Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
18
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.3 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
repeated dose toxicity

Workers - Hazard for the eyes

Additional information - workers

INTRODUCTORY NOTE

N,N-dimethylbenzylamine is a liquid at room temperature. But there is no long-term study available using the dermal route. N,N-dimethylbenzylamine proved to be corrosive when applied to the skin of rabbits and therefore studies using dermal application are not appropriate. In addition, the available subchronic inhalation studies are unsuitable for use in the evaluation of the systemic toxicity of N,N-dimethylbenzylamine (BG-Chemie 1995) and cannot be taken into account to derive DNELs.

There are, however, two subacute gavage studies in male and female rats in which these animals received 0, 6, 30, 150, 200 mg/kg bw/day (BG Chemie 1988, 1990) or 0, 50, 100, 200, 400 mg/kg bw/day (MHLW 1997). In male and female rats dosed with 400 mg/kg bw/day were observed from week 2. Miosis and salivation was observed in those rats receiving 200 and 400 mg/kg bw/day. The 150 mg/kg bw/day males had slightly higher testis weights than the controls. However, there was no histopathological correlate. In males and females dosed with 100 mg/kg bw/day miosis was the only observed finding..There were no differences between controls and male and female rats dosed with 50, 30, or 6 mg/kg bw/ day. Thus, the overall NOAEL is considered to be 150 mg/kg bw/day .

This NOAEL of 150 mg/kg/day will be taken as the starting point for the DNEL(systemic) calculations.

WORKER-DNEL; SYSTEMIC; LONG-TERM; INHALATION ROUTE

There is a basic toxicokinetic study in human volunteers available which clearly shows that N,N-dimethylbenzylamine is well aborbed through respiratory tract because it is reported that 90 % of the inhaled concentration is excreted via urine within 24 hours (Stahlbom 1997). Thus, the following calculation can be made:

NOAEL (rat) oral: 150 mg/kg bw/day

For interspecies differences rat vs. human 4

150 mg/kg: 4 = 37,5 mg/kg bw/d

Body weight worker = 70 kg bw/person

37.5 mg/kg * 70 kg bw/person= 2625 mg/person/d

Respiratory volume worker = 10 m³/person (8h exposure; light activity for worker)

2625 mg/person/d: 10 m³/person = 262.5 mg/m³/8h

NOAC worker (8h) = 262..5 mg/m³

For remaining interspecies differences: 1 *

For extrapolation of exposure duration subacute to chronic: 6

For intraspecies differences in worker: 3**

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 18

Worker DNEL systemic, long-term for inhalation route = 14.6 mg/m³/8h

– This DNEL covers only systemic effects and does not take into account the corrosive properties.

WORKER-DNEL; SYSTEMIC LONG-TERM; DERMAL ROUTE

There is no long term study available using the dermale route. According to ECHA Guidance document R8, p 25 it can be assumed that dermal absorption will not be higher than the oral absorption and no additional defaut factor should be introduced when performing oral-to-dermal extrapolation. Therefore the following calculation is made:

NOAEL (rat) oral: 150 mg/kg bw/day

Dermal NOAEL= oral NOAEL

NOAEL (rat) dermal:150 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in worker: 3**

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 72

Worker-DNEL systemic, long-term for dermal route = 2.3 mg/kg bw/d

– This DNEL covers only systemic effects and does not take into account the corrosive properties.

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* In an evaluation by ECETOC TR. 86, 2003 and TR 110, 2010 it is considered that routine application of the factor 2.5 is scientifically unjustified as a default factor.

**according to ECETOC TR 110, 2010

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LOCAL TOXICITY

WORKER-DNEL; LONG-TERM; INHALATION-ROUTE

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.

A toxicological TF within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available, the TF developed a generic upper boundary value of 10 mg/m³; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m³ is developed.

N,N-Dimethylbenzylamine is corrosive and labelled accordingly.

Thus, a DNEL long-term, inhalation route for local effects of 1 mg/m³ is proposed based on the VCI evaluation on irritating/corrosive compounds.

DERMAL APPLICATION

N, N-Dimethylbenzylamine is corrosive and labelled accordingly. ECHA “Guidance on information requirements and chemical safety assessment Part E: "Risk Characterization of Substances” warranted that these substances should be allocated to the moderated hazard band with defined risk management measures and operational conditions on the basis that exposure to such substances should be well controlled:

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
other: NOAC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

INTRODUCTORY NOTE

N,N-dimethylbenzylamine is a liquid at room temperature. But there is no long-term study available using the dermal route. N,N-dimethylbenzylamine proved to be corrosive when applied to the skin of rabbits and therefore studies using dermal application are not appropriate. In addition, the available subchronic inhalation studies are unsuitable for use in the evaluation of the systemic toxicity of N,N-dimethylbenzylamine (BG-Chemie 1995) and cannot be taken into account to derive DNELs.

There are, however, two subacute gavage studies in male and female rats in which these animals received 0, 6, 30, 150, 200 mg/kg bw/day (BG Chemie 1988, 1990) or 0, 50, 100, 200, 400 mg/kg bw/day (MHLW 1997). In male and female rats dosed with 400 mg/kg bw/day were observed from week 2. Miosis and salivation was observed in those rats receiving 200 and 400 mg/kg bw/day. The 150 mg/kg bw/day males had slightly higher testis weights than the controls. However, there was no histopathological correlate. In males and females dosed with 100 mg/kg bw/day miosis was the only observed finding. There were no differences between controls and male and female rats dosed with 50, 30, or 6 mg/kg bw/ day. Thus, the overall NOAEL is considered to be 150 mg/kg bw/day .

This NOAEL of 150 mg/kg/day will be taken as the starting point for the DNEL(systemic) calculations.

CONSUMER DNEL;SYSTEMIC; LONG TERM; ORAYAL ROUTE:

NOAEL (rat) oral: 150 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1 *

For intraspecies differences in consumer: 5**

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 120

Consumer-DNEL systemic, long-term for oral route = 1.25 mg/kg bw/d

– This DNEL covers only systemic effects and does not take into account the corrosive properties.

CONSUMER DNEL; SYSTEMIC; LONG TERM;INHALATION ROUTE

There is a basic toxicokinetic study in human volunteers available which clearly shows that N,N-dimethylbenzylamine is well aborbed through respiratory tract because it is reported that 90 % of the inhaled concentration is excreted via urine within 24 hours (Stahlbom 1997). Thus, the following calculation can be made:

NOAEL (rat) oral: 150 mg/kg bw/day

For interspecies differences rat vs. human 4

Body weight consumer = 70 kg bw/person

Respiratory volume (consumer) = 20 m³/person (24 h exposure)

NOAC consumer (24 h) = 1312.5 mg/m³

For remaining interspecies differences: 1 *

For extrapolation of exposure duration subacute to chronic: 6

For intraspecies differences in consumer: 5**

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 30

Consumer DNEL systemic long-term for inhalation route = 43.75 mg/m³/24h

– This DNEL covers only systemic effects and does not take into account the corrosive properties.

CONSUMER DNEL; SYSTEMIC; LONG TERM; DERMAL ROUTE

There is no long term study available using the dermale route. According to ECHA Guidance document R8, p 25 it can be assumed that dermal absorption will not be higher than the oral absorption and no additional defaut factor should be introduced when performing oral-to-dermal extrapolation. Therefore the following calculation is made:

NOAEL (rat) oral: 150 mg/kg bw/day

Dermal NOAEL= oral NOAEL

NOAEL (rat) dermal: 150 mg/kg bw/day

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in consumer: 5**

For extrapolation of exposure duration subacute to chronic: 6

For reliability of dose response: 1

For quality of whole database: 1

Overall factor: 120

Consumer-DNEL systemic long-term for dermal route = 1.25 mg/kg bw/d

– This DNEL covers only systemic effects and does not take into account the corrosive properties.

---------------------------------------

* In an evaluation by ECETOC RR 86, 2003 and TR 110, 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. . .

**according to ECETOC TR 110, 2010

-------------------------------------------------

LOCAL TOXICITY

APPLICATION by INHALATION EXPOSURE or by DERMAL ROUTE

N, N-Dimethylbenzylamine is corrosive and labelled accordingly ECHA “Guidance on information requirements and chemical safety assessment Part E: Risk Characterization of Substances” warranted that these substances should be allocated to the moderated hazard band with defined risk management measures and operational conditions on the basis that exposure to such substances should be well controlled