D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.58 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance with substance specific modifications

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Value:

211.58 mg/m³

Explanation for the modification of the dose descriptor starting point:

No data for registration substance on repeated dose toxicity following inhalation exposure

AF for dose response relationship:

1

Justification:

ECHA Guidance (reliable dose-response, POD is NOAEL)

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Guidance (inhalation route)

AF for other interspecies differences:

1

Justification:

Substance characteristics and ADME suggests no significant interspecies differences

AF for intraspecies differences:

5

Justification:

No differences in ADME and/or toxicity expected as test item consists of natural occuring constituents (sugar derivatives and fatty acids). Combined AF for intraspecies and remaining uncertainty (toxicokinetic plus toxicodynamic aspect) based on German Committee on Hazardous Substances (AGS; BekGS901 dated April 2010) and ECETOC.

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:

30 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

1 200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no data for registration substance on repeated dose toxicity following dermal exposure

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:

2

Justification:

ECHA Guidance (subchronic 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 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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

Selection of assessment factors

Workers - Hazard via inhalation route

From experimental evidence, only a low acute inhalation toxicity is attributable to the registration substance. In addition, the low vapour pressure of Glucamide CC is minimizing the potential for generating vapour, and thus the risk of inhaling this substance in general.

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 150 mg/kg body weight per day based on parental toxicity of the read-across compound Glucamide 24 in a reproductive toxicity study in rats, which was identified as key study for DNEL derivation. The fact that this NOAEL is not really supported by the NOAEL of 700 mg/kg body weight per day coming from the available 28-day repeated dose toxicity study with Glucamide CC, demonstrates that in favor of animal welfare considerations a more conservative evaluation approach is considered for Glucamide CC .

The NOAEL of 150 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 identity, both compounds, Glucasmide CC and Glucamide 24 are chemically reaction products of fatty acids with sugar derivatives and thus, comparability is given and 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, again 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 211.58 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). The adjustment for remaining differences is not considered scientificall justified based on the above mentioned substance identity. 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). Although the assessment takes into account the outcome of a 90 -day repeated toxicity study, time extrapolation to chronic exposure conditions generally have to be considered and the respective default factor of 2 (subchronic 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. The resulting overall assessment factor is 20 (2 x 5 x 2) resulting in a worker DNEL "long-term inhalation exposure - systemic effects" of 10.58 mg/m³.

Workers - Hazard via dermal route

Based on the LD50 of greater 2000 mg/kg body weight revealed in an acute dermal toxicity study with Glucamide CC, no concern with respect to acute dermal exposure is deducible for the registration substance. However, no route-specific repeated dermal toxicity data is available for the submission substance. As default, route-to-route extrapolation is performed using the NOAEL of 150 mg/kg body weight per day from parental toxicity findings in a reproductive toxicity study in rats with the structural and biological analogue Glucamide 24 as most conservative value.

The NOAEL of 150 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 10% (instead the kinetically determined 1%), the corrected "dermal" NOAEL is obtained according to ECHA Guidance R.8 as 1200 mg/kg body weight. This PoD used can 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 2 for time extrapolation can be used. Based on the LD50 of greater 2000 mg/kg body weight revealed in an acute dermal toxicity study, no concern with respect to dermal exposure is deducible. This view is supported considering a very low dermal penetration potential (approximately 1%) based on toxicokinetics following dermal exposure to the read-across compound Glucamide 24.

Although it is concluded from the 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 40 (2 x 4 x 5) leading to a DNEL "long-term dermal exposure - systemic effects" of 30 mg/kg body weight per day.

Additional information

No DNELs are derived for acute systemic toxicity and for local effects following acute exposure. Based on the result from an available acute dermal toxicity study resulting in a LD50 value greater 2000 mg/kg body weight, it is concluded that no risk is deducible for this exposure condition. It is further concluded that short-term exposures are well-controlled by conditions for long-term exposure. Additionally, proper technical and personal risk management measures are in place to protect against local effects and ensure safe use conditions.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.73 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance with substance specific modifications

Overall assessment factor (AF):

28

Modified dose descriptor starting point:

NOAEC

Value:

104.35 mg/m³

Explanation for the modification of the dose descriptor starting point:

No data for registration substance on repeated dose toxicity following inhalation exposure

AF for dose response relationship:

1

Justification:

ECHA Guidance (reliable dose-response, PoD is NOAEL)

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance (subacute to chronic extrapolation)

AF for interspecies differences (allometric scaling):

1

Justification:

ECHA Guidance (inhalation route)

AF for other interspecies differences:

1

Justification:

Substance characteristics and ADME suggests no significant interspecies differences

AF for intraspecies differences:

7

Justification:

No differences in ADME and/or toxicity expected as test item consists of natural occuring constituents (sugar derivatives and fatty acids). Combined AF for intraspecies and remaining uncertainty (toxicokinetic plus toxicodynamic aspect) modified for general population from German Committee on Hazardous Substances (AGS; BekGS901 dated April 2010) and ECETOC.

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:

21.43 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance with substance specific modifications

Overall assessment factor (AF):

56

Modified dose descriptor starting point:

NOAEL

Value:

1 200 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No data for registration substance on repeated dose toxicity following dermal exposure

AF for dose response relationship:

1

Justification:

ECHA Guidance (reliable dose-response, PoD is NOAEL)

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance

AF for other interspecies differences:

1

Justification:

Substance characteristics and ADME suggests no significant interspecies differences.

AF for intraspecies differences:

7

Justification:

No differences in ADME and/or toxicity expected as test item consists of natural occuring constituents (sugar derivatives and fatty acids). Combined AF for intraspecies and remaining uncertainty (toxicokinetic plus toxicodynamic aspect) modified for general population from German Committee on Hazardous Substances (AGS; BekGS901 dated April 2010) and ECETOC.

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:

2.14 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance with substance specific modifications

Overall assessment factor (AF):

56

Modified dose descriptor starting point:

NOAEL

Value:

120 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

no route-to-route extrapolation used

AF for dose response relationship:

1

Justification:

ECHA Guidance (reliable dose-response, PoD is NOAEL)

AF for differences in duration of exposure:

2

Justification:

ECHA Guidance (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance

AF for other interspecies differences:

1

Justification:

Substance characteristics and ADME suggests no significant interspecies differences.

AF for intraspecies differences:

7

Justification:

No differences in ADME and/or toxicity expected as test item consists of natural occuring constituents (sugar derivatives and fatty acids). Combined AF for intraspecies and remaining uncertainty (toxicokinetic plus toxicodynamic aspect) modified for general population from German Committee on Hazardous Substances (AGS; BekGS901 dated April 2010) and ECETOC.

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:

medium hazard (no threshold derived)

Additional information - General Population

Selection of assessment factors

Consumers - Hazard via inhalation route

From experimental evidence, only a low acute inhalation toxicity is attributable to the registration substance. In addition, the low vapour pressure of Glucamide CC is minimizing the potential for generating vapour, and thus the risk of inhaling this substance in general. However, as no route-specific repeated inhalation toxicity data is available per default a route-to-route extrapolation is performed using the NOAEL of 150 mg/kg body weight per day based on parental toxicity of the read-across compound Glucamide 24 in a reproductive toxicity study in rats, which was identified as key study for DNEL derivation. The fact that this NOAEL is not really supported by the NOAEL of 700 mg/kg body weight per day coming from the available 28-day repeated dose toxicity study with Glucamide CC, demonstrates that in favor of animal welfare considerations a more conservative evaluation approach is considered for Glucamide CC .

The NOAEL of 150 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 identity, Glucamide CC and Glucamide 24 are chemically reaction products of fatty acids with sugar derivatives and thus, comparability is given and 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 104.35 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). The adjustment for remaining differences is not considered scientificall justified based on the above mentioned substance identity. 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), 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 - as proposed by ECETOC (2010) - is scientifically justified.

Although the presented assessment takes into account the outcome of a 90 -day repeated toxicity study, time extrapolation to chronic exposure conditions generally have to be considered and the respective default factor of 2 (subchronic 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. The resulting overall assessment factor is 28 (2 x 7 x 2) resulting in a consumer DNEL "long-term inhalation exposure - systemic effects" of 3.73 mg/m³.

Consumers - Hazard via dermal route

Based on the LD50 of greater 2000 mg/kg body weight revealed in an acute dermal toxicity study with Glucamide CC, no concern with respect to acute dermal exposure is deducible for the registration substance. However, no route-specific repeated dermal toxicity data is available for the submission substance. As default, route-to-route extrapolation is performed using the NOAEL of 150 mg/kg body weight per day from parental toxicity findings in a reproductive toxicity study in rats with the structural and biological analogue Glucamide 24 as most conservative value.

The NOAEL of 150 mg/kg body weight per day is used as starting point for the derivation of the consumer 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 10% (instead the kinetically determined 1%), the corrected "dermal" NOAEL is obtained according to ECHA Guidance R.8 as 1200 mg/kg body weight. This PoD used can 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 2 for time extrapolation can be used. Based on the LD50 of greater 2000 mg/kg body weight revealed in an acute dermal toxicity study, no concern with respect to dermal exposure is deducible. This view is supported considering a very low dermal penetration potential (approximately 1%) based on experimental toxicokinetics following dermal exposure to the read-across compound Glucamide 24.