2,2'-dimethyl-4,4'-methylenebis(cyclohexylamine)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEC

Value:

12 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction of exposure duration in study (6 hrs/day, 5 days/week) to default worker exposure (8 hrs/day, 5 days/week); Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3). Please refer to "Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling is needed in case of inhalation exposure.

AF for other interspecies differences:

1

Justification:

No additional factor is used, because rats are known to be more susceptibile towards inhalation exposure of corrosive substances than humans. Therefore, the worst case has already been considered.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The OECD TG 413 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7.5

Dose descriptor:

NOAEC

Value:

8 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

The concentration plays a more important role than the duration for the development of the local adverse effects. In this case, an assessment factor of 1 is justified.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling is needed since local effects are independend of the metabolic rate.

AF for other interspecies differences:

3

Justification:

The appropriate assessment factors were set based on the publication of Bruening et al (2014). In this publication the sensory irritation pathway in humans was compared to the tissue irritation pathway in animals. Experimental exposure studies with human volunteers provided the empirical basis for effects along the sensory irritation pathway and thus, sensory NOAEChuman was derived. In contrast, inhalation studies with rodents investigated the second pathway that yielded an irritative NOAECanimal. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an interspecies assessment factor of 3 for extrapolating animal data concerning local sensory irritating effects.

AF for intraspecies differences:

1

Justification:

There is no evidence for species differences in the general mode of action or kinetics.

AF for the quality of the whole database:

1

Justification:

The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor

AF for remaining uncertainties:

2.5

Justification:

There could be significant quantitative differences in deposition, airflow patterns, clearance rates and protective mechanisms between humans and animals and there is no data available to inform on this uncertainty. In such a situation, a default factor of 2.5 should be applied.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.05 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

40

Dose descriptor starting point:

NOAEL

Value:

1.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

2.1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No repeated dose dermal toxicity study with the substance is available. Therefore, it was necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. Please refer to "Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

1

Justification:

The most prominent effect after skin contact is the induction of local corrosion. However, interspecies differences were already included to address the differences in metablolism between humans and rats. To address systemic effects also, there is no need to use an addtitional factor for other interspecies differences. The worst case has therefore already been considered.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Long term, systemic DNEL – exposure via inhalation (workers)

For the inhalation route, a 90-day study with rats (GLP and OECD TG 413) was performed with concentrations of 2, 12 and 48 mg/m³. The NOAEC was 12 mg/m³ for local and systemic effects. Repeated inhalation of the test item showed systemic toxicity in the target organs liver and spleen in the form of hepatotoxicity and a disturbed hemoglobin metabolism. The amine-specific local toxicity was manifest in the form of changes in the target organs skin and nasal mucosa and led to hyperkeratosis or to a degeneration of the olfactory epithelium. The NOAEC of 12 mg/m³ was used as PoD for the DNEL derivation.

Step 1:PoD and most sensitive endpoint: NOAEC (systemic toxicity) = 12 mg/m³

Step 2:Modification of PoD:

Standard respiratory volume, human (sRVhuman): 6.7 m³

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m³

Correction for difference between human and experimental exposure conditions: 5 d rat/5 d worker

Corrected NOAEC (inhalation) for workers: 0.75 (6 h rat/ 8 h worker)

= 12 mg/m³× (6.7 m³/10 m³) × 0.75

= 6 mg/m³

Step 3: Overall AF= 10

Exposure duration AF (subchronic to chronic): 2 (default)

Intraspecies AF (worker): 5 (default)

Interspecies AF, remaining differences: 1 (No additional factor is used, because rats are known to be more susceptibile towards inhalation exposure of corrosive substances than humans. Therefore, the worst case has already been considered.)

Whole database AF: 1

The OECD TG 413 toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic inhalation DNEL, workers = 0.24 mg/m³

 

Acute, systemic DNEL- exposure via inhalation (workers)

The substance is classified for acute inhalation toxicity Cat.2 (H330) according to Regulation (EC) No 1272/2008 (CLP Regulation). The substance did not cause mortality at a concentration of 53 mg/m³ in the acute inhalation toxicity study reported by BASF AG (1979). This concentration is much higher than the NOAEC of 12 mg/m³ for systemic/local effects after long term inhalation of the substance (BASF AG, 1992). Thus, systemic effects after long term exposure are more relevant and the DNEL after long term exposure is considered to ensure a sufficient level of protection for the systemic effects following acute/short term inhalative exposure.

Long term, local DNEL- exposure via inhalation (workers)

The NOAEC of 12 mg/m³(local) has to be adapted considering different respiratory volumes of humans at rest (6.7 m³) and with physical light activity (10 m³) for 8 hours. Thus, the modified NOAEC is 8 mg/m³.

Corrected NOAEC (inhalation) for workers:

= 12 mg/m³x (6.7 m³/10 m³)

= 8 mg/m³

Step 3: Overall AF= 7.5

Exposure duration AF: 1

The concentration plays a more important role than the duration for the development of the local adverse effects. In this case, an assessment factor of 1 is justified.

 

Interspecies: AF: 1

Local effects are independent of the basal metabolic rate, allometric scaling should not be applied.

 

Interspecies AF, other: 3

A subchronic repeated dose toxicity study for inhalation according to OECD 413 is available for DNEL derivation. The appropriate assessment factors were set based on the publication of Bruening et al (2014). In this publication the sensory irritation pathway in humans was compared to the tissue irritation pathway in animals. Experimental exposure studies with human volunteers provided the empirical basis for effects along the sensory irritation pathway and thus, sensory NOAEChuman was derived. In contrast, inhalation studies with rodents investigated the second pathway that yielded an irritative NOAECanimal. The comparison of the sensory NOAEChuman with the irritative NOAECanimal (chronic) resulted in an assessment factor of 3 for extrapolating animal data concerning local sensory irritating effects.

Interspecies AF, remaining uncertainties: 2.5

There could be significant quantitative differences in deposition, airflow patterns, clearance rates and protective mechanisms between humans and animals and there is no data available to inform on this uncertainty. In such a situation, a default factor of 2.5 should be applied.

Intraspecies AF: 1

There is no evidence for species differences in the general mode of action or kinetics.

Whole database AF: 1

The repeated dose inhalation toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term local inhalation DNEL, workers = 1 mg/m³

This concentration is higher than the DNEL of 0.24 mg/m³ for systemic effects after long term inhalation of DMDC. Thus, systemic effects after long term exposure are more relevant and the DNEL after long term exposure is considered to ensure a sufficient level of protection for the local effects following long term inhalative exposure.

Short term, local DNEL- exposure via inhalation (workers)

The substance did not cause mortality as well as local effects at a concentration of 53 mg/m³ in the acute inhalation toxicity study reported by BASF AG (1979). This concentration is much higher than the NOAEC of 12 mg/m³ for systemic/local effects after long term inhalation of DMDC (BASF AG, 1992). Thus, local effects after long term exposure are more relevant and the DNEL after long term exposure is considered to ensure a sufficient level of protection for the local effects following acute/short term inhalative exposure. Nevertheless, a qualitative approach has to be implemented to deal with the corrosive potential of DMDC.

2. Dermal

Long term, systemic DNEL- dermal exposure (workers)

No repeated dose dermal toxicity study with the substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation. For the oral route, a EOGRTS study with rats (OECD TG 443, GLP) was performed with dose levels of 1.5, 5 and 15 mg/kg bw/day that gave a NOAEL of 1.5 mg/kg bw/day. Under the conditions of the present extended 1-generation reproduction toxicity study the NOAEL for general, systemic toxicity is the low dose of 1.5 mg/kg bw/d for the F0 animals. This was based on treatment-related, adverse effects such as a reduction in water and food consumption, decrease in body weight (change), altered clinical pathology parameters as well as histopathological changes in several organs, which were observed at the high- and mid-dose of 15 and 5 mg/kg bw/d. The NOAEL of 1.5 mg/kg bw/day was used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 1.5 mg/kg bw/day

Step 2: Modification into a correct starting point:

Oral absorption of the rat/ dermal absorption of humans (ABS oral-rat / ABS derm-human): 100%/100%

Dermal penetration is predicted to be very slow for the substance. Internal exposure through dermal contact was calculated using IH SkinPerm model (AIHA) showing a maximal dermal absorption of 0.00257 mg/cm²/h.

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker -- > factor 1.4

Corrected NOAEL (dermal) for workers:

= 1.5 mg/kg bw/day x (100/100) x 1.4

= 2.1 mg/kg bw/day

Step 3: Overall AF= 40

Exposure duration AF: 2 for sub-chronic to chronic (default)

Interspecies AF, allometric scaling (rat to human): 4 (default)

Interspecies AF, remaining differences: 1 (The most prominent effect after skin contact is the induction of local corrosion. However, interspecies differences were already included to address the differences in metablolism between humans and rats. To address systemic effects also, there is no need to use an addtitional factor for other interspecies differences. The worst case has therefore already been considered.)

Intraspecies AF (worker): 5 (default)

Whole database AF: 1

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

In conclusion, long term systemic dermal DNEL, workers = 0.05 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

An acute dermal study was performed with the substance in Vienna White rabbits (BASF AG, 1979). Mortality was observed during the course of the study in female animals only at a dose level of 200 mg/kg bw (3/5; no mortality in males). Therefore, an acute toxicity hazard leading to C&L has been identified for substance (Cat 3 acute dermal, H311). Based on these data, the worker-DNEL long-term for dermal route - systemic is considered to ensure a sufficient level of protection for the dermal route.

Long term & acute, local DNEL- dermal exposure (workers)

According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterization, a qualitative risk characterization should be performed for this endpoint. This qualitative approach has to be implemented to deal with the eye as well as skin corrosive properties of the substance. As a result, a medium hazard is derived. In order to guarantee "adequately control of risks", it is necessary to stipulate risk management measures that prevent skin, eye and mucous membrane exposure.

Hazard to the eye-local effects (worker)

The test item is classified as corrosive to skin and eyes (Cat 1B, H314), according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted (medium hazard).

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

Bruening et al 2014, Sensory irritation as basis for setting occupational exposure limits, Arch Toxicol (2014) 88:1855-1879

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

1.5 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL was correction for difference between human and experimental exposure conditions. Please refer to "Additional information".

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default value for interspecies differences is used.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The repeated dose oral toxicity study was conducted according to regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Currently, a consumer use of DMDC is not foreseen. However, a long-term, systemic DNEL for the oral exposure of human via the environment was dervived.

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012).

Long term, systemic DNEL- exposure by oral route (human via enviroment)

For the oral route, a EOGRTS with rats (OECD TG 443 and GLP) was performed with dose levels of 1.5, 5 and 15 mg/kg bw/day that gave a NOAEL of 1.5 mg/kg bw/day. This NOAEL is used as PoD for DNEL derivation.

Step 1: PoD: NOAEL = 1.5 mg/kg bw/day

Correction for difference between human and experimental exposure conditions: No further correction necessary. PoD = 1.5 mg/kg bw/day

Step 2: Overall AF= 200

Exposure duration AF: 2 for sub-chronic to chronic (default)

Interspecies AF, allometric scaling (rat to human): 4 (default)

Interspecies AF, remaining differences: 2.5 (default)

Intraspecies AF (general population): 10 (default)

Dose-response relationship AF: 1

In conclusion, long term systemic oral DNEL, human via environment= 0.008 mg/kg bw/day