Sodium N-(2-carboxyethyl)-N-dodecyl-β-alaninate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15.5 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: according to ECETOC

Overall assessment factor (AF):

18

Dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

280 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation according to ECHA guidance R8

Workers (8 h exposure) assuming 100% absorption

- Most relevant endpoint: Repeated dose toxicity via the oral route (NOAEL=160 mg/kg bw/day)

- Standard respiratory volume (rat to human for 8 h exposure): 6.7 m3/ person

- Respiratory volume light activity for worker (wRV): 10 m3/person

NOAEC calulation

- NOAEC human(8h worker) = NOAELoral-rat / sRVrat * bw human /wRV = 160 mg/kg bw/d / 4 * 70 kg / 10 m3/person = 280 mg / m3 / 24h  

AF for dose response relationship:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dose ...) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86; ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rat according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

3

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended, in the absence of relevant substance-specific information.

AF for remaining uncertainties:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: according to ECETOC

Overall assessment factor (AF):

72

Dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Workers (8 h exposure), assuming worst case absorption of 10% (according to Kroes et al., Food Chem Toxicol 2007 Dec; 45(12): 2533-62)

- Most relevant endpoint: Repeated dose toxicity via the oral route (NOAEL=160 mg/kg bw/day)

- Absorption oral-rat: 100

- Absorption dermal-rat: 10

- Absorption dermal-human: 10

Modified dose description starting point

NOAEL oral → NOAEL dermal: corrected NOAEL dermal = oral NOAEL rat 160 * ABS oral rat 100 / ABS dermal rat 10 x ABS dermal rat 10 / ABS dermal human 10 = 160*(100/10)*(10/10) = 1600 mg/kg bw/day

AF for dose response relationship:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dos) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86; ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

3

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. As the worker population is more homogeneous (i.e. younger, healthier, protected from exposures), a default assessment factor of 3 is recommended. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended, in the absence of relevant substance-specific information.

AF for remaining uncertainties:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

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:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

QUALITATIVE CSA - SKIN IRRITATION AND EYE DAMAGE

Worker

The available data for irritation do not provide quantitative dose-response information; thus, no short-term / long term local DNELs can be derived and no quantitative risk assessment was performed for irritation. Exposure assessment and risk characterization are instead performed on a qualitative basis.

 

The purpose of a qualitative risk characterization is to assess "the likelihood that effects are avoided when implementing the exposure scenario…" (REACH Annex 1, Section 6.5) when there is no basis for setting a DNEL/DMEL.

 

Implementation of risk management measures (RMMs) and operational conditions (OCs) need to be proportional to the degree of concern for the health hazard presented by the substance. Therefore the substance is categorized by the hazard according to ECHA Guidance on information requirements and chemical safety assessment, Part E; November 2012.

 

The substance shows the following hazards:Skin Irrit. 2, Eye Damage 1

Skin irritation is considered a low hazard while eye damage represents a moderate hazard therefore the substance is categorized to the moderate hazard group.

 

RMM should be appropriate for hazard class and operational condition. Therefore a code of behaviour is communicated via the Safety Data Sheet (SDS) containing precaution statements and response phrases and general handling instructions.

 

Recommendations for general behavior and RMM are:

H315: Causes skin irritation, H318: Causes serious eye damage.

and

P310: Immediately call a POISON CENTER or doctor/physician.

P305+P351+P338: IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.

P280: Wear protective gloves/protective clothing/eye protection/face protection.

P264: Wash ... thoroughly after handling.

P302+P352: IF ON SKIN: Wash with plenty of soap and water.

P332+P313: If skin irritation occurs: Get medical advice/attention.

P362: Take off contaminated clothing and wash before reuse.

 

A review of this information on RMM and behaviour advice given with the product indicates that, if the user complies to the advice, the risk of exposure to skin and eye for worker and professional user can be considered as adequately controlled.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.7 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: according to ECETOC 2003

Overall assessment factor (AF):

30

Dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

140 mg/m³

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation according to ECHA guidance R8

General population assuming 100% absorption

- General population assuming 100% absorption according ECHA Guidance R8 assuming absorption rate of 100%

- Most relevant endpoint: Repeated dose toxicity via the oral route (NOAEL = 160 mg/kg bw/day)

- Allometric scaling (rats to human): 4

- Respiratory volume: 20 m3/person

NOAEC calculation

- Starting point correction NOAEL oral -> NOAEC human (24h): NOAEC human (24h) = oral NOAEL rat 160 / sRVrat (AS) 4 x bw human 70 / 24h Volume 20 =140 mg / m3 / 24h  

AF for dose response relationship:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dos) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86; ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

1

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, as long as route-to-route extrapolation is not needed, allometric scaling should not be applied in cases where doses in experimental animal studies are expressed as concentrations (e.g. in mg/m3 air, ppm in diet, or mg/L in the drinking water) as these are assumed to be already scaled according to the allometric principle, since ventilation rate and food intake directly depend on the basal metabolic rate. In this case the NOAEC is expressed as concentration (mg/m3), therefore a factor for allometric scaling is not needed. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. The rationale here is that allometric scaling should not be applied because in humans inhalation rate is 4-fold lower compared to rat according to the slower metabolic rate and thereby the allometric species difference is already implicitly taken into account.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended, in the absence of relevant substance-specific information.

AF for remaining uncertainties:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: according to ECETOC

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 600 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Route to route extrapolation assuming worst case absorption of 10% according to Kroes et al., Food Chem Toxicol 2007 Dec; 45(12): 2533 -62

- Most relevant endpoint: Repeated dose toxicity via the oral route (NOAEL = 160 mg/kg bw/day)

- Absorption oral-rat: 100

- Absorption dermal-rat: 10

- Absorption dermal-human: 10

Modified dose description starting point

NOAEL oral → NOAEL dermal: corrected NOAEL dermal = oral NOAEL rat 160 * ABS oral rat 100 / ABS dermal rat 10 x ABS dermal rat 10 / ABS dermal human 10 = 160*(100/10)*(10/10) = 1600 mg/kg bw/day

AF for dose response relationship:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dos) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86; ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended, in the absence of relevant substance-specific information.

AF for remaining uncertainties:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

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:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: according to ECETOC

Overall assessment factor (AF):

120

Dose descriptor starting point:

NOAEL

Value:

160 mg/kg bw/day

AF for dose response relationship:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, for the dose-response relationship, consideration should be given to the uncertainties in the dose descriptor (NOAEL, benchmark dos) as the surrogate for the true no-adverse-effect-level (NAEL). In this case the starting point for the DNEL calculation is a NOAEL, derived from a study which is of good quality and without uncertainties. Therefore the default assessment factor, as a standard procedure, is 1.

AF for differences in duration of exposure:

6

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86; ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110 and ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, a factor allowing for differences in the experimental exposure duration and the duration of exposure for the worker and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. Consequently, to end up with the most conservative DNEL for repeated dose toxicity, chronic exposure is the ‘worst case’. So, as only a sub-acute toxicity study is available, default assessment factor of 6 is to be applied, as a standard procedure.

AF for interspecies differences (allometric scaling):

4

Justification:

In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight to the power of 0.75. This results a default allometric scaling factor for the rat when compared with humans, namely 4. In ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a similar approach is followed. Toxicokinetic differences can be explained by basal metabolic rate which can be accounted for by allometric scaling. The underlying principle is that due to the faster metabolic rate of small animals, humans would less effectively detoxify and/or excrete xenobiotics than laboratory animals and thus are more vulnerable. The allometric scaling factor for the rat versus humans is 4.

AF for other interspecies differences:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110: Potential differences in biological sensitivity between species are largely accounted for in the default assessment factor proposed for intraspecies variability.

AF for intraspecies differences:

5

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a default assessment factor for the general population is based on the distributions of human data for various toxicokinetic and toxicodynamic parameters. The upper extreme of the variability in these data was estimated by calculating the 95th percentile of the distribution, which is considered sufficiently conservative to account for intraspecies variability in the general population (the data analysed included both sexes, a variety of disease states and ages). This results in recommended default assessment factor of 5 for the general population. This proposal of ECETOC is based on an evaluation of the available scientific literature while the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health refers to standard default procedures. Until the scientific basis for using an alternative approach has been established, it is proposed to follow the ECETOC guideline.

AF for the quality of the whole database:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended, in the absence of relevant substance-specific information.

AF for remaining uncertainties:

1

Justification:

In accordance with ECETOC Derivation of Assessment Factors for Human Health Risk Assessment – Technical Report No. 86 and ECETOC Guidance on Assessment Factors to Derive a DNEL – Technical Report No. 110, a factor allowing for remaining uncertainties should be used where necessary. As the approach used for DNEL derivation is conservative, no further assessment factors are required.

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

QUALITATIVE CSA - SKIN IRRITATION AND EYE DAMAGE

The available data for irritation do not provide quantitative dose-response information; thus, no short-term / long term local DNELs can be derived and no quantitative risk assessment was performed for irritation. Exposure assessment and risk characterization are instead performed on a qualitative basis.

 

The purpose of a qualitative risk characterization is to assess "the likelihood that effects are avoided when implementing the exposure scenario…" (REACH Annex 1, Section 6.5) when there is no basis for setting a DNEL/DMEL.

 

The general population will not come into contact with the neat substance. By dilution of the substance in a product/preparation the hazard potential will decrease accordingly. Furthermore suited risk management measures may be used to prevent consumer exposure (e.g. like increased viscosity of products in order to avoid splashes and spills during handling, child-resistant fastenings or further product-integrated measures, like increase of particle size to decrease the inhalable fraction of powders or tableting of powders etc.). Additional general handling instructions will be given on the product (like wash of immediately if in contact with skin, use only in well ventilated room, etc.).

 

Thus, the irritating potential of the substance in consumer products is assumed to be sufficiently controlled, via a variety of risk management measures, if the given advice is followed.