Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.8 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):
75
Dose descriptor starting point:
NOAEC
Explanation for the modification of the dose descriptor starting point:

No modification necessary as systemic NOAEC from subacute inhalation toxicity study is taken.

AF for dose response relationship:
1
Justification:
NOAEC as determined in study is taken
AF for differences in duration of exposure:
6
Justification:
Transformation subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for inhalation toxicity
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
5
Justification:
Default value for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Acute/short term exposure
Hazard assessment conclusion:
medium 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
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:
NOAEL as determined in study is taken
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity 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 value
AF for intraspecies differences:
5
Justification:
Default value for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Route of original study:
Dermal
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 inhalation NOAEC of 60 mg/m3 air derived from a subacute (28-days) study in rats. Route-to-route extrapolation and allometric scaling was hence not necessary in the derivation of the DNEL. Differences in the duration of the exposure have been accounted for with an assessment factor of 6 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 0.8 mg/m³ air has been determined.

No acute systemic inhalation DNEL has been derived. The substance is classified as Acute Tox 4 for inhalation (H332), irritating to the skin (Skin Irrit. 2, H315) and causing serious damage to the eyes (Eye Damage 1, H318), which also comprise mucous membranes. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, TableE.3-1” the hazard via the inhalation route has to be considered as low. However, since the effects observed in the acute inhalation studies after 4 hours exposure, are considered as secondary effects due to the irritating characteristics of the substance the derivation of an acute DNEL is not recommended. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health” time scaling is not considered as appropriate when the toxic effect is mainly driven by exposure concentration, as is the case for irritation. However, the substance is classified as acutely harmful by inhalation and is irritating to the respiratory tract (although it is not classified accordingly due to lack of study data) as demonstrated by its significant self-warning ability known from handling experience. Due to those well-known irritating characteristics general Risk Management Measures and Operational Conditions (RMMs/OCs) are implemented, and the corresponding use of Personal Protection Equipment (PPE) including appropriate respiratory protection is mandatory. In conclusion, the risk of peak exposures of workers by inhalation is considered to be sufficiently controlled.

Local DNELs for the inhalation 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 regarded as acutely harmful and is classified as Acute Tox 4 for the inhalation route (H332), as irritating to the skin (Skin Irrit. 2, H315) and as causing serious damage to the eyes (Eye Damage 1, H318), which also comprise mucous membranes in form of the conjunctivae. Therefore, a comparable effect on the mucous membranes of the respiratory tract can be assumed and is confirmed by the well-known irritation of the respiratory tract reported from handling experience. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1” the local hazard by respiratory irritation would have to be considered as low, but due to the lack of route specific data and the demonstrated induction of serious damage to the eyes (and the corresponding classification) the moderate hazard band has been chosen for the local endpoints representing a conservative worst case approach. Due to the well-known irritating characteristics and the classification as Acute Tox 4 for the inhalation route (H332) general RMMs and OCs are implemented, and the corresponding use of PPE including appropriate respiratory protection is mandatory. In conclusion, the risk of local effects, both long-term and acute, on the respiratory tract of workers is considered to be sufficiently controlled.

Dermal

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day derived from 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 the establishment of acute toxicity DNELs for the dermal route appears superfluous. Short-term exposures should normally be assessed using the long-term DNELs. However, no data on 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 and the concentration contained in the industrially marketed formulation are classified as irritating to the skin (Skin Irrit. 2, H315). 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 well-known irritant characteristics general RMMs and OCs are implemented, and the corresponding use of PPE including appropriate gloves and skin coverage with appropriate barrier material is mandatory. In conclusion, the risk of peak exposures of workers via the dermal route is considered to be sufficiently controlled although no DNELs can be derived from irritation studies.

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”. According to this guidance DNELs covering local dermal effects can only be derived if route-specific data is available. However, no data on toxicity via the dermal route is available, and DNELs cannot be derived from irritation studies; hence, there are no results to derive a local DNEL. The neat substance and the concentration contained in the industrially marketed formulation are classified as irritating to the skin (Skin Irrit. 2, H315), 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 well-known 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, although no DNELs can be derived from irritation studies.

Eyes

The neat substance is anticipated to cause serious damage to the eyes, resulting in the corresponding classification Eye Damage 1 (H318). 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 well-known 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:
0.4 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):
150
Dose descriptor starting point:
NOAEC
Explanation for the modification of the dose descriptor starting point:

No modification necessary as systemic NOAEC from subacute inhalation toxicity study is taken.

AF for dose response relationship:
1
Justification:
NOAEC as determined in study is taken
AF for differences in duration of exposure:
6
Justification:
Transformation subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable for inhalation toxicity
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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
Modified dose descriptor starting point:
LOAEC

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
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
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
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study.
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on study in rat.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Route of original study:
Dermal
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
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
AF for differences in duration of exposure:
1
Justification:
DNEL is based on an oral chronic (2-year) toxicity study.
AF for interspecies differences (allometric scaling):
4
Justification:
DNEL is based on study in rat.
AF for other interspecies differences:
2.5
Justification:
Default value
AF for intraspecies differences:
10
Justification:
Default value for general population.
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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 inhalation NOAEC of 60 mg/m3 air derived from a subacute (28-days) study in rats. Route-to-route extrapolation and allometric scaling was hence not necessary in the derivation of the DNEL. Differences in the duration of the exposure have been accounted for with an assessment factor of 6 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 0.4 mg/m³ air has been determined.

No acute systemic inhalation DNEL has been derived. The substance is classified as Acute Tox 4 for inhalation, irritating to the skin (Skin Irrit. 2) and causing serious damage to the eyes (Eye Dam. 1), which also comprise mucous membranes. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, TableE.3-1” the hazard via the inhalation route has to be considered as low. However, since the effects observed in the acute inhalation studies after 4 hours exposure are considered as secondary effects due to the irritating characteristics of the substance the derivation of an acute DNEL is not recommended. According to “ECHA Guidance on Information Requirements and Chemical Safety Assessment – Chapter R.8: Characterisation of dose [concentration]-response for human health” time scaling is not considered as appropriate when the toxic effect is mainly driven by exposure concentration, as is the case for irritation. However, the neat substance is classified as acutely harmful by inhalation and is irritating to the respiratory tract (although it is not classified accordingly due to lack of study data) as demonstrated by its significant self-warning ability known from handling experience. 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 by inhalation is considered to be adequately controlled.

Local DNELs for the inhalation 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 has to be regarded as acutely harmful and is classified as Acute Tox 2 for the inhalation route, as irritating to the skin (Skin Irrit. 2) and as causing serious damage to the eyes (Eye Dam. 1), which also comprise mucous membranes in form of the conjunctivae. Therefore, a comparable effect on the mucous membranes of the respiratory tract can be assumed and is confirmed by the well-known irritation of the respiratory tract reported from handling experience. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment – Part E: Risk Characterisation, Table E.3-1” the local hazard by respiratory irritation would have to be considered as low, but due to the lack of corresponding data and the demonstrated induction of serious damage to the eyes (including the corresponding classification) the moderate hazard band has been chosen for the local endpoints representing a conservative worst case approach. 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 respiratory tract of consumers is considered to be adequately controlled.

Dermal

The long-term systemic dermal DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day derived from 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 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 the establishment of acute toxicity DNELs for peak exposures via the dermal route appears superfluous. Short-term exposures should normally be assessed using the long-term DNELs. However, no data on 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 and the concentration contained in the industrially marketed formulation are 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 would have to be 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 although no DNELs can be derived from irritation studies.

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”. According to this guidance DNELs covering local dermal effects can only be derived if route-specific data is available. However, no data on toxicity via the dermal route is available, and DNELs cannot be derived from irritation studies; hence, there are no results to derive a local DNEL. The neat substance and the concentration contained in the industrially marketed formulation are classified as irritating to the skin (Skin Irrit. 2), so the hazard for the dermal route would have to be 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 although no DNELs can be derived from irritation studies.

Oral

The long-term systemic oral DNEL has also been derived from the oral NOAEL of 1000 mg/kg bw/day derived from 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 the establishment of acute toxicity DNELs for peak exposures via the oral route appears superfluous. Short-term exposures should normally be assessed using the long-term DNELs. However, there are data from an acute limit test on toxicity via the oral route available. No mortalities occured and, 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 of peak exposures via the oral route is considered to be adequately controlled although no acute DNEL has been derived.

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.