Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

185.1 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:

2

Justification:

Default value (ECHA) for sub-chronic 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

210 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:

2

Justification:

Default value (ECHA) for sub-chronic 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

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 2.1mg/kg bw/day

Dermal (short term) moderate hazard band 4.2 mg/kg bw

Inhalation (long term) moderate hazard band 7.4 mg/m³ per day

Inhalation (short term) moderate hazard band 14.8 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:

Subacute study:

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

Subchronic study:

In a test according to OECD TG 408 and GLP groups of male and female Han Wistar rats received N,N-Dimethylbenzylamine in 1% Carboxymethyl cellulose + 0.1% Tween 80 by daily oral gavage for at least 90 days at 75 and 150 and mg/kg/day and for 52 days at 250 mg/kg/day. A further group received the vehicle alone and served as control. At 250 mg/kg/day there was test material-related mortality, which was regarded adverse. In the remaining animals, adverse clinical signs of generalized tremors were observed. At 150 mg/kg/day, there was one spontaneous dead male of which a test material-related cause of death could not be excluded. In addition, adverse clinical signs of generalized tremors were observed in males and females. From the results presented in this report a No Observed Adverse Effect Level (NOAEL) for N,N-Dimethylbenzylamine of 75 mg/kg/day was established (Charles River, 2023).

Study

Title:

A 90-day study on N,N-Dimethylbenzylamine by Oral gavage in Wistar Han Rats.

Administration period:

90-day (52-day) oral (gavage) sub-chronic toxicity study in the rat

Doses:

rat: 0 (control), 75, 150 or 250 mg/kg bw/day via gavage.

NOAEL

NOAEL = 75 mg/kg bw/day

Reference

A 90-day study on N,N-Dimethylbenzylamine by Oral gavage in Wistar Han Rats.

Study No. 20342599

Charles River Laboratories Den Bosch BV, Hambakenwetering 7, 5231 DD ‘s-Hertogenbosch, The Netherlands

2023

The study with the longest duration has been selected as the starting point for DNEL derivation.

Long-term toxicity – systemic effects (worker)

Long-term inhalation route – systemic effects (worker) using extrapolation factors:

Starting point : NOAEL(oral) = 75 mg/kg bw/day

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalatory NOAEC = Oral NOAEL (75 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1

=> NOAEC worker = 132,2.5 mg/m³

In the 90 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 = x 1.4 mg/m³ =185,1 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 2 Default value (ECHA) for subchronic 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

Overall factor 25

Worker DNEL long-term for inhalation route - systemic 7.4 mg/m³

Short-term toxicity (inhalation) – systemic effects (worker)

An exceeding factor of 2 is used.

Therefore:

Worker DNEL short-term for inhalation exposure: 14,8 mg/m³

Long-term dermal route systemic effects (worker)

Starting point : NOAEL(oral) = 75 mg/kg bw/day

In the oral 90 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 90 day study and the NOAEL taken for risk assessment is the highest dose tested.

=> NOAEL worker = 75 kg bw/day x 1.4 x 2 = 210 mg/kg bw/day

Factors to be applied Justification

AF for dose response relationship 1

AF for differences in duration of exposure 2 Default value (ECHA) for subchronic 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 100

Worker DNEL long-term for dermal route - systemic 2.1 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: 4.2 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.

Pre-natal / developmental toxicity study in rats:

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.

Pre-natal / developmental toxicity study in rabbits:

In a developmental toxicity study, N-N-Dimethylbenzylamine was administered to 22 New Zealand White female rabbits per dose by gavage at dose levels of 0, 50, 100 and 200 mg/kg bw/day from days 7 through 28 of gestation, inclusive.

In total, three females did not survive until scheduled necropsy.
One female at 200 mg/kg bw/day was sacrificed in extremis for humane reasons on Day 18 post‑coitum based on prolonged (nearly) absent food consumption. The other two deaths occurred in the 100 mg/kg bw/day group and were considered related to the gavage procedure.

At 100 mg/kg bw/day, body weight loss was noted over Days 7-9 post-coitum and lower food consumption was observed over Days 7-21 post-coitum. Both findings were considered non-adverse at this dose level.

At 200 mg/kg bw/day, increased respiratory rate and slight tremors were noted in one female each on a single day towards the end of the treatment period. Based on similar data from a previous dose range finder study (Test Facility No. 20342602), this was considered test material-related but in the context of the current study non-adverse. Furthermore, non-adverse body weight loss over Days 7-15 post-coitum and non-adverse lower gravid uterus adjusted body weight gain were noted. The test material related lower food consumption was noted during the entire dosing period, with most prominent difference over Days 12-15 post-coitum was considered adverse at this dose level. In several females at 200 mg/kg bw/day, macroscopic and microscopic findings in the stomach were observed. These included red foci or depressed foci in the pyloric region, partially correlated to minimal mucosal haemorrhages or minimal to mild mucosal erosions microscopically, and minimal dilatation of the gastric glands in the cardiac region. Given the low incidence and severity these findings, they were considered to be non-adverse.

No test material-related changes were noted in any of the remaining maternal parameters investigated in this study (i.e., corpora lutea, uterine contents including implantation sites and pre- and post-implantation loss).

At 200 mg/kg bw/day, fetal weights (male, female and combined) were lower. This change was considered adverse. Secondary to the lower fetal weights, a non-adverse increased incidence of unossified hindpaw phalanges was observed at 200 mg/kg bw/day.

No test material-related changes were noted in any of the remaining developmental parameters investigated in this study (i.e., litter size, sex ratio, external and visceral variations and malformations, and skeletal malformations).

In conclusion, based on the results of this prenatal developmental toxicity study in time‑mated female New Zealand White rabbits, the following maternal and developmental No Observed Adverse Effect Levels (NOAELs) for N,N-Dimethylbenzylamine were established:

Maternal NOAEL:	100 mg/kg bw/day (based on mortality and low food consumption at 200 mg/kg bw/day).
Developmental NOAEL:	100 mg/kg bw/day (based on lower fetal weights at 200 mg/kg bw/day).

Note: It should be noted that developmental effects (lower fetal weight) in this study were observed at a maternal toxic dose.

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 rats and 100 mg/kg bw/day in rabbits, the DNELs (systemic) of 7.4 mg/m3 (inhalation) and 2.1 mg/kg bw/day (dermal) are 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.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

65.22 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:

2

Justification:

Default value (ECHA) for sub-chronic 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 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:

2

Justification:

Default value (ECHA) for synchronic 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

75 mg/kg bw/day

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

Justification:

Default value (ECHA) for subchronic 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

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.8 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNELs (general population)

V.: Conclusion - general population (systemic and local effects):

Route of exposure Local effect Systemic effect

Oral (long term) not required 0.4 mg/kg bw/day

Oral (short term) not required 0. 8 mg/kg bw

Dermal (long term) moderate hazard band 0. 8 mg/kg bw/day

Dermal (short term) moderate hazard band 1.5 mg/kg bw

Inhalation (long term) moderate hazard band 1.3 mg/m³ per day

Inhalation (short term) moderate hazard band 2.6 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:

Subacute study:

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).

Subchronic study:

In a test according to OECD TG 408 and GLP groups of male and female Han Wistar rats received N,N-Dimethylbenzylamine in 1% Carboxymethyl cellulose + 0.1% Tween 80 by daily oral gavage for at least 90 days at 75 and 150 and mg/kg/day and for 52 days at 250 mg/kg/day. A further group received the vehicle alone and served as control. At 250 mg/kg/day there was test material-related mortality, which was regarded adverse. In the remaining animals, adverse clinical signs of generalized tremors were observed. At 150 mg/kg/day, there was one spontaneous dead male of which a test material-related cause of death could not be excluded. In addition, adverse clinical signs of generalized tremors were observed in males and females. From the results presented in this report a No Observed Adverse Effect Level (NOAEL) for N,N-Dimethylbenzylamine of 75 mg/kg/day was established (Charles River, 2023).

Long-term toxicity – systemic effects (general population)

Long-term inhalation route – systemic effects (general population) using extrapolation factors:

NOAEL(oral) = 75 mg/kg bw/day

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalatory NOAEC = Oral NOAEL (75 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOAEC general population = 65,22 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 2 Default value (ECHA) for subchronic 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 50

General population DNEL long-term for inhalation route - systemic: 1.3 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: 2.6 mg/m³

Long-term oral route systemic effects (general population)

NOAEL(oral) = 75 mg/kg bw/day

Factors to be applied Justification

AF for dose response relationship 1

AF for differences in duration of exposure 2 Default value (ECHA) for subchronic 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 200

General population DNEL long term for oral route - systemic: 0.4 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: 0.8 mg/kg bw

Long-term dermal route systemic effects (general population)

NOAEL(dermal) = NOAEL(oral) x 2 = 150 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 2 Default value (ECHA) for subchronic 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 200

General population DNEL long term for oral and dermal route - systemic: 0.8 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: 1.5 mg/kg bw

Reproductive Toxicity – systemic effects (general population)