Registration Dossier

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.