Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.8 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance with substance specific modifications
Overall assessment factor (AF):
60
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
528.95 mg/m³
Explanation for the modification of the dose descriptor starting point:

Based on experimental evidence only a low toxicity is attributable to the registration substance. In addition, the low vapour pressure is additionally minimizing the potential for airborne material and thus the risk of inhaling this substance is generally low. However, as no route-specific repeated inhalation toxicity data is available per default a route-to-route extrapolation is performed using the lowest NOAEL of 300 mg/kg body weight per day from a reproductive toxicity study in rats, which was identified as key study for DNEL derivation.

The NOAEL of 300 mg/kg body weight per day is used as starting point for the derivation of the worker DNEL "long-term inhalation exposure - systemic effects". Based on the substance characteristics, no uncertainties regarding inter- and/or intraspecies differences have to be assumed. In addition, no species differences due to differences in toxicokinetic aspects are to be expected. However, a conservative approach is taken and the default factor of 2 for remaining uncertainties due to route-to-route extrapolation is applied.

The corrected inhalatory NOAEC is obtained according to REACH Guidance R.8 as 528.95 mg/m3. With regard to interspecies differences, allometric scaling concerning oral-to-inhalation extrapolation is not appropriate and no assessment factor is applied (ECHA Guidance). In addition, a respective adjustment is also not deemed necessary based on ECETOC (2010). Analysis of various data sets have revealed that a separate factor for remaining interspecies differences need not always be established because these are being accounted for by the assessment of intraspecies variability. Based on scientific evidence, ECETOC is proposing overall assessment factors of 3 for workers, which includes the remaining interspecies differences. A factor of 1 for remaining interspecies differences is also supported, because toxicokinetics differed not between species. The same arguments can be applied here based on the chemical composition of the registration substance. However, although the available data from studies with repeated exposure have not revealed significant differences in the systemic toxicity profile (despite significant differences in exposure duration) a somewhat more conservative approach is taken and a combined inter-/intraspecies assessment factor of 5 is considered. This is in line with a similar concept developed by the German Committee for Hazardous Substances (AGS 2010,Technische Reglen für gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für Gefahrstoffe. BekGS 901, April 2010). Because the assessment takes into account the outcome of a 28 -day repeated toxicity study as well, time extrapolation to chronic exposure conditions generally have to be considered and the respective default factor of 6 (subacute to chronic) is used. Since the available data are considered adequate for labelling and classification purposes of the registration substance, the quality of the data base is judged sufficient for evaluation and thus, an assessment factor of 1 is applied. According to ECHA, remaining uncertainties exist when route-to-route extrapolation is conducted and thus an assessment factor of 2 is used to account for oral to inalation extrapolation. The resulting overall assessment factor is 60 (5 x 6 x 2) resulting in a worker DNEL "long-term inhalation exposure - systemic effects" of 8.8 mg/m3.

AF for dose response relationship:
1
Justification:
ECHA Guidance (reliable dose-response, POD is NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (subacute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA Guidance (inhalation route)
AF for other interspecies differences:
1
Justification:
Substance characteristics suggest no significant interspecies differences (see also remark regarding intraspecies differences)
AF for intraspecies differences:
5
Justification:
Modified according to German Committee of Hazardous Substances (AGS) and ECETOC, combined inter-/intraspecies AF (toxicokinetic and toxicodynamic aspect)
AF for the quality of the whole database:
1
Justification:
Available data package comprehensive and plausible
AF for remaining uncertainties:
2
Justification:
ECHA Guidance, route-to-route extrapolation (oral to inhalation)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance with substance specific modifications
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on experimental evidence only a low toxicity is attributable to the registration substance. However, as no route-specific repeated dermal toxicity data is available per default a route-to-route extrapolation is performed using the lowest NOAEL of 300 mg/kg body weight per day from a reproductive toxicity study in rats, which was identified as key study for DNEL derivation.

The NOAEL of 300 mg/kg body weight per day is used as starting point for the derivation of the worker DNEL "long-term dermal exposure - systemic effects". With respect to dermal DNEL derivation, the same data basis and thus a comparable rational apply like for the inhalation route. Assuming a conservative dermal pentration rate of 100%, no corrected "dermal" NOAEL is used according to ECHA Guidance R.8. This PoD used can still be considered to be conservative and assessment factors of 1 for dose-response and quality of data base are appropriate. Additionally, the same factor of 6 for time extrapolation can be used. Based on experimental evidence from studies with dermal substance administration, no concern with respect to dermal exposure is deducible.

Although it is concluded from the experimentally established toxicity profile and anticipated metabolism that no toxic metabolites are to be expected during catabolic degradation of the registration substance, allometric scaling is performed using an AF of 4 (rat to human). As explained in more detail above, a combined AF of 5 is used to account for potential inter- / intraspecies differences. The resulting overall assessment factor is 120 (6 x 4 x 5) leading to a DNEL "long-term dermal exposure - systemic effects" of 2.5 mg/kg body weight per day.

AF for dose response relationship:
1
Justification:
ECHA Guidance (PoD is NOAEL, reliable dose-response supported by kinetic data)
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Guidance
AF for other interspecies differences:
1
Justification:
Modified based on kinetic data (no differences in skin penetration behaviour between spesies to be expected)
AF for intraspecies differences:
5
Justification:
Modified according to German Committee of Hazardous Substances (AGS) and ECETOC, combined inter-/intraspecies AF (toxicokinetic and toxicodynamic aspect)
AF for the quality of the whole database:
1
Justification:
Available data package comprehensive and plausible, read-across robust and scientifically valid
AF for remaining uncertainties:
1
Justification:
No relevant effects observed (no acute toxicity and no effects in studies with dermal route of exposure)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Despite the low toxicity of the registration substance, proper technical and personal risk management measures are in place to protect against systemic and local effects and ensure general safe use conditions.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance with substance specific modifications
Overall assessment factor (AF):
84
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
262.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Based on experimental evidence only a low toxicity is attributable to the registration substance. In addition, the low vapour pressure is additionally minimizing the potential for airborne material and thus the risk of inhaling this substance is generally low. However, as no route-specific repeated inhalation toxicity data is available per default a route-to-route extrapolation is performed using the lowest NOAEL of 300 mg/kg body weight per day from a reproductive toxicity study in rats, which was identified as key study for DNEL derivation.

The NOAEL of 300 mg/kg body weight per day is used as starting point for the derivation of the consumer DNEL "long-term inhalation exposure - systemic effects". Based on the substance characteristics, no uncertainties regarding inter- and/or intraspecies differences have to be assumed. In addition, no species differences due to differences in toxicokinetic aspects are to be expected.

The corrected inhalatory NOAEC is obtained according to REACH Guidance R.8 as 262.5 mg/m3. With regard to interspecies differences, allometric scaling concerning oral-to-inhalation extrapolation is not appropriate and no assessment factor is applied (ECHA Guidance). In addition, a respective adjustment is also not deemed necessary based on analysis of various data sets which revealed that a separate factor for remaining interspecies differences need not always be established because these are being accounted for by the assessment of intraspecies variability (ECETOC 2010). Based on these analysis, ECETOC has concluded that assessment factors of 3 for workers and 5 for the general population are sufficient for covering any intra-species variability, which includes the remaining differences factor of 2.5. A similar concept is in place by the German `Ausschuss für Gefahrstoffe` (AGS 2010,Technische Reglen für gefahrstoffe. Begründungen und Erläuterungen zu Grenzwerten in der Luft am Arbeitsplatz. Ausschuss für Gefahrstoffe. BekGS 901, April 2010) , although arriving at different factors. Apart from allometric scaling (which is not appropriate in oral-to-inhalation extrapolation), but taking interspecies differences for metabolism and toxicokinetics into account, a separate overall (inter- and intra-species) variability for the workplace of 5 is taken. In this respect, AGS explicitly did not differentiate between inter- and intra-species variability. Although AGS did not specifically propose an assessment factor for the general population, following the same principles an increased overall factor of 7 for the general population seems scientifically justified.

Although the presented assessment takes into account the outcome of a 28 -day repeated toxicity study, time extrapolation to chronic exposure conditions generally have to be considered and the respective default factor of 6 (subacute to chronic) is used. Since the available data are considered adequate for labelling and classification purposes of the registration substance, the quality of the data base is judged sufficient for evaluation and thus, an assessment factor of 1 is applied. According to ECHA, remaining uncertainties exist when route-to-route extrapolation is conducted and thus an assessment factor of 2 is used to account for oral to inalation extrapolation. The resulting overall assessment factor is 84 (2 x 7 x 6) resulting in a consumer DNEL "long-term inhalation exposure - systemic effects" of 3.125 mg/m3.

AF for dose response relationship:
1
Justification:
ECHA Guidance (reliable dose-response, PoD is NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (subacute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA Guidance (inhalation route)
AF for other interspecies differences:
1
Justification:
Substance characteristics suggest no significant interspecies differences (see also remark regarding intraspecies differences)
AF for intraspecies differences:
7
Justification:
Modified according to German Committee of Hazardous Substances (AGS) and ECETOC, combined inter-/intraspecies AF (toxicokinetic and toxicodynamic aspect)
AF for the quality of the whole database:
1
Justification:
Available data package comprehensive and plausible
AF for remaining uncertainties:
2
Justification:
ECHA Guidance, route-to-route extrapolation (oral to inhalation)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.79 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance with substance specific modifications
Overall assessment factor (AF):
168
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on experimental evidence only a low toxicity is attributable to the registration substance. However, as no route-specific repeated dermal toxicity data is available per default a route-to-route extrapolation is performed using the lowest NOAEL of 300 mg/kg body weight per day from a reproductive toxicity study in rats, which was identified as key study for DNEL derivation.

The NOAEL of 300 mg/kg body weight per day is used as starting point for the derivation of the worker DNEL "long-term dermal exposure - systemic effects". With respect to dermal DNEL derivation, the same data basis and thus a comparable rational apply like for the inhalation route. Assuming a conservative dermal pentration rate of 100%, no corrected "dermal" NOAEL is used according to ECHA Guidance R.8. This PoD used can still be considered to be conservative and assessment factors of 1 for dose-response and quality of data base are appropriate. Additionally, the same factor of 6 for time extrapolation can be used. Based on experimental evidence from studies with dermal substance administration, no concern with respect to dermal exposure is deducible.

Although it is concluded from the experimentally established toxicity profile and anticipated metabolism that no toxic metabolites are to be expected during catabolic degradation of the registration substance, allometric scaling is performed using an AF of 4 (rat to human). As explained in more detail above, a combined AF of 7 is used to account for potential inter- / intraspecies differences. The resulting overall assessment factor is 168 (6 x 4 x 7) leading to a DNEL "long-term dermal exposure - systemic effects" of 1.79 mg/kg body weight per day.

AF for dose response relationship:
1
Justification:
ECHA Guidance (reliable dose-response, PoD is NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Guidance
AF for other interspecies differences:
1
Justification:
Substance characteristics suggest no significant interspecies differences (see also remark regarding intraspecies differences)
AF for intraspecies differences:
7
Justification:
Modified according to German Committee of Hazardous Substances (AGS) and ECETOC, combined inter-/intraspecies AF (toxicokinetic and toxicodynamic aspect)
AF for the quality of the whole database:
1
Justification:
Available data package comprehensive and plausible
AF for remaining uncertainties:
1
Justification:
No relevant effects observed (no toxicity in acute systemic dermal toxicity study)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.79 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA Guidance with substance specific modifications
Overall assessment factor (AF):
168
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Although no oral uses of the registration substance are supported, a consumer DNEL "long-term oral exposure" is derived using the most conservative NOAEL of 300 mg/kg body weight per day obtained from a reproductive toxicity study in rats. The same data base applies like for the above DNEL considerations for long-term inhalation and long-term dermal exposure. Assuming 100% oral absorption, no modification of the starting point was considered and the NOAEL of 300 mg/kg body weight per day was used as PoD. Based on the comprehensive and plausible data base, assessment factors of 1 for dose-response and quality of data base are appropriate. Additionally, the same factor of 6 for time extrapolation can be used. Likewise, allometric scaling is performed using an AF of 4 (rat to human). As explained in more detail above, a combined AF of 7 is used to account for potential inter- / intraspecies differences. The resulting overall assessment factor is 168 (6 x 4 x 7) leading to a consumer DNEL "long-term oral exposure - systemic effects" of 1.79 mg/kg body weight per day.

AF for dose response relationship:
1
Justification:
ECHA Guidance (reliable dose-response, PoD is NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA Guidance (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA Guidance
AF for other interspecies differences:
1
Justification:
Substance characteristics suggest no significant interspecies differences (see also remark regarding intraspecies differences)
AF for intraspecies differences:
7
Justification:
Modified according to German Committee of Hazardous Substances (AGS) and ECETOC, combined inter-/intraspecies AF (toxicokinetic and toxicodynamic aspect)
AF for the quality of the whole database:
1
Justification:
Available data package comprehensive and plausible
AF for remaining uncertainties:
1
Justification:
No additional uncertainties (no route-to-route extrapolation)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population