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EC number: 203-149-1 | CAS number: 103-83-3
- 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
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- Endpoint summary
- Stability
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- 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
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- Sediment toxicity
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- 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:
- DNEL (Derived No Effect Level)
- Value:
- 4.9 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 75
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 370.3 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- No repeated dose inhalation study available
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 6
- Justification:
- Default value (ECHA) for sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- rat versus human According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 5
- Justification:
- Default value (ECHA) for workers
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 9.9 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.4 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):
- 300
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 420 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- No repeated dose dermal study available
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 6
- Justification:
- Default value (ECHA) for sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 5
- Justification:
- Default value (ECHA) for workers
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 2.8 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - workers
I. Introduction:
Harmonized classification – Annex VI of Regulation (EC) (No 1272/2008 (CLP Regulation)
Acute Tox. 4, H302: Harmful if swallowed , Acute Tox. 4, H312: Harmful in contact with skin, Acute Tox. 4 H332: Harmful if inhaled, Skin Corr. 1B H314: Causes severe skin burns and eye damage.
Self-classification: Acute Tox. 4, H302: Harmful if swallowed , Acute Tox. 4, H312: Harmful in contact with skin, Acute Tox. 3, H331: Toxic if inhaled, Skin Corr. 1B H314: Causes severe skin burns and eye damage.
Known occupational exposure limit(s):
SCOEL: no data, TRGS 900: no data, MAK: no data
Remarks/Limitations
No remarks/limitations
DNELs (worker)
II: Conclusion - worker (systemic and local effects):
Route of exposure Local effect Systemic effect
Dermal (long term) moderate hazard band 1.4mg/kg bw/day
Dermal (short term) moderate hazard band 2.8 mg/kg bw
Inhalation (long term) moderate hazard band 4.9 mg/m³ per day
Inhalation (short term) moderate hazard band 9.9 mg/m³
Hazard for eyes N,N-Dimethylbenzylamine is classified and labelled as Skin Corrosion Category 1B (H314: Causes severe skin burns and eye damage)
III. DNEL systemic (worker)
Basis for delineation of the DNELs systemic:
In a test according to OECD TG 407 and GLP groups of male and female Crl:CD(SD)BR rats received N,N-Dimethylbenzylamine in corn oil by daily oral gavage at nominal dose levels of 6, 30 or 150 mg/kg bw/day. A further group of the same size received corn oil alone and served as control. There were no major differences between control and treated rats. The high dose group males had slightly higher testis weights than the controls. However there was no histopathological correlate. Therefore this finding was considered not to be of toxicological relevance. The NOAEL was determined to be 150 mg/kg bw/day (BG Chemie 1988).
Study
Title:
N,N-Dimethylbenzylamine:28-day oral (gavage)sub-chronic toxicity study in the rat
Administration period:
28-day oral (gavage) sub-chronic toxicity study in the rat
Doses:
rat: 0 (control), 6, 30 or 150 mg/kg bw/day via gavage.
NOAEL
NOAEL = 150 mg/kg bw/day
Based on the following effects:
There were no major differences between control and treated rats. The high dose group males had slightly higher testis weights than the controls. However there was no histopathological correlate. Therefore this finding was considered not to be of toxicological relevance.
Reference
N,N-Dimethylbenzylamine:28-day oral (gavage)sub-chronic toxicity study in the rat
Report no.: 5667-624/3
Hazleton UK, Otley Road, Harrogate, North Yorkshire, England, HG3 1PY
At the request of BG-Chemie,
1988-05-24
Long-term toxicity – systemic effects (worker)
Long-term inhalation route – systemic effects (worker) using extrapolation factors:
NOAEL(oral) = 150 mg/kg bw/day
Correction of the starting point according ECHA Guidance Chapter R.8:
Corrected inhalatory NOAEC = Oral NOAEL (150 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1
=> NOAEC worker = 264.5 mg/m³
In the 28 day study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 is used.
=> NOAEC worker = 264.5 x 1.4 mg/m³ = 370.3 mg/m³
N,N-dimethylbenzylamine has a water solubility of 8000 mg/L (20°C) and a log Pow of 1.98 (25°C). Bioavailability after inhalation exposure in humans is 76%. No data are available for the oral route but similar bioavailability is assumed . No factor is used for route-to-route extrapolation and oral absorption is assumed to be similar to inhalation absorption.
Factors to be applied Justification
AF for dose response relationship 1
AF for differences in duration of exposure 6 Default value (ECHA) for subacute to chronic exposure
AF for interspecies differences1 rat versus human, According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
AF for intraspecies differences5 Default value (ECHA) for workers
AF for other interspecies differences2.5 Default value (ECHA).
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences 1
Worker DNEL long-term for inhalation route - systemic 4.9 mg/m³
Short-term toxicity (inhalation) – systemic effects (worker)
An exceeding factor of 2 is used.
Therefore:
Worker DNEL short-term for inhalation exposure: 9.9 mg/m³
Long-term dermal route systemic effects (worker)
NOAEL(dermal) = NOAEL(oral) x 2 = 300 mg/kg bw/day
In the 28 day study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 is used.
On the assumption that, in general, dermal absorption will be lower than oral absorption, a factor of 2 is applied to take also into account that the starting point for DNEL calculation is conservative since no effect level was observed in the oral 28 day study and the NOAEL taken for risk assessment is the highest dose tested.
=> NOAEL worker = 150 kg bw/day x 1.4 x 2 = 420 mg/kg bw/day
Factors to be applied Justification
AF for dose response relationship 1
AF for differences in duration of exposure 6 Default value (ECHA) for subacute to chronic exposure
AF for interspecies differences 4 Default value (ECHA) for rat versus human
AF for intraspecies differences: worker 5 Default value (ECHA) for workers
AF for other interspecies differences 2.5 Default value (ECHA) for workers
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences 1
Overall factor 300
Worker DNEL long-term for dermal route - systemic 1.4 mg/kg bw/day
Short-term toxicity (dermal) – systemic effects (worker)
An exceeding factor of 2 is used.
Therefore:
Worker DNEL short-term for dermal exposure: 2.8 mg/kg bw
Reproductive Toxicity – systemic effects
There is no 2-generation reproductive toxicity study available. However , there are subacute toxicity studies available using the oral exposure route in which also the reproductive organs were considered histopathologically. Male and female rats were given N,N-dimethylbenzylamine daily up to doses of 400 mg/kg bw/day (IUCLID section 7.5.1). No significant compound related effects on reproductive organs were reported.
According to OECD TG 414 and under GLP conditions pregnant female rats received orally 0, 35, 75 and 150 mg/kg bw/day by gavage on gestation day 5 -19. All females were terminated on gestation day 20 and cesarian section was performed to evaluate the developing organism.
At the highest dose of 150 mg/kg bw/day females gained markedly less body weight (by 41 % compared to control) and a reduction (-13 %) in overall food consumption. Fertility index and gestation index was calculated to be 100 % in all treated animals including control animals. Post mortem, no macroscopic abnormalities were observed. Thus, due to the reduced weight gain at 150 mg/kg bw/day the NOAEL (maternal toxicity) is considered 75 mg/kg bw/day.
No treatment related effects were detected in foetal viability (male and female), or in foetal weights (male and females), or in growth and development. Sex ratio was in the normal range. No treatment related effects were detected on fetal external findings.
No treatment-related effects were detected on skeletal development (including osseous and cartilaginous tissue) and none in the type and incidence of skeletal or visceral findings in fetuses from females treated with 150, 75 or 35 mg/kg bw/day.
A teratogenic effect of treatment was not evident up to and including the highest dose level (150 mg/kg bw/day)
Thus, the NOEL (No Adverse Effect Level) for reproductive and developmental toxicity is considered to be 150 mg/kg bw/day
Since no potential fertility effects are observed at 400 mg/kg bw/day and no teratogenic effects are observed at 150 mg/kg bw/day (in each study the highest applied dose), the DNEL (systemic) of 1.4 mg/kg bw/day (dermal) is regarded to be protective for potential fertility and teratogenic effects.
IV. DNEL local (worker)
Basis for delineation of the DNELs local (long and short term toxicity):
Irritation/corrosion
SKIN IRRITATION/CORROSION
N,N-dimethylbenzylamine was applied to the skin of rabbits to evaluate the irritant potency the test was performed according to OECD TG 404 and resulted in severe erythema score 4 of (max) 4 including black areas, crusts, edema, slight to severe indurations. According to these severe skin reactions observed (deep red to black injuries) the animals were kept only for an observation period of 24 hours they were killed due to ethical reason after this period (BG Chemie 1987).
EYE IRRITATION
Groups of 5 rabbits received N,N-dimethylbenzylamine into the conjunctival sac of one eye of each rabbit (second eye served as control) and were observed up to 7 days post dosing: (1) 0.005 ml of undiluted test material resulting in severe corneal opacity and iritis and marked chemosis but eyes recovered by 7 days, (2) 0.5 ml of a 5% test material solution in propylene glycol resulting in moderate to severe corneal injury and iritis and chemosis; the eyes of 4/5 rabbits recovered within 10 days. One rabbit exhibited corneal injury, with vascularization, and conjunctival irritation after 10 days. (3) 0.5 ml of a 1% test material solution in propylene glycol which caused no reactions in the eyes during the observation period. Overall, N,N-dimethylbenzylamine was evaluated as a severe irritant (Ballantyne 1985).
According to Regulation (EC) 1272/2008 (CLP/GHS) N,N-dimethylbenzylamine is already classified and labelled: for Skin Corrosion Category 1B (H314).
RESPIRATORY IRRITATION/CORROSION
In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.
In an approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements it was shown that the OEL for irritating substances is not lower than 10 mg/m³ and for corrosives not lower than 1 mg/m³ (Messinger H, Regulatory Toxicology and Pharmacology 68 (2014) 317–324)
N,N-dimethylbenzylamine is corrosive and labelled accordingly.
Thus, a DNEL long-term, inhalation route for local effects of 1 mg/m³ is proposed.
Sensitization
In a Guinea Pig Maximization Test according to OECD TG 400 (Magnusson and Klingman) male guinea pigs were tested with following concentrations of the test substance:
1st application: Induction 2.5 % intracutaneous
2nd application: Induction 12 % occlusive epicutaneous
3rd application: Challenge 6 % and 3% occlusive epicutaneous
The test substance was formulated as an emulsion with Cremophor EL in sterile physiological saline solution (2% V/V).
No skin reddening was observed after the provocation with 6% and 3% of test substance neither in the test animals nor in the control animals. The test substance therefore shows no skin sensitisation potential (Bayer AG 1993).
Conclusion on local DNEL:
For local effects the derivation of a long-term DNEL for dermal toxicity is not appropriate due to the skin corrosion.
Based on the classification as Skin Corr. Cat 1B; H314, N,N-dimethylbenzylamine should be allocated to the moderate hazard band.
Overall, the allocation of N,N-dimethylbenzylamine to the moderate hazard band is justified for local dermal and inhalation effects.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.87 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 150
- Modified dose descriptor starting point:
- NOAEC
- Value:
- 130.4 mg/m³
- Explanation for the modification of the dose descriptor starting point:
- No repeated dose inhalation study available
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 6
- Justification:
- Default value (ECHA) for sub-acute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1.74 mg/m³
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- irritation (respiratory tract)
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.5 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):
- 600
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 300 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
- No repeated dose dermal study available
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 6
- Justification:
- Default value (ECHA) for subacute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 1 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
Local effects
Long term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
Acute/short term exposure
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
- Most sensitive endpoint:
- skin irritation/corrosion
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
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
- Overall assessment factor (AF):
- 600
- Modified dose descriptor starting point:
- NOAEL
- Value:
- 150 mg/kg bw/day
- AF for dose response relationship:
- 1
- AF for differences in duration of exposure:
- 6
- Justification:
- Default value (ECHA) for subacute to chronic exposure
- AF for interspecies differences (allometric scaling):
- 4
- Justification:
- Default value (ECHA) for rat versus human
- AF for other interspecies differences:
- 2.5
- Justification:
- Default value (ECHA)
- AF for intraspecies differences:
- 10
- Justification:
- Default value (ECHA) for general population
- AF for the quality of the whole database:
- 1
- Justification:
- There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
- AF for remaining uncertainties:
- 1
Acute/short term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 0.5 mg/kg bw/day
- Most sensitive endpoint:
- repeated dose toxicity
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- DNEL extrapolated from long term DNEL
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
DNELs (general population)
V: Conclusion - general population (systemic and local effects):
Route of exposure Local effect Systemic effect
Oral (long term) not required 0.25 mg/kg bw/day
Oral (short term) not required 0. 5 mg/kg bw
Dermal (long term) moderate hazard band 0. 5 mg/kg bw/day
Dermal (short term) moderate hazard band 1.0 mg/kg bw
Inhalation (long term) moderate hazard band 0.87 mg/m³ per day
Inhalation (short term) moderate hazard band 1.74 mg/m³
Hazard for eyes N,N-dimethylbenzylamine is classified and labelled as Skin Corrosion Category 1B (H314: Causes severe skin burns and eye damage)
VI. DNEL systemic (general population)
Basis for delineation of the DNELs systemic:
In a test according to OECD TG 407 and GLP groups of male and female Crl:CD(SD)BR rats received N,N-dimethylbenzylamine in corn oil by daily oral gavage at nominal dose levels of 6, 30 or 150 mg/kg bw/day. A further group of the same size received corn oil alone and served as control. There were no major differences between control and treated rats. The high dose group males had slightly higher testis weights than the controls. However there was no histopathological correlate. Therefore this finding was considered not to be of toxicological relevance. The NOAEL was determined to be 150 mg/kg bw/day (BG Chemie 1988).
Long-term toxicity – systemic effects (general population)
Long-term inhalation route – systemic effects (general population) using extrapolation factors:
NOAEL(oral) = 150 mg/kg bw/day
Correction of the starting point according ECHA Guidance Chapter R.8:
Corrected inhalatory NOAEC = Oral NOAEL (150 mg/kg) x 1/1.15 m³/kg x 1.0
=> NOAEC general population = 130.43 mg/m³
N,N-dimethylbenzylamine has a water solubility of 8000 mg/L (20°C) and a log Pow of 1.98 (25°C). Bioavailability after inhalation exposure in humans is 76%. No data are available for the oral route but similar bioavailability is assumed . No factor is used for route-to-route extrapolation and oral absorption is assumed to be similar to inhalation absorption.
Factors to be applied Justification
AF for dose response relationship
AF for differences in duration of exposure 6 Default value (ECHA) for subacute to chronic exposure
AF for interspecies differences 1 rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
AF for intraspecies differences 10 Default value (ECHA) for general population
AF for other interspecies differences 2.5 Default value (ECHA).
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences 1
Overall factor 150
General population DNEL long-term for inhalation route - systemic: 0.87 mg/m³
Short-term toxicity (inhalation) – systemic effects (general population)
An exceeding factor of 2 is used.
Therefore:
General population DNEL short-term for inhalation exposure: 1.74 mg/m³
Long-term oral route systemic effects (general population)
NOAEL(oral) = 150 mg/kg bw/day
Factors to be applied Justification
AF for dose response relationship 1
AF for differences in duration of exposure 6 Default value (ECHA) for subacute to chronic exposure
AF for interspecies differences 4 Default value (ECHA) for rat versus human
AF for intraspecies differences 10 Default value (ECHA) for general population
AF for other interspecies differences 2.5 Default value (ECHA)
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences 1
Overall factor 600
General population DNEL long term for oral and dermal route - systemic: 0.25 mg/kg bw/day
Short-term toxicity (oral) – systemic effects (general population)
An exceeding factor of 2 is used.
Therefore:
General population DNEL short-term for oral exposure: 0.5 mg/kg bw
Long-term dermal route systemic effects (general population)
NOAEL(dermal) = NOAEL(oral) x 2 = 300 mg/kg bw/day
On the assumption that, in general, dermal absorption will be lower than oral absorption, a factor of 2 is applied to take also into account that the starting point for DNEL calculation is conservative since no effect level was observed in the oral 28 day study and the NOAEL taken for risk assessment is the highest dose tested.
Factors to be applied Justification
AF for dose response relationship 1
AF for differences in duration of exposure 6 Default value (ECHA) for subacute to chronic exposure
AF for interspecies differences 4 Default value (ECHA) for rat versus human
AF for intraspecies differences 10 Default value (ECHA) for general population
AF for other interspecies differences 2.5 Default value (ECHA)
AF for quality of the whole database 1 There is information available to cover all relevant toxicological endpoints. The available studies are performed according to guideline and GLP.
AF for remaining differences 1
Overall factor 600
General population DNEL long term for oral and dermal route - systemic: 0.5 mg/kg bw/day
Short-term toxicity (dermal) – systemic effects (general population)
An exceeding factor of 2 is used.
Therefore:
General population DNEL short-term for dermal exposure: 1.0 mg/kg bw
Reproductive Toxicity – systemic effects (general population)
There is no 2-generation reproductive toxicity study available.
However , there are subacute toxicity studies available using the oral exposure route in which also the reproductive organs were considered histopathologically. Male and female rats were given N,N-dimethylbenzylamine daily up to doses of 400 mg/kg bw/day. No significant compound related effects on reproductive organs were reported.
According to OECD TG 414 and under GLP conditions pregnant female rats received orally 0, 35, 75 and 150 mg/kg bw/day by gavage on gestation day 5 -19. All females were terminated on gestation day 20 and cesarian section was performed to evaluate the developing organism.
At the highest dose of 150 mg/kg bw/day females gained markedly less body weight (by 41 % compared to control) and a reduction (-13 %) in overall food consumption. Fertility index and gestation index was calculated to be 100 % in all treated animals including control animals. Post mortem, no macroscopic abnormalities were observed. Thus, due to the reduced weight gain at 150 mg/kg bw/day the NOAEL (maternal toxicity) is considered 75 mg/kg bw/day.
No treatment related effects were detected in foetal viability (male and female), or in foetal weights (male and females), or in growth and development. Sex ratio was in the normal range. No treatment related effects were detected on fetal external findings.
No treatment-related effects were detected on skeletal development (including osseous and cartilaginous tissue) and none in the type and incidence of skeletal or visceral findings in fetuses from females treated with 150, 75 or 35 mg/kg bw/day.
A teratogenic effect of treatment was not evident up to and including the highest dose level (150 mg/kg bw/day)
Thus, the NOEL (No Adverse Effect Level) for reproductive and developmental toxicity isconsidered to be 150 mg/kg bw/day
Since no potential fertility effects are observed at 400 mg/kg bw/day and no teratogenic effects are observed at 150 mg/kg bw/day (in each study the highest applied dose), the DNEL (systemic) of 0.25 mg/kg bw/day (oral) and 0.5 mg/kg bw/day (dermal) is regarded to be protective for potential fertility and teratogenic effects.
VII. DNEL local (general population)
Basis for delineation of the DNELs local (long and short term toxicity):
Irritation/corrosion
SKIN IRRITATION/CORROSION
N,N-dimethylbenzylamine was applied to the skin of rabbits to evaluate the irritant potency the test was performed according to OECD TG 404 and resulted in severe erythema score 4 of (max) 4 including black areas, crusts, edema, slight to severe indurations. According to these severe skin reactions observed (deep red to black injuries) the animals were kept only for an observation period of 24 hours they were killed due to ethical reason after this period (BG Chemie 1987).
EYE IRRITATION
Groups of 5 rabbits received N,N-dimethylbenzylamine into the conjunctival sac of one eye of each rabbit (second eye served as control) and were observed up to 7 days post dosing: (1) 0.005 ml of undiluted test material resulting in severe corneal opacity and iritis and marked chemosis but eyes recovered by 7 days, (2) 0.5 ml of a 5% test material solution in propylene glycol resulting in moderate to severe corneal injury and iritis and chemosis; the eyes of 4/5 rabbits recovered within 10 days. One rabbit exhibited corneal injury, with vascularization, and conjunctival irritation after 10 days. (3) 0.5 ml of a 1% test material solution in propylene glycol which caused no reactions in the eyes during the observation period. Overall, N,N-dimethylbenzylamine was evaluated as a severe irritant (Ballantyne 1985).
According to Regulation (EC) 1272/2008 (CLP/GHS) N,N-dimethylbenzylamine is already classified and labelled: for Skin Corrosion Category 1B (H314)
RESPIRATORY IRRITATION/CORROSION
In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.
In an approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements it was shown that the OEL for irritating substances is not lower than 10 mg/m³ and for corrosives not lower than 1 mg/m³ (Messinger H, Regulatory Toxicology and Pharmacology 68 (2014) 317–324)
N,N-dimethylbenzylamine is corrosive and labelled accordingly.
Thus, a DNEL long-term, inhalation route for local effects of 1 mg/m³ is proposed.
Sensitization
In a Guinea Pig Maximization Test according to OECD TG 400 (Magnusson and Klingman) male guinea pigs were tested with following concentrations of the test substance:
1st application: Induction 2.5 % intracutaneous
2nd application: Induction 12 % occlusive epicutaneous
3rd application: Challenge 6 % and 3% occlusive epicutaneous
The test substance was formulated as an emulsion with Cremophor EL in sterile physiological saline solution (2% V/V).
No skin reddening was observed after the provocation with 6% and 3% of test substance neither in the test animals nor in the control animals. The test substance therefore shows no skin sensitisation potential (Bayer AG 1993).
Conclusion on local DNEL:
For local effects the derivation of a long-term DNEL for dermal toxicity is not appropriate due to the skin corrosion.
Based on the classification as Skin Corr. Cat 1B; H314, N,N-Dimethylbenzylamine should be allocated to the moderate hazard band.
Overall, the allocation of N,N-dimethylbenzylamine to the moderate hazard band is justified for local dermal and inhalation effects.
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.
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