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EC number: 204-679-6 | CAS number: 124-09-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
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 DNELacutefor 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/m3for 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 m3 respirator volume per work shift |
Correct starting point = relevant dose descriptor / overall factor for uncertainties |
6.75 mg/m3 |
72.92 mg/m3 |
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/m3= 0.11 ppm |
2.43 mg/m3= 0.50 ppm |
|
1 mg/m3= 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 DNELacutefor 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 DNELacutefor 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/m3for 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 m3 respiratory volume per day |
Correct starting point = relevant dose descriptor / overall factor for uncertainties |
10 mg/m3 |
36.46 mg/m3 |
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/m3= 0.08 ppm |
0.61 mg/m3= 0.13 ppm |
|
1 mg/m3= 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
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.