DMA, no dose-response information is available. There is no repeated dose dermal toxicity data on DMA from that a non-irritant dose/concentration could be derived. A qualitative approach to assessing and controlling the risks is more appropriate in this case. Severe irritation and corrosive effects on skin, respiratory and gastrointestinal tract were reported in more than one study. DMA is considered to be irritant to skin.

 

Irritation/corrosivity (eye):

There is no identified quantitative dose descriptor available from animal data for this endpoint. The test material is considered to be irritating / corrosive to the eyes.

 

Irritation/corrosivity (respiratory tract):

Qualitative approach:

From acute, repeated dose and developmental inhalation toxicity studies it is clear, that DMA caused irritation of respiratory tract.

 

Sensitization (skin and respiratory tract):

There is no experimental data available for this endpoint.

Reproductive toxicity:

 

The principles of the setting DNELs for the reproductive toxicity are similar to those of the repeated dose toxicity (Appendix R.8-12).

No DNELs for reproductive toxicity were derived, because DMA is not characterized as an reprotoxic substance.

Comparison with the existing OEL values:

From ECHA Guidance for the Implementation of REACH (Chapter R.8) is is clearly stated that there may already exist occupational limits (OELs) for workplace exposure. Additionally it is declared that under certain circumstances those values can be used in place of developing the DNEL. Generally the calculated DNELs from experimental animal data will tend to be lower (sometimes significantly) than any corresponding health-based OEL for a chemical. An Occupational Exposure Limit (OEL) of 2 ppm (3.8 mg/m³) is recommended by the Scientific Expert Group on Occupational Exposure Limits (SCOEL).  This value covers the long-term systemic exposure. There exists also an OEL of 5 ppm (9.4 mg/m³) which covers the short-term exposure. A scientific justification is available (SEG/SUM/11B, 1991) which would be required according to the REACH guidance and understood as a prerequisite to use such a value. The underlying effect for repeated dose exposure is local irritation of the upper respiratory tract, but the value is also intended to prevent local effects on skin.

Respiratory or occular irritation have not been reported in workers exposed to concentrations at or near the existing OEL.

The conversion of ppm into mg/m³ was performed according to the ECHA Guidance R7A: mg/m³ = (MW x ppm)/24.5; where 24.5 is the volume of ideal gas as 25°C.

Calculation of endpoint-specific DNELs for general population

Long-term exposure - systemic effects (inhalation):

The inhalationNOAEC (systemic) = 50 ppm = 92.26 mg/m³ was not modified for differences in absorption by inhalation route since no substance- and route specific information is available. However, the NOAEC was corrected for differences concerning exposure and the differences in respiratory volumes depending on the activity level. Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics have been shown to be simliar in rats and humans.

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6 h/8 h)* (6.7 m³/10 m³ ) = 46.36 mg/m³

DNEL = 46.36 mg/m³/ (1 x 2 x 1 x 2.5 x 5 x 1 x 1) = 1.8544 mg/m³

Assessment factors are: 2 - study duration, 1 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 25.

Short-term exposure - systemic effects (inhalation):

The inhalationNOAEC (systemic) = 100 ppm = 184.85 mg/m³ was modified according to the Modified Habers Law: c³ * t = k

184.85E3 (exponent of 3 is a default values derived of R8) * 6 = 37897417.4

Then: CE3 = 37897417.4/0.25 = CE3 = 151589669.6, and C = 533.2

This value needs to be further corrected for factor of 0.67 = 357.244

DNEL = 357.244 mg/kg bw/ (1 x 1 x 1 x 2.5 x 10 x 1 x 1) = 28.56 mg/m³.

Assessment factors are: 1 - study duration, 1 – interspecies, 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 12.5

Long-term exposure - local effects (inhalation):

The inhalation LOAEC (systemic) = 10 ppm = 18.45 mg/m³ was not modified for differences in absorptionby inhalation route of exposure since no substance- and route specific information is available.. The LOAEC was also not further modified.

Corr. LOAEL = 18.45 mg/m³ x 0.67 = 12.36 mg/m³

DNEL = 12.36 mg/m³/ (3 x 1 x 1 x 1 x 5 x 1 x 1) = 0.824 mg/m³.

Assessment factors are: 1 - study duration, 1 – interspecies, 1 – remaining interspecies differences, 5 – intraspecies, 3 – dose response (LOAEC to NOAEC extrapolation), 1 – quality of data base (default).

The total AF amounts to 15.

Long-term exposure - systemic effects (dermal):

The inhalation NOAEC (systemic) = 50 ppm = 92.26 mg/m³ was not modified for differences in absorption by inhalation or dermal route since no substance- and route specific information is available. However, the NOAEC was corrected fordifferences concerning exposure and the differences in respiratory volumes depending on the activity level.Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics have been shown to be simliar in rats and humans.

corrected NOAEC = 92.26 mg/m³ * 6 h/8 h * (100 %/100 %)*(100 %/100 %)*0.38 m³/kg bw/day= 26.29 mg/kg bw/day

DNEL = 26.29 mg/m³/ (1 x 2 x 4 x 2.5 x 5 x 1 x 1) = 0.2629 mg/m³

Assessment factors are: 1 - dose response (clear dose response), 2 - study duration, 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – quality of data base (default).

The total AF amounts to 100.

Summary of derived DNELs:

Long-term exposure – systemic effects (inhalation DNEL):

DNEL = 1.8544 mg/m³

Short-term exposure – systemic effects (inhalation DNEL):

DNEL = 28.56 mg/m³

Long-term exposure – local effects (inhalation DNEL):

DNEL = 0.824 mg/m³

Long-term exposure – systemic effects (dermal DNEL):

DNEL = 0. 2629mg/kg bw/day

 

Selected DNELs

DNEL systemic inhalation = 1.8544 mg/m³

DNEL systemic dermal (long-term) = 0.2629 mg/kg bw  

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

92.26 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

16.475 mg/m³

Explanation for the modification of the dose descriptor starting point:

Use systemic NOAEC of 50 ppm corresponding to 92.26 mg/m³ (Buckley, 1985) for derivation of DNEL systemic long-term

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6 h/24 h)* (5 d/7 d ) = 16.475 mg/m³

These 2 adjustments take into consideration the differences concerning exposure andthe differnces in respiratory volume depending on the activity level. Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics has been shown to be similar in rats and humans. 

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for differences in duration of exposure:

2

Justification:

default (for extrapolation of subchronic to chronic exposure durations)

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

10

Justification:

A factor of 10 is included for intraspecies differences for the general population (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

21.33 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

184.85 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

533.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

Use of systemic short-term NOAEL of 100 ppm = 184.85 mg/m³ for derivation of DNEL systemic acute (14 day DRF).

 

Modified Habers Law: c³ * t = k

184.85E3 (exponent of 3 is a default values derived of R8) * 6 = 37897417.4

Then: CE3 = 37897417.4/0.25 = CE3 = 151589669.6, and C = 533.2 mg/m³

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

10

Justification:

A factor of 10 is included for intraspecies differences for the general population (default value)

AF for the quality of the whole database:

1

Justification:

default (GLP guideline study of high quality)

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.615 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

30

Dose descriptor:

LOAEC

Value:

18.45 mg/m³

AF for dose response relationship:

3

Justification:

An AF or 3 was used for LOAEL to NOAEL extrapolation.

AF for differences in duration of exposure:

1

Justification:

The default AF of 2 for study duration differences normally applicable was omitted in this case, as it does not apply in this case, as here local effects occur at the immediate port of entry.

AF for interspecies differences (allometric scaling):

1

Justification:

default (no allometric scalling should be applied in case of inhalation-to-inhalation extrapolation)

AF for other interspecies differences:

1

Justification:

The default AF of 2.5 for other interspecies differences normally applicable was omitted in this case, as it does not apply in this case, as here local effects at the immediate port of entry are expected. There no differences in deposition, airflow patterns or clearance rate are in this case expected between rat and human.

AF for intraspecies differences:

10

Justification:

A factor of 10 is included for intraspecies differences for the general population (default value)

AF for the quality of the whole database:

1

Justification:

default (GLP guideline study of high quality)

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.095 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEC

Value:

92.26 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

18.95 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The inhalation -NOAEC of 50 ppm (corresponding to 92.26 mg/m³) for systemic effects is used to assess dermal systemic effects in humans

 

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(1.15 m³/kg bw/day) * 5d/7d * 6 h/24 h = 18.95 mg/kg bw/day

These adjustments take into consideration the different route-of exposure of human (dermal) versus rat (inhalation) and the differences in exposure duration.

Additional adjustments for species differences in absorption and metabolism are not required, and since the metabolism and kinetics has been shown to be similar in rats and humans.

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for differences in duration of exposure:

2

Justification:

default (for extrapolation of subchronic to chronic exposure durations)

AF for interspecies differences (allometric scaling):

4

Justification:

The factor 4 is used for interspecies differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

10

Justification:

A factor of 10 is included for intraspecies differences for the general population (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

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)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.095 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

other: NOAEC of 92.26 mg/m³

Modified dose descriptor starting point:

NOAEL

Value:

18.95 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The inhalation -NOAEC of 50 ppm (corresponding to 92.26 mg/m³) for systemic effects is used to assess oral systemic effects in humans

 

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(1.15 m³/kg bw/day) * 5d/7d * 6 h/24 h = 18.95 mg/kg bw/day

These adjustments take into consideration the different route-of exposure of human (oral) versus rat (inhalation) and the differences in exposure duration.

Additional adjustments for species differences in absorption and metabolism are not required, and since the metabolism and kinetics has been shown to be similar in rats and humans.

AF for dose response relationship:

1

Justification:

default (three doses were tested, using a spacing range of 2-4 fold)

AF for differences in duration of exposure:

2

Justification:

default (for extrapolation of subchronic to chronic exposure durations)

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

AF for other interspecies differences:

2.5

Justification:

default (no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans)

AF for intraspecies differences:

10

Justification:

A factor of 10 is included for intraspecies differences for the general population (default value)

AF for the quality of the whole database:

1

Justification:

default

AF for remaining uncertainties:

1

Justification:

There are no remaining uncertainties to take account for.

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:

medium 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:

Adaptions in the respiratory volumes under normal conditions and by light activity in humans were taken into account for workers.

Applying of assessment factors:

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

Calculation of endpoint-specific DNELs for general population

Long-term exposure - systemic effects (inhalation):

The inhalation NOAEC (systemic) = 50 ppm = 92.26 mg/m³ was not modified for differences in absorption by inhalation route since no substance- and route specific information is available. However, the NOAEC was corrected for differences concerning exposure and the differences in respiratory volumes depending on the activity level. Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics have been shown to be simliar in rats and humans.

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(6 h/24 h) * (5 d/7 d) = 16.475 mg/m³

DNEL = 16.475 mg/m³/ (1 x 2 x 1 x 2.5 x 10 x 1 x 1) = 0.3295 mg/m³

Assessment factors are: 2 - study duration, 1 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 50.

Short-term exposure - systemic effects (inhalation):

The inhalation NOAEC (systemic) = 100 ppm = 184.85 mg/m³ was modified according to the Modified Habers Law: c³ * t = k

184.85E3 (exponent of 3 is a default values derived of R8) * 6 = 37897417.4

Then: CE3 = 37897417.4/0.25 = CE3 = 151589669.6, and C = 533.2 mg/m³

DNEL = 533.2 mg/kg bw/ (1 x 1 x 1 x 2.5 x 10 x 1 x 1) = 21.33 mg/m³.

Assessment factors are: 1 - study duration, 1 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – dose response (clear dose response), 1 – quality of data base (default).

The total AF amounts to 25

Long-term exposure - local effects (inhalation):

The inhalation LOAEC (systemic) = 10 ppm = 18.45 mg/m³ was not modified for differences in absorptionby inhalation route of exposure since no substance- and route specific information is available.. The LOAEC was also not further modified.

corrected LOAEC = 18.45 mg/m³ * (100 %/100 %)*(100 %/100 %) = 18.45 mg/m³

DNEL = 18.45 mg/m³/ (3 x 1 x 1 x 1 x 10 x 1 x 1) = 0.615mg/m³.

Assessment factors are: 1 - study duration, 1 – interspecies, 1 – remaining interspecies differences, 10 – intraspecies, 3 – dose response (LOAEC to NOAEC extrapolation), 1 – quality of data base (default).

The total AF amounts to 30.

Long-term exposure - systemic effects (dermal):

The inhalation NOAEC (systemic) = 50 ppm = 92.26 mg/m³ was not modified for differences in absorption by inhalation or dermal route since no substance- and route specific information is available. However, the NOAEC was corrected for differences concerning exposure and the differences in respiratory volumes depending on the activity level. Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics have been shown to be simliar in rats and humans.

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(1.15 m³/kg bw/day) * 5d/7d * 6 h/24 h = 18.95 mg/kg bw/day

DNEL = 18.95 mg/m³/ (1 x 2 x 4 x 2.5 x 10 x 1 x 1) = 0.0946 mg/m³

Assessment factors are: 1 - dose response (clear dose response), 2 - study duration, 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – quality of data base (default).

The total AF amounts to 200.

 

Long-term exposure - systemic effects (oral):

The inhalationNOAEC (systemic) = 50 ppm = 92.26 mg/m³ was not modified for differences in absorption by inhalation or oral route since no substance- and route specific information is available. However, the NOAEC was corrected for differences concerning exposure and the differences in respiratory volumes depending on the activity level. Additional adjustments for species differences in absorption and metabolism are not required since the route of exposure was inhalation, and since the metabolism and kinetics have been shown to be simliar in rats and humans.

corrected NOAEC = 92.26 mg/m³ * (100 %/100 %)*(100 %/100 %)*(1.15 m³/kg bw/day) * 5d/7d * 6 h/24 h = 18.95 mg/kg bw/day

DNEL = 18.95 mg/m³/ (1 x 2 x 4 x 2.5 x 10 x 1 x 1) = 0.0946 mg/m³

Assessment factors are: 1 - dose response (clear dose response), 2 - study duration, 4 – interspecies, 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – quality of data base (default).

The total AF amounts to 200.

Summary of derived DNELs:

Long-term exposure – systemic effects (inhalation DNEL):

DNEL = 0.3295 mg/m³

Short-term exposure – systemic effects (inhalation DNEL):

DNEL = 21.33 mg/m³

Long-term exposure – local effects (inhalation DNEL):

DNEL = 0.615 mg/m³

Long-term exposure – systemic effects (dermal DNEL):

DNEL = 0. 0946 mg/kg bw/day

Long-term exposure – systemic effects (oral DNEL):

DNEL =0. 0946 mg/kg bw/day

Selected DNELs:

DNEL systemic inhalation = 0.3295 mg/m³

DNEL systemic dermal (long-term) = 0.0946 mg/kg bw  

DNEL systemic oral (long-term) = 0.0946 mg/kg bw