Hexamethylenediamine

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:

0.54 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor:

other: corrected dose descriptor (after considering differences in respiratory volumes: 6.7 vesus 10 mg/m3)

Value:

6.75 mg/m³

AF for dose response relationship:

1

Justification:

NOAEC

AF for differences in duration of exposure:

1

Justification:

similar irritative effects were observed after subacute and subchronic effects

AF for interspecies differences (allometric scaling):

1

Justification:

inhalation concentration

AF for other interspecies differences:

2.5

Justification:

R.8

AF for intraspecies differences:

5

Justification:

R.8

AF for the quality of the whole database:

1

Justification:

good quality database

AF for remaining uncertainties:

1

Justification:

none observed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.62 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3

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:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

1. Introduction:

In this chapter, all the endpoints from Hexamethylenediamine (HMD) are re-examined and analyzed in order to establish a DNEL (s)/DMEL (s) for each one of them if possible. The followed method is that proposed in the guidance for the implementation of REACH (Chapter R.8: Characterisation of dose (concentration)-response for human health).

 

2. Classification in the Annex VI of CLP Regulation (1272/2008)

Hexamethylenediamine is classified in the Annex VI of CLP Regulation (1272/2008) (Tables 3.1 and 3.2) as:

- Harmful if swallowed (H302), Category 4

- Harmful in contact with skin (H312), Category 4

- Corrosive to skin (H314), Category 1B

- Irritating to respiratory system (H335), STOT SE3

No other self-classification is proposed

 

3. DNELs/DMELs derivation according to the toxicological profile of HMD

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

Neither indications of systemic toxicity nor evidence of a reprotoxic potential were observed in rats and mice. Systemic toxicity observed in rabbits were observed in an OECD 414 study. 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 HMD in vitro and in vivo provided no evidence of mutagenic or genotoxic activity.

 

3.1 DNEL for acute exposure - local effects:

 

3.1.1 Inhalation route:

 

Only one study is reported for this endpoint, LC50 inhalation (4h)/rat > 0.95 mg/L air (Kr: 3, Goode, 1976), (see the specific end-point). This study shall not be used for DNEL derivation, due to the limitation of the data. Moreover, Industrial Biotest Laboratory was found to use fraudulent practices in some of their studies and reports (Good laboratory practice regulations, Sandy Weinberg, 2003, ed. 3, p. 4). Since these studies were performed before the implementation of Good Laboratory Practices, it is not possible to verify the scientific credibility of most of these studies.

 

HMD is classified as corrosive and irritating to respiratory system (see repeated dose toxicity endpoint summary), therefore the waiving for this endpoint is justified. Effects from repeated concentrations in rats and mice exposed to HMD by inhalation are limited to effects on the upper respiratory tract caused by important local irritation in the nasal passages and the larynx.

Therefore, the acute inhalation DNEL for local effects can be extrapolated from the long-term inhalation DNEL for local effects (0.54 mg/m³) by multiplying by a default factor of 3 considering that the observed adverse effects are mainly driven by the exposure concentration to HMD considering its corrosive properties.

Hence, the DNEL acute for local effects can be set based on the long-term inhalation DNEL (Chapter R.8, Box 6, p112).

 

The inhalation DNEL_acutefor local effects in the worker = 1.62 mg/m³ ( 0.34 ppm) in the worker

 

3.1.2 Dermal route

 

HMD 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).

 

3.2 DNEL for long-term exposure - local effects:

 

3.2.1 Inhalation route:

 

The concentration descriptor has been obtained from the repeated dose toxicity study by inhalation (OECD 413; see 7.5.3).

Effects from repeated exposure in rats and mice exposed to HMD by inhalation are limited to effects on the respiratory tract caused by local irritation (larynx and nasal passages). In the 13 week studies, the NOAEC for respiratory local damage was 10 mg/m³ for rats (Kr: 2, Hébert, 1993) and mice (Kr: 2, Hébert, 1993), (see the specific end- point).

 

The following Table indicates the inhalation DNEL-long term for local effects calculation.

 

 

 

Workers long-term DNEL inhalation	Local	Systemic
Step a: determination of dose-descriptor
Key study	NTP, 1993, OECD 413, K2	CiToxLab 2017, OECD 414
Relevant dose descriptor	NOAEC = 10 mg/m^3for local irritant effects of the upper respiratory tract in rats (similar effects in the mice/same NOAEC)	NOAEL = 25 mg/kg bw/day (systemic toxicity in female pregnant rabbits)
Step b: correct starting point
Differences in metabolic rate per b.w. (allometric scaling)	- (local effects)	2.4
Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)	-         (local effects)	-         (full absorption via oral and inhalation exposure, see Toxicokinetics)
Modification for exposure (experiment and human)	-         (local irritant effects depending on concentration, only)	-         (daily dose)
Modification for respiratory volume	6.7 / 10 (difference respiratory rates under standard conditions and under conditions of light activity for 8 hours)	X 70 kg bw / 10 m^3 respirator volume per work shift
Correct starting point = relevant dose descriptor / overall factor for uncertainties	6.75 mg/m3	72.92 mg/m^3
Step c : assessment factors
Interspecies differences	2.5 (effects on respiratory tract)	1 (data on three species available, rabbits more sensitive than rats or mice)
Intraspecies differences	5	5
Duration extrapolation (sub-acute/sub-chronic/chronic)	1 (similar respiratory irritant effects were observed after 14 day exposure in both mice and rats)	6 (subacute to chronic
Issues related to dose-response	1	1
Quality of whole database	1	1
Overall assessment factor	12.5	30
DNEL calculation	0.54 mg/m^3= 0.11 ppm	2.43 mg/m^3= 0.50 ppm
	1 mg/m^3= 24.05 / 116 ppm at 20°C

 

The inhalation workers DNEL long-term calculated for local effects is 0.54 mg/m3 compared to 2.43 mg/m³for systemic effects. The lower DNEL for local effects is considered to be protective also regarding systemic effects and taken forward for risk characterisation.

 

The inhalation DNEL long-term for local effects is 0.54 mg/m³ in the worker.

 

3.2.2 Dermal route

 

No repeated toxicity study conducted by dermal route was available. However, the waiving is justified considering animal welfare since HMD is classified as corrosive, category 1B (H314) in the Annex VI of the CLP regulation (1272/2008).

Regarding this local effects potential, it is necessary to be considered in the selection of the respective risk management tools at the workplaces.

 

4. Conclusion:

 

The threshold limit value TLV-TWA: 2.3 mg/m³ (0.5 ppm) is recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2003). This value was set based on the repeated dose toxicity by inhalation of:

- Ben-Dyke study (1981) identifying a NOEC = 12.8 mg/m³ in the rats (2.7 ppm)

- NTP (1993) identifying a NOEC = 5 mg/m³ in the mice (1.1 ppm)

Hence, the assessment factor applicated to derive the TLV-TWA was 5.4 from the value in the rats and 2.2 from the value in the mice. No explanation was indicated to justify these assessment factors.

 

However, the global evaluation of the REACH dossier showed that the reliable descriptor concentration was the NOAEC (10 mg/m3) identified in the NTP report (1993) for the study perfomed in the rats considered as a worst case. Hence, the inhalation DNEL long-term for local effects is 0.54 mg/m³ (0.11 ppm) in the worker.

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:

0.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor:

NOAEC

Value:

10 mg/m³

AF for dose response relationship:

1

Justification:

NOAEC used

AF for differences in duration of exposure:

1

Justification:

local irritating effect, similar effects were observed after 14 days and 90 days of exposure in both mice and rats

AF for interspecies differences (allometric scaling):

1

Justification:

air concentration

AF for other interspecies differences:

2.5

Justification:

R.8

AF for intraspecies differences:

10

Justification:

R.8

AF for the quality of the whole database:

1

Justification:

good database

AF for remaining uncertainties:

1

Justification:

none observed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.17 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):

144

Dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

25 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

subacute exposure (OECD 414 study, dams exposed for 22 days)

AF for interspecies differences (allometric scaling):

2.4

Justification:

rabbit scaling factor, R.8

AF for other interspecies differences:

1

Justification:

experimental data from 3 species, rabbit by far the most senstive

AF for intraspecies differences:

10

Justification:

R.8

AF for the quality of the whole database:

1

Justification:

good database

AF for remaining uncertainties:

1

Justification:

none observed

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

1. Introduction:

In this chapter, all the endpoints from Hexamethylenediamine (HMD) are re-examined and analyzed in order to establish a DNEL (s)/DMEL (s) for each one of them if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health).

 

2. Classification in the Annex VI of CLP Regulation (1272/2008)

Hexamethylenediamine is classified in the Annex VI of CLP Regulation (1272/2008) (Tables 3.1 and 3.2) as:

- Harmful if swallowed (H302), Category 4

- Harmful in contact with skin (H312), Category 4

- Corrosive to skin (H314), Category 1B

- Irritating to respiratory system (H335), STOT SE3

 

No other self-classification is proposed.

 

3. DNELs/DMELs derivation according to the toxicological profile of HMD

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

 

3.1 DNEL for acute exposure - general population - local effects:

3.1.1 Inhalation route:

Only one study is reported for this endpoint, LC50 inhalation (4h)/rat > 0.95 mg/L air (Kr: 3, Goode, 1976), (see the specific end-point). This study shall not be used for DNEL derivation, due to the limitation of the data. Moreover, Industrial Biotest Laboratory was found to use fraudulent practices in some of their studies and reports (Good laboratory practice regulations, Sandy Weinberg, 2003, ed. 3, p. 4). Since these studies were performed before the implementation of Good Laboratory Practices, it is not possible to verify the scientific credibility of most of these studies.

 

HMD is classified as corrosive and irritating to respiratory system (see repeated dose toxicity endpoint summary); therefore the waiving for this endpoint is justified. Effects from repeated concentrations in rats and mice exposed to HMD by inhalation are limited to effects on the upper respiratory tract caused by important local irritation in the nasal passages and the larynx.

Therefore, the acute inhalation DNEL for local effects can be extrapolated from the long-term inhalation DNEL for local effects (0.4 mg/m³) by multiplying by a default factor of 3 considering that the observed adverse effects are mainly driven by the exposure concentration to HMD considering its corrosive properties.

Hence, the DNEL acute for local effects can be set based on the long-term inhalation DNEL (Chapter R.8).

The inhalation DNEL_acutefor local effects in humans (general population) is 1.2 mg/m³(0.25 ppm)

 

3.1.2 Dermal route

Indirect exposure of humans via the environment is very unlikely, and therefore dermal exposure will not be handled (see R.16.5.8).

 

3.1.3 Oral route

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). Although classified as harmful if swallowed, no peak exposure is predicted for human exposed to HMD via the environment. Therefore no DNEL_acutefor oral route has been derived.

 

3.2 DNEL for long-term exposure - general population:

3.2.1 Inhalation route:

Local effects were only observed in repeated inhalation dose toxicity studies. Therefore a DNEL was not derived for long-term systemic effects.

The concentration descriptor has been obtained from the repeated dose toxicity study by inhalation (OECD 413; see 7.5.3).

Effects from repeated exposure in rats and mice exposed to HMD by inhalation are limited to effects on the respiratory tract caused by local irritation (larynx and nasal passages). In the 13 week studies, the NOAEC for respiratory local damage was 10 mg/m³ for rats (Kr: 2, Hébert, 1993) and mice (Kr: 2, Hébert, 1993) (see the specific end- point).

 

The following Table indicates the inhalation DNEL-long term for local effects calculation.

 

 

 

General population long-term DNEL inhalation	Local	Systemic
Step a: determination of dose-descriptor
Key study	NTP, 1993, OECD 413, K2	CiToxLab 2017, OECD 414
Relevant dose descriptor	NOAEC = 10 mg/m^3for local irritant effects of the upper respiratory tract in rats (similar effects in the mice/same NOAEC)	NOAEL = 25 mg/kg bw/day (systemic toxicity in female pregnant rabbits)
Step b: correct starting point
Differences in metabolic rate per b.w. (allometric scaling)	- (local effects)	2.4
Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)	-         (local effects)	-         (full absorption via oral and inhalation exposure, see Toxicokinetics
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 respiratory volume per day
Correct starting point = relevant dose descriptor / overall factor for uncertainties	10 mg/m3	36.46 mg/m^3
Step c : assessment factors
Interspecies differences	2.5 (effects on respiratory tract)	1 (data on three species available, rabbits more sensitive than rats or mice)
Intraspecies differences	10	10
Duration extrapolation (sub-acute/sub-chronic/chronic)	1 (similar respiratory irritant effects were observed after 14 day exposure in both mice and rats)	6 (subacute to chronic
Issues related to dose-response	1	1
Quality of whole database	1	1
Overall assessment factor	25	60
DNEL calculation	0.4 mg/m^3= 0.08 ppm	0.61 mg/m^3= 0.13 ppm
	1 mg/m^3= 24.05 / 116 ppm at 20°C

The general population inhalation DNEL long-term calculated for local effects is 0.4 mg/m3 compared to 0.61 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.

 

The inhalation DNEL long-term for the general population for local effects is 0.4 mg/m³.

 

3.2.2 Dermal route

Indirect exposure of humans via the environment is very unlikely, and therefore dermal exposure will not be handled (see R.16.5.8).

 

3.2.3 Oral route

The dose descriptor has been obtained from the prenatal developmental toxicity study in rats (see 7.8.2).

Under the test conditions, toxicity in female pregnant rabbits was observed at 50 mg/kg bw/day and no effects were observed at oral HMD doses of 25 mg/kg bw./day (CiToxLab 2017)

The following Table indicates the derivation of the oral DNEL-long term for systemic effects.

 

General population long-term DNEL oral	Systemic
Step a: determination of dose-descriptor
Key study	CiToxLab 2017, OECD 414
Relevant dose descriptor	NOAEL = 25 mg/kg bw/day (systemic toxicity in female pregnant rabbits)
Step b: correct starting point
Differences in metabolic rate per b.w. (allometric scaling)	2.4
Correct starting point = relevant dose descriptor / overall factor for uncertainties	10.42 mg/kg bw/day
Step c : assessment factors
Interspecies differences	1 (data on three species available, rabbits more sensitive than rats or rabbits)
Intraspecies differences	10
Duration extrapolation (sub-acute/sub-chronic/chronic)	6 (subacute to chronic)
Issues related to dose-response	1
Quality of whole database	1
Overall assessment factor	60
DNEL calculation	0.17 mg/kg bw/day

 

 

The oral DNEL long-term for the general population is 0.17 mg/kg bw/day