Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
141.1 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 763.2 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAECcorr=NOAELoral*(1/0.38 m³/kg/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) = 1000 mg/kg/day*(1/0.38 m³/kg/day)*(1/1)*0.67 = 1763.2 mg/m³

ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans. Available data on oral absorption in rats obtained with a structural analogue substance indicates an oral absorption of > 80% and complete absorption was assumed by the authors (Bureau of Biological Research, 1994). Therefore, the default oral absorption rate of 50% (default factor of 0.5/1) for the rat was not used in the calculation of the NOAECcorr.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 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):
50
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=NOAELoral*( ABSoral-rat/ABSdermal-human) = 1000 mg/kg bw/day*(1/1) = 1000 mg/kg bw/day. ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
5
Justification:
Default AF for workers
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high quality study
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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

Inhalation

The long-term systemic inhalation DNEL has been derived from an oral NOAEL of 1000 mg/kg bw/day which was determined in a chronic (2-year) study in rats. After route to route extrapolation by correction for the differences in the respiratory volumes of rats and humans over the relevant assessment period and correction for the differences in the respiratory volumes of humans in rest and during light activity, a NOAECcorr of 1763.2 mg/m³ has been used as dose descriptor starting point. Available data on oral absorption in rats obtained with a structural analogue substance indicate an oral absorption of > 80% and complete absorption was assumed by the authors (Bureau of Biological Research, 1994). Therefore, an oral absorption of 100% instead of the default oral absorption rate of 50% (default factor of 0.5/1) for the rat has been used in the calculation of the NOAECcorr. Since respiratory rates depend directly on caloric demand, no additional allometric scaling for metabolic differences between rats and humans is required anymore, and only an assessment factor of 2.5 has been included to account for remaining uncertainties between species. An additional assessment factor of 5 has been included to account for intraspecies differences among workers. In conclusion, a DNEL of 141.1 mg/m³ has been determined.

Derivation of a short-term systemic DNEL for inhalation is not required due to the “self-warning” characteristics of the substance and marketing in non-solid (as solution) or granular form. The substance has a low vapour pressure and is marketed in aqueous formulation or as waxy solid, and development of inhalable material is not expected. The substance meets the criteria to be classified for acute inhalation toxicity (Acute Tox. 4, H332) according to Regulation (EC) No. 1272/2008 (CLP), based on the results from a structurally related substance.

The local long-term DNEL for the inhalation route is not derived. The DNEL is not required as the substance has a low vapour pressure and is marketed in aqueous solution only. Due to the anticipated use pattern of the substance, spray applications are not expected. Hence, generation of inhalable material cannot occur under normal and reasonably foreseeable conditions of use.

Derivation of a short-term local DNEL for inhalation is not required due to the “self-warning” characteristics of the substance and marketing in non-solid or granular form. The substance has a low vapour pressure and is marketed in aqueous formulation or as waxy solid, and development of inhalable material is not expected. The substance meets the criteria for classification for acute inhalation toxicity (Acute Tox. 4, H332) according to Regulation (EC) No. 1272/2008 (CLP), based on the results from a structurally related substance.

Dermal

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day obtained in the chronic (2-year) study in rats. Route to route extrapolation has been done assuming equal rates for the oral absorption of the rat and the dermal absorption of humans. In a worst case approach the oral absorption rate of the rat is not assumed to be higher than the dermal absorption rate of humans, although a study demonstrating more than 80% oral absorption in the rat is available, and complete absorption is anticipated by the authors (Bureau of Biological Research, 1994), while complete absorption via the human skin is unlikely. Hence, as dose descriptor starting point for DNEL derivation a NOAELcorr of 1000 mg/kg bw/day has been used, followed by allometric scaling for interspecies differences between rats and humans, inclusion of an additional factor of 2.5 for other interspecies differences and an assessment factor of 5 to account for intraspecies differences among the workers. In conclusion, a DNEL of 20 mg/kg bw/day has been derived.

No acute systemic dermal DNEL has been derived. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health – Appendix R.8-8” a DNEL for acute toxicity should be derived if an acute toxicity hazard has been identified and if there is a potential for high peak exposures. High peak exposures are usually assessed for the inhalation route only. Although peak exposures in theory may also occur for the dermal route they are not normally assessed, so establishing a DNEL for acute dermal toxicity appears superfluous. Short-term exposures should normally be assessed using the long-term DNELs. However, no data on long-term toxicity via the dermal route are available, and DNELs cannot be derived from irritation studies; hence, there are no results to derive an acute DNEL. The neat substance is classified as irritating to the skin (Skin Irrit. 2). According to “ECHA Guidance on Information requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1” the hazard via the dermal route has been considered as low. Due to the irritant characteristics of the substance general RMMs and OCs are implemented, and the corresponding use of PPE including appropriate gloves and skin coverage with suitable barrier material is mandatory. In conclusion, the risk of peak exposures of workers via the dermal route is considered to be sufficiently controlled.

Local DNELs for the dermal route are not derived in compliance with “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health”. The neat substance is classified as irritating to the skin (Skin Irrit. 2), so the hazard for the dermal route has been considered as low according to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1”. Due to the irritating characteristics of the substance general RMMs and OCs are implemented, and the corresponding use of PPE including appropriate gloves and skin coverage with suitable barrier material is mandatory. In conclusion, the risk of local effects, both long-term and acute, on the skin of workers is considered to be sufficiently controlled.

Eyes

The neat substance is anticipated to cause serious damage to the eyes, resulting in the corresponding classification Eye Damage 1. According to "ECHA Guidance on Information Requirements and Chemical Safety Assessment - Part E: Risk Characterisation, Table E.3-1" the substance is considered to exert a moderate hazard for the eyes. Due to the irritating characteristics of the substance general RMMs and OCs are implemented, and the corresponding use of PPE including appropriate eye protection in form of chemical goggles is mandatory. In conclusion, the risk for effects on the eyes of workers is considered to be sufficiently controlled.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
34.8 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):
25
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
869.6 mg/m³
Explanation for the modification of the dose descriptor starting point:

NOAECcorr=NOAELoral*(1/1.15 m³/kg/day)*(ABSoral-rat/ABSinh-human) = 1000 mg/kg/day*(1/1.15 m³/kg/day)*(1/1) = 869.6 mg/m³

ABSoral-rat=oral absorption rate in rats, ABSinh-human=inhalation absorption rate in humans. Available data on oral absorption in rats obtained with a structural analogue substance indicates an oral absorption of > 80% and complete absorption was assumed by the authors (Bureau of Biological Research, 1994). Therefore, the default oral absorption rate of 50% (default factor of 0.5/1) for the rat was not used in the calculation of the NOAECcorr.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling already included in ECHA starting point derivation method; no further factor required.
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
100
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL=oral NOAEL*( ABSoral-rat/ABSdermal-human) = (1000 mg/kg bw/day)*(1/1) = 1000 mg/kg bw/day

ABSoral-rat=oral absorption rate in rats, ABSdermal-human=dermal absorption rate in humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
1
Justification:
DNEL is based on a chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high quality study
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
low 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:
10 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):
100
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
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 required, NOAEL derived from oral study. Equal oral absorption is anticipated for rats and humans.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on a study in rat
AF for other interspecies differences:
2.5
Justification:
Default AF
AF for intraspecies differences:
10
Justification:
Default AF for general population
AF for the quality of the whole database:
1
Justification:
DNEL is based on a high quality study
AF for remaining uncertainties:
1
Justification:
No remaining uncertaintie
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Inhalation

The long-term systemic inhalation DNEL has been derived from an oral NOAEL of 1000 mg/kg bw/day which was obtained in a chronic (2-year) study in rats. After route to route extrapolation by correction for the differences in the respiratory volumes of rats and humans over the relevant assessment period for the general public, a NOAECcorr of 869.6 mg/m³ has been used as dose descriptor starting point. Available data on oral absorption in rats obtained with a structural analogue substance indicates an oral absorption of > 80% and complete absorption was assumed by the authors (Bureau of Biological Research, 1994). Therefore, an oral absorption of 100% instead of the default oral absorption rate of 50% (default factor of 0.5/1) for the rat has been used in the calculation of the NOAECcorr.  Since respiratory rates depend directly on caloric demand no additional allometric scaling for metabolic differences between rats and humans is required anymore, and only an assessment factor of 2.5 has been included to account for remaining uncertainties between species. An additional assessment factor of 10 has been included to account for intraspecies differences in the general population. In conclusion, a DNEL of 34.8 mg/m³ has been determined.

Derivation of a short-term systemic DNEL for inhalation is not required due to the “self-warning” characteristics of the substance and marketing in non-solid or granular form. The substance has a low vapour pressure and is marketed in aqueous formulation or as waxy solid, and development of inhalable material is not expected. The substance meets the criteria for classification for acute inhalation toxicity (Acute Tox. 4, H332) according to Regulation (EC) No. 1272/2008 (CLP), based on the results from a relevant source substance.

The local long-term DNEL for the inhalation route is not derived. The DNEL is not required as the substance has a low vapour pressure and is marketed in aqueous solution only. Due to the anticipated use pattern of the substance, spray applications are not expected. Hence, generation of inhalable material cannot occur under normal and reasonably foreseeable conditions of use.

Derivation of the short-term local DNEL for inhalation is not required due to the “self-warning” characteristics of the substance and marketing in non-solid or granular form. The substance has a low vapour pressure and is marketed in aqueous formulation or as waxy solid, and development of inhalable material is not expected. The substance meets the criteria for classification for acute inhalation toxicity (Acute Tox. 4, H332) according to Regulation (EC) No. 1272/2008 (CLP), based on the results from a relevant source substance.

Dermal

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day obtained in the chronic (2-year) study in rats. Route to route extrapolation has been done assuming equal rates for the oral absorption of the rat and the dermal absorption of humans. In a worst case approach the oral absorption rate of the rat is not assumed to be higher than the dermal absorption rate of humans, although a study demonstrating more than 80% oral absorption in the rat is available, and complete absorption is anticipated by the authors (Allison, 1994), while complete absorption via the human skin is unlikely. Hence, as dose descriptor starting point for DNEL derivation a NOAELcorr of 1000 mg/kg bw/day has been used, followed by allometric scaling for interspecies differences between rats and humans, inclusion of an additional factor of 2.5 for other interspecies differences and an assessment factor of 10 to account for intraspecies differences in the general population. In conclusion, a DNEL of 10 mg/kg bw/day has been derived.

No acute systemic dermal DNEL has been derived. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health – Appendix R.8-8” a DNEL for acute toxicity should be derived if an acute toxicity hazard has been identified and if there is a potential for high peak exposures. High peak exposures are usually assessed for the inhalation route only. Although peak exposures in theory may also occur for the dermal route they are not normally assessed, so establishing a DNEL for acute dermal toxicity appears superfluous. Short-term exposures should normally be assessed using the long-term DNELs. However, no data on long-term toxicity via the dermal route is available, and DNELs cannot be derived from irritation studies; hence, there are no results to derive an acute DNEL. The neat substance is classified as irritating to the skin (Skin Irrit. 2). According to “ECHA Guidance on Information requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1” the hazard via the dermal route is considered as low. The risk for workers in industrial and professional settings is controlled by the implementation of appropriate RMMs and OCs; however, since compliance with RMMs and OCs could not be controlled for the general population, and the use of PPE could not be assumed, the risk for the general population is controlled by limiting the concentration of the substance in consumer products to levels resulting in no hazard or low hazard via the respective routes according to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1”, including appropriate labelling, and by establishing appropriate use profiles. In conclusion, the risk of peak exposures of consumers via the dermal route is considered to be adequately controlled.

Local DNELs for the dermal route are not derived in compliance with “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health”. The neat substance is classified as irritating to the skin (Skin Irrit. 2), so the hazard for the dermal route is considered as low according to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1”. The risk for workers in industrial and professional settings is controlled by the implementation of appropriate RMMs and OCs; however, since compliance with RMMs and OCs could not be controlled for the general population, and the use of PPE could not be assumed, the risk for the general population is controlled by limiting the concentration of the substance in consumer products to levels resulting in no hazard or low hazard via the respective routes according to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1”, including appropriate labelling, and by establishing appropriate use profiles. In conclusion, the risk of local effects, both long-term and acute, on the skin of consumers is considered to be adequately controlled.

Oral

The long-term systemic oral DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day obtained in the chronic (2-year) study in rats. Route to route extrapolation is not required, and in a worst case approach equal oral absorption for rats and humans (absorption of 100% is assumed for the rat) has been anticipated. Hence, as dose descriptor starting point for DNEL derivation a NOAELcorr of 1000 mg/kg bw/day has been used, followed by allometric scaling for interspecies differences between rats and humans, inclusion of an additional factor of 2.5 for other interspecies differences and an assessment factor of 10 to account for intraspecies differences in the general population. In conclusion, a DNEL of 10 mg/kg bw/day has been derived.

No acute systemic oral DNEL has been derived. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health – Appendix R.8-8” a DNEL for acute toxicity should be derived if an acute toxicity hazard has been identified and if there is a potential for high peak exposures. High peak exposures are usually assessed for the inhalation route only. Although peak exposures in theory may also occur for the oral route they are not normally assessed, so establishing a DNEL for acute oral toxicity appears superfluous. Short-term exposures should normally be assessed using the long-term DNELS. However, there are data from acute oral toxicity studies of structural analogue substances available; there were no adverse effects observed in any of the studies. Hence, no hazard via the oral route has been identified. The substance is not classified for acute toxicity via the oral route, and the derivation of an acute DNEL is not required. In conclusion, the risk with respect to the oral route is considered to be adequately controlled.

Eyes

The neat substance is anticipated to cause serious damage to the eyes, resulting in the corresponding classification Eye Damage 1. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1” the substance is considered to exert a moderate hazard for the eyes. The risk for workers in industrial and professional settings is controlled by the implementation of appropriate RMMs and OCs; however, since compliance with RMMs and OCs could not be controlled for the general population, and the use of PPE could not be assumed, the risk for the general population is controlled by limiting the concentration of the substance in consumer products to levels resulting in no hazard or low hazard via the respective routes according to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1”, including appropriate labelling, and by establishing appropriate use profiles. In conclusion, the risk of effects on the eyes of consumers is considered to be adequately controlled.