2-methylpentane-1,5-diamine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.25 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor:

LOAEC

Justification:

starting point is LOAEC instead of NOAEC

Justification:

no additional factor is required for time duration since the effect observed is not dependent on the time of exposure

Justification:

no allometric scaling foreseen

Justification:

no deficiencies

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

1     Short overview of substance specific data to be considered for MPMD

Inhalation and dermal exposure are the most appropriate route for assessing occupational risk in workers. Effects from exposure of animals to MPMD are limited to effects on the upper respiratory tract (larynx and nasal passages) caused by important local irritation.

Some sort of general systemic toxicity was observed in an OECD 408 study (90-day exposure via oral gavage). This is compared below as a basis for deriving a long-term inhalation DNEL for workers with local effects observed after inhalation exposure.

Tests assessing the mutagenic potential of MPMD in vitro provided no evidence of mutagenic or genotoxic activity.

2          DNELs/DMELs derivation according to the toxicological profile of MPMD

For the dermal route no DNELs were derived as MPMD is classified as corrosive. Considering these data, it is very difficult to derive a threshold and to set a DNEL. Hence, only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

 Worker-DNEL long-term for inhalation route- local effects:

In a subacute inhalation toxicity study male rats were exposed for 6 hours per day and overall 10times within two weeks to an aerosol/vapour mixture of the test material (i. e. MPMD). Concentrations used were 0, 9.2, 59 and 250 mg/m³ (analytical). Systemic effects and macroscopic lesions of the lung were obvious in the lung were observed in the high dose group. Microscopically exposure-related lesions were confined to the respiratory tract and were dose related. In the 59 and 250 mg/m³groups, lesions were observed in the nose, trachea, larynx/pharynx, and lung. These lesions were mainly minimal to mild in the 59 mg/m³group and mild to moderate in the 250 mg/m³group. Within the low dose group minimal to mild inflammation of the nasal epithelium was observed. Due to the fact that local effects on the respiratory tract were seen in all concentration groups tested and these effects were clearly concentration related a no observed adverse effect level could not be determined. The LOAEC of this study with MPMD was established to be 9.2 mg/m³.

The results of this study were confirmed using another amine which is structurally related to the registration substance. This amine, i.e. namely 1,2-Diaminicyclohexane (CAS 694-83-7), is another C6-diamine but cyclic instead of branched as MPMD. In a study with the same study design (10 times à 6-hour exposure of rats during a 14-day period) using DCH as test material comparable local effects were observed in all treated groups thus yielding also a LOAEC of 10 mg/m³ (minimal to moderate effects on upper respiratory tract, fully reversible within 14-day recovery period).

Furthermore, there is experimental evidence from a subchronic study with Hexamethylenediamine dihydrochloride (CAS 6055-52-3, HDDC = salt of Hexamethylenediamine (HMD, CAS 124-09-4)). HMD is another C6-diamine but linear instead of branched as MPMD. In this study with inhalation exposure of rats (6h/day, 5d/week for 13 weeks) also local respiratory effects were identified as critical. Under the test conditions, the NOAEC (HDDC) = 16 mg/m³/day for local respiratory damage (nasal respiratory epithelium degeneration), corresponding to a NOAEC (HMD) = 10 mg/m³/day. In another subchronic inhalation toxicity study with rats, the animals were repeatedly exposed to aqueous HMD aerosol for six hours per day, five days per week at mean analytical concentrations of 0, 12.8, 51 and 215 mg/m³. Under the test conditions, no systemic effects were observed related to the treatment with HMD. The significant local irritation of respiratory tract, inducing clinical signs, was observed at the two highest concentrations tested. The NOAEC in male and female rats exposed by whole-body inhalation was 12.8 mg HMD/m³.

Only one study is available using the submission substance. Thus, the LOAEC of the study will serve as starting point for the DNEL derivation. However, the experimental data on related amines serves as supporting evidence for verifying the local irritating nature of amines in general. Especially the subchronic studies with HMD and HMD-dihydrochlorid verify that the effect is not crucially time dependent either - therefore no assessment factor was used for differences in duration of exposure.

DNEL derivation:

Basis LOAEC: 9.2 mg/m³ from 14 days toxicity study after aerosol/vapour exposure

Effects: dose dependent effects seen on the upper respiratory tract (e. g. nasal lesions) which were from minimal to moderate severity and were reversible within the 14-day recovery period

No correction of LOAEC was performed as local irritating effects are concentration dependent and are independent of the absorbed dose.

Assessment factors:

• Interspecies differences:         no allometric scaling, 2.5 (remaining differences)


• Intraspecies differences:     5


• Differences in duration of exposure:           1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure))


• Issues related to dose-response:             3 (starting point is LOAEC instead of NOAEC)


• Quality of whole database:       1 (no deficiencies)

--> Overall assessment factor: 37.5

DNEL = 9.2 mg/m³/37.5

DNEL = 245.3 µg/m³ = 0.245 mg/m³ ≈ 0.25 mg/m³

 

Worker-DNEL short-term for inhalation route- local effects:

As an acute toxicity hazard has been identified (leading to C&L, i.e. Acute toxicity, inhalation Category 4 (H332) and STOT Single Exp. 3 (H335)) a DNEL for peak exposure has to be derived. Ideally sub-lethal toxicity should be the starting point rather than mortality. In our case from the acute inhalation toxicity study only information on mortality could be extracted as there were no detailed descriptions on pathological findings included. Therefore repeated-dose data from the sub-acute inhalation study with the submission substance is thought to better characterize the acute hazard originating from the toxicological profile of the substance.

Effects after repeated application of the submission substance by inhalation to rats were restricted to the respiratory tract. Therefore, an acute DNEL inhalation for local effects was established from the WORKER DNEL LONG-TERM FOR INHALATION ROUTE, LOCAL EFFECTS by using a multiplying factor of 2 considering that the observed adverse effects are mainly driven by the exposure concentration of the submission substance with respect to its corrosive properties.

 DNEL: 245 µg/m³ *2 = 490 µg/m³ = 0.49 mg/m³ ≈ 0.5 mg/m³

 

Below, the DNEL derivation for local and systemic effects are compared to evaluate which of the effects leads to the more conservative assessment. As systemic effects were only observed after oral exposure route-to-route extrapolation has to be performed. The study which identified the lowest NOAEL was used.

Workers long-term DNEL inhalation	Local	Systemic
Step a: determination of dose-descriptor
Key study	HLR 45-91, no OECD Guideline	Labcorp 2022, OECD 408
Relevant dose descriptor	LOAEC = 9.2 mg/m^3for local irritant effects of the upper respiratory tract in rats	NOAEL = 50 mg/kg bw/day (systemic effects on male rats)
Step b: correct starting point		*
Differences in metabolic rate per b.w. (allometric scaling)	- (local effects)	4 (rat)
Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)	-       - (local effects)	-     2 (worst case assumption according to ECHA guidance R.8: 50% oral and 100% inhalation exposure)
Modification for exposure (experiment and human)	-       - (local irritant effects depending on concentration, only)	-      - (daily dose)
Modification for respiratory volume	-	X 70 kg bw / 10 m^3 respirator volume per work shift
Correct starting point = relevant dose descriptor / overall factor for uncertainties	9.2 mg/m³	44 mg/m^3
Step c : assessment factors
Interspecies differences	2.5 (effects on respiratory tract)	2.5 (remaining differences
Intraspecies differences	5	5
Duration extrapolation (sub-acute/sub-chronic/chronic)	1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure)	2 (subchronic to chronic)
Issues related to dose-response	3 (LOAEC)	1
Quality of whole database	1	1
Overall assessment factor	37.5	25
DNEL calculation	0.245 mg/m^3	1.76 mg/m^3

* Please note this is one of the ways shown in ECHA Guidance on information requirements and chemical safety assessment Chapter R.8, APPENDIX R. 8-2, Example R. 8-2 Workers (or Figure R. 8-3) for correction of the starting point. This is not the preferred way, but here differences from the local DNEL derivation can be pointed out. The preferred way (i.e. 50 mg/kg bw/day / 0.38 m³/kg bw * 50% / 100%* 6.7 m³ / 10 m³) leads to the same numerical value.

Final conclusion:

The inhalation workers DNEL long-term calculated for local effects is 0.245 mg/m³ ≈ 0,25 mg/m³ compared to 1.76 mg/m³ for systemic effects. The lower DNEL for local effects is considered to be protective also regarding systemic effects and taken forward for risk characterisation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

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:

0.125 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Dose descriptor:

LOAEC

Justification:

starting point is LOAEC instead of NOAEC

Justification:

no additional factor is required for time duration since the effect observed is not dependent on the time of exposure

Justification:

no deficiencies

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Modified dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Justification:

subchronic to chronic

Justification:

no deficiencies

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

1          DNELs/DMELs derivation according to the toxicological profile of MPMD

The general population includes consumers and humans exposed via the environment. Consumer exposure is not expected as MPMD has no consumer use. But exposure of human via the environment is of potential concern. Inhalation and oral exposure were the most appropriate route for assessing risks for human exposed via the environment.

General population-DNEL long-term for inhalation route- local effects:

DNEL derivation:

Basis LOAEC: 9.2 mg/m³ from 14 days toxicity study after aerosol/vapour exposure

Effects: dose dependent effects seen on the upper respiratory tract (e. g. nasal lesions) which were from minimal to moderate severity and were fully reversible within the 14-day recovery period

No correction of LOAEC was performed as local irritating effects are concentration dependent and are independent of the absorbed dose.

Assessment factors:

• Interspecies differences: no allometric scaling, 2.5 (remaining differences)


• Intraspecies differences: 10


• Differences in duration of exposure:    1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure)


• Issues related to dose-response:   3 (starting point is LOAEC instead of NOAEC)


• Quality of whole database: 1 (no deficiencies)

--> Overall assessment factor: 75

DNEL = 9.2 mg/m³/75

DNEL = 123 µg/m³ ≈ 125 µg/m³ = 0.125 mg/m³

 

General Population-DNEL short-term for inhalation route- local effects:

--> DNEL: 125 µg/m³ *2 = 250 µg/m³ = 0.25 mg/m³

 

Below, the DNEL derivation for local and systemic effects are compared to evaluate which of the effects leads to the more conservative assessment. As systemic effects were only observed after oral exposure route-to-route extrapolation has to be performed. The study which identified the lowest NOAEL was used.

General population long-term DNEL inhalation	Local	Systemic
Step a: determination of dose-descriptor
Key study	HLR 45-91, no OECD Guideline	Labcorp 2022, OECD 408
Relevant dose descriptor	LOAEC = 9.2 mg/m^3for local irritant effects of the upper respiratory tract in rats	NOAEL = 50 mg/kg bw/day (systemic effects on male rats)
Step b: correct starting point		*
Differences in metabolic rate per b.w. (allometric scaling)	- (local effects)	4 (rat)
Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)	-       - (local effects)	-     2 (worst case assumption according to ECHA guidance R.8: 50% oral and 100% inhalation exposure)
Modification for exposure (experiment and human)	-       - (local irritant effects depending on concentration, only)	-      - (daily dose)
Modification for respiratory volume	-	X 70 kg bw / 20 m^3 respirator volume per 24 h
Correct starting point = relevant dose descriptor / overall factor for uncertainties	9.2 mg/m³	22 mg/m^3
Step c : assessment factors
Interspecies differences	2.5 (effects on respiratory tract)	2.5 (remaining differences
Intraspecies differences	10	10
Duration extrapolation (sub-acute/sub-chronic/chronic)	1 (no additional factor is required for exposure duration since the effect observed is not dependent on the time of exposure)	2 (subchronic to chronic)
Issues related to dose-response	3 (LOAEC)	1
Quality of whole database	1	1
Overall assessment factor	75	50
DNEL calculation	0.125 mg/m^3	0.44 mg/m^3

* Please note this is one of the ways shown in ECHA Guidance on information requirements and chemical safety assessment Chapter R.8, APPENDIX R. 8-2, Example R. 8-1 Workers (or Figure R. 8-3) for correction of the starting point. This is not the preferred way, but here differences from the local DNEL derivation can be pointed out. The preferred way (i.e. 50 mg/kg bw/day / 1.15 m³/kg bw * 50% / 100%) leads to the same numerical value.

Final conclusion:

The inhalation general population DNEL long-term calculated for local effects is 0.125 mg/m³ compared to 0.44 mg/m³ for systemic effects. The lower DNEL for local effects is considered to be protective also regarding systemic effects and taken forward for risk characterisation.

 

General population-DNEL long-term oral - systemic effects:

The DNEL long-term, oral exposure, systemic effects is derived from a toxicity study with oral exposure. The most sensitive NOAEL for this category was the NOAEL of 50 mg/kg bw/day identified in the Repeated Dose 90-day Oral Toxicity Study (OECD 408) with oral exposure to MPMD. In the high and mid dose groups (i.e. 500 mg/kg bw/d and 150 mg/kg bw/d, respectively) an adverse reduction of body weight gain was observed for male rats. Additionally observed non-adverse findings in these dose groups comprised adaptive responses by liver and kidney in both sexes. No mortality attributed to the test material treatment was observed during the study (highest dose tested 500 mg/kg bw/day).

DNEL derivation:

Basis NOAEL: 50 mg/kg bw/day from Repeated Dose 90-day Oral Toxicity Study (OECD 408; male rats)

As no specific values on oral absorption are available --> defaut assumption for oral absorption: 100%

Assessment factors:

• Interspecies differences:       4 (allometric scaling), 2.5 (remaining differences)


• Intraspecies differences:     10


• Differences in duration of exposure:           2 (sub-chronic to chronic)


• Issues related to dose-response:           1 (none)


• Quality of whole database:      1 (no deficiencies)

--> Overall assessment factor: 200

DNEL = 50 mg/kg bw/day / 200

DNEL = 0.25 mg/kg bw/day

 

General population-DNEL short-term oral - systemic effects:

An acute DNEL by oral route should be derived if an acute toxicity hazard has been identified AND if the exposure assessment has predicted high peaks (see Appendix R8.8 in Guidance on information requirements and chemical safety assessment Chapter R.8, version 2.1 of Nov 2012). Although classified as harmful if swallowed, no peak exposure is predicted for human exposed to MPMD via the environment. Therefore, no DNEL acute for oral route has been derived.