Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

51.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance document R.8 in combination with the ERASM project (Batke et al, 2011)

Overall assessment factor (AF):

25.5

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1 322 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral rat NOAEL for systemic toxicity (750 mg/kg bw) was converted into the inhalative human NOAEC corrected for differences between the 8 -hour standard inhalation volume of rats versus humans, and for differences between the 8 -hour inhalation volume of workers in rest versus worker in light activity, by multiplying with the corresponding factors (1/0.38 m³/kg/d * 6.7m³/10m³). The resulting corrected starting point for inhalation DNEL derivation for workers is 1322 mg/m³.

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

3.4

Justification:

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to chronic factor was 3.4 (Batke et al., 2011).

AF for interspecies differences (allometric scaling):

1

Justification:

The allometric scaling factor was already taken into account for the starting point correction.

AF for other interspecies differences:

1

Justification:

Besides the allometric scaling factors, no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to humans as the rat's ventilation frequency is higher. Also anatomical differences as well as ait flow patterns between rodents and humans have to be taken into account.

AF for intraspecies differences:

3

Justification:

There were no systemic effects observed in the repeated dose study with rats. Therefore, an intraspecies factor of 3 is considered to be sufficient.

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

2.5

Justification:

An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.11 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

42.5

Dose descriptor:

NOAEC

Value:

1 322 mg/m³

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

3.4

Justification:

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to chronic factor was 3.4 (Batke et al., 2011).

AF for interspecies differences (allometric scaling):

1

Justification:

The allometric scaling factor was already taken into account for the starting point correction.

AF for other interspecies differences:

1

Justification:

Besides the allometric scaling factors, no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to humans as the rat's ventilation frequency is higher. Also anatomical differences as well as ait flow patterns between rodents and humans have to be taken into account.

AF for intraspecies differences:

5

Justification:

Standard factor as outlined in REACH Guidance document R.8

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

2.5

Justification:

An additional safety factor for remaining uncertainties was used to cover possible risks of the performed read-across.

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:

no hazard identified

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Explanation for the modification of the dose descriptor starting point:

An induction-specific DNEL was derived for skin sensitization (local effects) according to Guidance on information requirements and chemical safety assessment, Chapter R.8 based on the EC3 value from a reliable LLNA with the read-across substance (Harlan, 2012). The EC3 value can be estimated to be 2.7% (w/v (675µg/cm²), indicative of a sensitizer of moderate potency according to Chapter R.8. The EC3 value (in µg/cm²) can be considered as the NOAEL for induction of local effects (Chapter R.8). Systemic effects are covered by the local dermal DNEL.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

67.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor:

other: EC3 value

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

1

Justification:

see discussion

AF for interspecies differences (allometric scaling):

1

Justification:

A number of other organizations were able to empirically show that the EC3 value (µg/cm²) also correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as asurrogate for the human sensitization threshold without the modification by uncertainty factors.

AF for other interspecies differences:

1

Justification:

see above

AF for intraspecies differences:

10

Justification:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al, 2008). The barrier function of the skin may be comprised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the gentic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase thze susceptibility to further sensitizers (Api et al. 2006, Api et al. 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

67.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: EC3 value

AF for dose response relationship:

1

Justification:

see discussion

AF for interspecies differences (allometric scaling):

1

Justification:

A number of other organizations were able to empirically show that the EC3 value (µg/cm²) also correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as asurrogate for the human sensitization threshold without the modification by uncertainty factors.

AF for other interspecies differences:

1

Justification:

see above

AF for intraspecies differences:

10

Justification:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al, 2008). The barrier function of the skin may be comprised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the gentic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase thze susceptibility to further sensitizers (Api et al. 2006, Api et al. 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

Worker:

Based on the available data, Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine, has to be considered as potentially skin sensitizing (R43; Cat. 1B).

The primary routes of anticipated industrial and professional exposure of the registered substance, are via inhalation and skin contact. In industrial settings, ingestion is not an anticipated route of exposure, but has to be considered for the general population (see below).

Dermal short-term and long-term exposure – local effects (also covers systemic toxicity):

An induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from a reliable LLNA study (Harlan, 2012). The EC3 value can be estimated to be 2.7 % w/v (675μg/cm²), indicative of a sensitizer of moderate potency according to Chapter R.8 (ECHA, May 2008). The EC3 value (in µg/cm²) can be considered as the NOAEL for induction, based on the Guidance on information requirements and chemical safety assessment, Chapter R.8.

Interspecies:

A number of other organizations were able to empirically show that the EC3 value (in µg/cm²) also closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

The DNEL for skin sensitization was calculated to be 67.5 µg/cm²/day.

 

 

Inhalation long-term exposure – local effects (also covers systemic toxicity):

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (Harlan Laboratories, 2013) performed with the read-across substance was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for local toxicity of the test substance was 75 mg/kg bw/d for rats (systemic: 750 mg/kg bw/d).

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors (x 1/0.38 m³/kg/d x 6.7 m³/10 m³). The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 132.23 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Intraspecies factor: 5

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8  

Total AF = 1 x 5 x 3.4 x 1 x 2.5 = 42.5

Based on this calculation the resulting DNEL is 3.11 mg/m³.

-Api AM, Basketter DA, Cadby PA, Cano M-F, Graham E, Gerberick F, Griem P, McNamee P, Ryan CA, Safford B (2006). Dermal Sensitization Quantitative Risk Assessment (QRA) for fragrance ingredients. Technical dossier. March 15, 2006 (revised May 2006).

- Batke M, Escher S, Hoffmann-Doerr S, Melber C, Messinger H, Mangelsdorf I.(2011).Evaluation of time extrapolation factors based on the database RepDose. Toxicology Letters 205 (2011) 122– 129.

 

- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

 - Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

-ECETOC (2003). Contact Sensitization: classification according to potency. Technical Report No. 87, April 2003.

-ECHA (2008). REACh Guidance document R.8

-ECETOC (2003). Derivation of Assessment factors for Human Health Risk Assessment. Technical Report No. 86, February 2003.

-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.67 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: ECHA REACH Guidance document R.8 in combination with the ERASM project (Batke et al, 2011)

Overall assessment factor (AF):

85

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

652.2 mg/m³

Explanation for the modification of the dose descriptor starting point:

The oral rat NOAEL for systemic toxicity (750 mg/kg bw) was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factors (1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for the general population is 652.2 mg/m³.

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

3.4

Justification:

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to chronic factor was 3.4 (Batke et al., 2011).

AF for interspecies differences (allometric scaling):

1

Justification:

The allometric scaling factor was already taken into account for the starting point correction.

AF for other interspecies differences:

1

Justification:

Besides the allometric scaling factors, no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to humans as the rat's ventilation frequency is higher. Also anatomical differences as well as ait flow patterns between rodents and humans have to be taken into account.

AF for intraspecies differences:

10

Justification:

Standard factor as outlined in REACH Guidance document R.8

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

2.5

Justification:

Standard factor as outlined in REACH Guidance document R.8

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.77 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

85

Dose descriptor:

NOAEC

Value:

65.2 mg/m³

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

3.4

Justification:

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to chronic factor was 3.4 (Batke et al., 2011).

AF for interspecies differences (allometric scaling):

1

Justification:

The allometric scaling factor was already taken into account for the starting point correction.

AF for other interspecies differences:

1

Justification:

Besides the allometric scaling factors, no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to humans as the rat's ventilation frequency is higher. Also anatomical differences as well as ait flow patterns between rodents and humans have to be taken into account.

AF for intraspecies differences:

10

Justification:

Standard factor as outlined in REACH Guidance document R.8

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

2.5

Justification:

Standard factor as outlined in REACH Guidance document R.8

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:

no hazard identified

DNEL related information

Explanation for the modification of the dose descriptor starting point:

An induction-specific DNEL was derived for skin sensitization (local effects) according to Guidance on information requirements and chemical safety assessment, Chapter R.8 based on the EC3 value from a reliable LLNA with the read-across substance (Harlan, 2012). The EC3 value can be estimated to be 2.7% (w/v (675µg/cm²), indicative of a sensitizer of moderate potency according to Chapter R.8. The EC3 value (in µg/cm²) can be considered as the NOAEL for induction of local effects (Chapter R.8). The local DNEL also covers for systemic effects.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

67.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor:

other: EC3 value

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

1

Justification:

see discussion

AF for interspecies differences (allometric scaling):

1

Justification:

A number of other organizations were able to empirically show that the EC3 value (µg/cm²) also correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as asurrogate for the human sensitization threshold without the modification by uncertainty factors.

AF for other interspecies differences:

1

Justification:

see above

AF for intraspecies differences:

10

Justification:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al, 2008). The barrier function of the skin may be comprised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the gentic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase thze susceptibility to further sensitizers (Api et al. 2006, Api et al. 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

67.5 µg/cm²

Most sensitive endpoint:

sensitisation (skin)

DNEL related information

Overall assessment factor (AF):

10

Dose descriptor starting point:

other: EC3 value

AF for dose response relationship:

1

Justification:

see discussion

AF for interspecies differences (allometric scaling):

1

Justification:

A number of other organizations were able to empirically show that the EC3 value (µg/cm²) also correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as asurrogate for the human sensitization threshold without the modification by uncertainty factors.

AF for other interspecies differences:

1

Justification:

see above

AF for intraspecies differences:

10

Justification:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al, 2008). The barrier function of the skin may be comprised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the gentic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase thze susceptibility to further sensitizers (Api et al. 2006, Api et al. 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

1

Justification:

see discussion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

Overall assessment factor (AF):

340

Dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

750 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, Harlan 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for general, systemic toxicity of the test substance was 750 mg/kg bw/day for rats.

AF for dose response relationship:

1

Justification:

see discussion

AF for differences in duration of exposure:

3.4

Justification:

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDose that currently contains about 670 substances and 2200 studies on repeated dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to chronic factor was 3.4 (Batke et al., 2011).

AF for interspecies differences (allometric scaling):

4

Justification:

Recommended for the rat in REACH Guidance document R.8

AF for other interspecies differences:

1

Justification:

see discussion

AF for intraspecies differences:

10

Justification:

Standard factor outlined in the REACH Guidance document R.8

AF for the quality of the whole database:

1

Justification:

see discussion

AF for remaining uncertainties:

2.5

Justification:

Standard factor outlined in the REACH Guidance document R.8

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

Consumer

Based on the available data, Hexamethylene diisocyanate, oligomers, reaction products with Bis-(Trimethoxysilylpropyl)amine has to be considered as potentially skin sensitizing (R43; Cat. 1B).

For the general population, all three possible routes of exposure (oral, dermal, inhalation) have to be taken into account.

Dermal short-term and long-term exposure – local effects:

An induction-specific DNEL was derived for skin sensitization according to Guidance on information requirements and chemical safety assessment, Chapter R.8 (ECHA, May 2008) based on the EC3 value from a reliable LLNA study with the read-across substance (BASF, 2009). The EC3 value can be estimated to be 2.7 % w/v (675μg/cm²), indicative of a sensitizer of moderate potency according to Chapter R.8 (ECHA, May 2008). The EC3 value (in µg/cm²) can be considered as the NOAEL for induction, based on the Guidance on information requirements and chemical safety assessment, Chapter R.8.

Interspecies:

A number of other organizations were able to empirically show that the EC3 value (in µg/cm²) also closely correlates with the NOEL from human sensitization tests designed to confirm lack of induction (Api et al., 2006, Api et al., 2008, ECETOC TR87, 2003). Therefore, it seems appropriate to use the EC3, expressed as dose per skin area, as a surrogate for the human sensitization threshold without the modification by uncertainty factors.

Intraspecies:

It is recognized that a general DNEL must take into account that the threshold for skin sensitization varies between individuals. This may be due to differences in parameters such as genetic effects, sensitive subpopulations, inherent barrier function, age, gender, and ethnicity (Api et al., 2008). Whereas the latter three are recognized to have some effect on the sensitization threshold, it is generally recognized that genetic differences, the inherent barrier function and especially sensitive subpopulations play a major role (Api et al., 2008). The barrier function of the skin may be compromised which in turn may lead to a greater susceptibility of the individual. At the same time the barrier function is thought to be very similar from infancy to adulthood. The influence of the genetic setting is not well understood, however, may be plausible in the light of the immunological effect under consideration. The term sensitive subpopulations refers mostly to individuals who have previously been sensitized to other substances which may increase the susceptibility to further sensitizers (Api et al., 2006, Api et al., 2008). All of these effects make up the intraspecies factor, a factor of 10 is thought to adequately address the combined influence of these effects.

The DNEL for skin sensitization was calculated to be 67.5 µg/cm²/day.

  

Inhalation long-term exposure – local effects (also covers systemic toxicity):

The NOAEL from an oral OECD Guideline 422 study (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (Harlan Laboratories, 2013) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for local toxicity of the test substance was 75 mg/kg bw/d for rats (systemic: 750 mg/kg bw/d).

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 26 f.:

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). The resulting corrected starting point for inhalation DNEL derivation for local effects for the general population is equal to 65.21 mg/m³ and for systemic toxicity is 652.1 mg/m³.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 1

Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used based on the fact that concerning inhalation, rodents like the rat are in general more sensitive compared to human as the rat's ventilation frequency is higher. Also anatomical differences as well as air flow patterns between rodents and humans have to be taken into account.

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8  

 

Total AF = 1 x 10 x 3.4 x 1 x 2.5 = 85

Based on this calculation the resulting local DNEL is 0.76 mg/m³ and the systemic DNEL is 7.6 mg/m³.

Oral long-term exposure – systemic effects:

The NOAEL from an oral OECD Guideline 422 study performed with a read-across substance (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) (Harlan Laboratories, 2013) was identified as the appropriate starting point for DNEL derivation for long-term oral exposure. The NOAEL for general, systemic toxicity of the test substance was 750 mg/kg bw/d for rats.

The NOAEL of 750 mg/kg bw/day was considered appropriate as point of departure for DNEL derivation. Subsequently, the following assessment factors are taken into account for the final DNEL calculation for the oral route: interspecies differences (4), remaining differences (1), intraspecies differences (5), exposure duration (3.4) (AF = 4 x 10 x 3.4 x 1 x 2.5 = 340).

As a consequence, the resulting DNEL for long-term oral local and systemic effects is 2.2 mg/kg bw/d for the general population.

For DNEL derivation, the following assessment factors (AF) were applied to the corrected starting point:

- Interspecies factor: 4

Recommended for the rat in REACh Guidance document R.8 for allometric scaling

- Intraspecies factor: 10

Standard factor as outlined in REACh Guidance document R.8  

- Exposure duration: 3.4 (Batke et.al., 2011)

Within the ERASM project, time-extrapolation factors were evaluated with the database RepDoseg that currently contains about 670 substances and 2200 studies on repeated-dose toxicity. It has been shown that as long as the material is soluble, the sub-acute to sub-chronic factor was 1.5, rather than 3 , the sub-acute to chronic factor was 3.4 and the sub-chronic to chronic factor was 1.4 (Batke et al, 2011).

- Dose-response: 1

- Remaining differences: 2.5

Standard factor as outlined in REACh Guidance document R.8  

 

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- Escher S and Mangelsdorf I. (2009). Evaluation of risk assessment factors for inter-species and time-extrapolation. Toxicol Lett 189:S247-S248. 46th Congress of the European Societies of Toxicology, 13-16 September 2009, Dresden.

 

- Bitsch A, Jacobi S, Melber C, Wahnschaffe U, Simetska N, Mangelsdorf I. (2006).REPDOSE: A database on repeated dose toxicity studies of commercial chemicals – a multifunctional tool. Regul Toxicol Pharmacol 46:202-210.

-Api AM, Basketter, DA, Cadby PA, Cano M-F, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R (2008). Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Reg Toxicol Pharmacol 52: 3-23.

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-ECETOC (2010). Guidance on Assessment Factors to Derive DNELs.Technical Report No. 110, October 2010.