Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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:
14 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
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Justification of read across in the human hazard assessment of Dialkylquaternaries

 

N-benzyl-N-C16-18(even numbered)-alkyl-N-methyl-C16-18(even numbered)-alkyl-1-aminium chloride, commonly referred Benzyl-dihydrogenated-methyl ammonium chloride (BDHTMAC)and N-C16-C18(even numbered) -alkyl-N,N-dimethyl-C16-C18(even numbered)-alkyl-1-aminium chloride, commonly referred dihydrogenated-dimethyl-ammonium chloride (DHTDMAC) share structural similarities, essential chemical key aspects and common toxicological properties, so that it is scientifically appropriate to consider data from DHTDMAC for cross-reading to BDHTDMAC when needed.

Dialkylquaternaries in general show the same chemical structure with an ionic positively charged part and apolar fatty acid chains. The anionic part, generally chloride, is of no toxicological significance. The primary effect of Dialkylquaternaries involves disruption of the cytoplasmic membrane causing cell damage or lysis of the cell content. Their toxicity is related to the same mode of action: toxicity is related to concentration dependent cytotoxicity. The potency shows a dependence on chain length with an optimum at C10 and a minimum at C16 and above. Unsaturation of the fatty carbon chains plays also a role in the reactivity of the dialkylquaternaries. The presence of a double bond is more reactive than a single bound because it is more electrophylic. The longer the alkyl chain attached to a double bond, the more positive charge is pushed towards the double bond, which will increase its electrophilicity. Therefore, for similar carbon chain lengths the unsaturated compound will be more reactive than the saturared one. As BDHTMAC and DHTDMAC are altogether unsaturated, have the same carbon chain lengths and the same mode of action, applying read-across principles is justified.

Moreover, an overview of available data existing on common toxicological endpoints for the two substances demonstrates their similar toxicological behaviour: Both substances have a low acute toxicity but strong skin and eye corrosive properties. They are not sensitising and not mutagenic. The 28-day repeated dose toxicity studies performed by oral route in rats conclude to the same NOAEL of 100 mg/kg bw /day. The same biochemical changes (increase in ALAT enzyme) and the same target organ (adrenals) have been identified by these studies. Based on these results, the two substances display a similar toxic profile and it is scientifically appropriate to use cross-reading. For information, some studies have been performed with the Dimethyldioctadecylammonium choride (DODMAC) which is the main active component of DHTDMAC.

For the delineation of DNELs the following exposure patterns are considered:

Since no consumer uses exist for N-benzyl-N-C16 -18 (even numbered) -alkyl- N- methyl- C16-18 (even numbered)-alkyl-1-aminium chloride (BDHTMAC), the only exposed population considered are workers which are expected to have infrequent and short-term exposures.

On account of the physico-chemical properties of the substance (ionic substance, low vapour pressure), inhalative exposure to vapours is assumed to be negligible but exposure to dusts / aerosols at the workplace must be taken into consideration. Taking into account the strong irritative effect of the paste-like preparation (ie the primary product), it is expected that repeated dermal contact is avoided.

However, for DNEL calculation chronic exposure conditions were assumed as worst-case scenario.

Based hereupon, the following critical DNELs with regard to N-benzyl-N-C16-18 (even numbered)-alkyl-N-methyl-C16-18 (even numbered) -alkyl -1 -aminium chloride (BDHTMAC) have been identified:

·   DNEL long-term,dermal, systemic

·   DNEL long-term, inhalation, systemic

Long-term exposure - systemic toxicity

1- Dermal DNEL

Identified key study for DNEL derivation is the 28-day oral toxicity study in rats (CIT, 2010a) which results in a NOAEL of 100 mg/kg body weight per day. Route to route extrapolation must therefore be applied.

Step 1) Relevant dose-descriptor:          

* NOAELoral,systemicrat = 100 mg/kg bw/d

Step 2) Modification of starting point:

* Absorption by dermal route in experimental animals and human

Experimental in vivo study in rabbits and in vitro data on human skin have revealed that the dermal absorption was very low. An increase of the concentration in the skin following dermal application was also not observed. These experimental findings are supported by the physico-chemical properties of the substance being poorly soluble in water and having a molecular weight of about 606-659 g/mol, usually only substance with lower molecular weight are absorbed. Therefore, the default factor of 10% skin absorption is used and no correction factor for differences in absorption between animals and human is applied

Correcteddermal, systemicNOAEL = 1000 mg/kg bw/d

Step 3) Assessment factors:

* Interspecies : 4 (Allometric scaling from rat to human)

* Intraspecies : 3 Analysis of various data sets have revealed that for workers a factor of 3 is sufficient for covering any intraspecies variability (ECETOC, 2010)

* Exposure duration: 6 (extrapolation from a subacute exposure to a chronic exposure)

* Dose response : 1 (the starting point for DNEL calculation is a NOAEL)

* Quality of database: 1 (there is no reason to assume a special concern)

DNEL Value based on theCorrecteddermal, systemicNOAEL = 1000 mg/kg bw/d:

= 1000 /(4 x 3 x 6 x 1 x 1) = 14 mg/kg bw/ day

2- Inhalation DNEL

Identified key study for DNEL derivation is the 28-day oral toxicity study in rats (CIT,2010a) which results in a NOAEL of 100 mg/kg body weight per day. Route to route extrapolation must therefore be applied.

Step 1) Relevant dose-descriptor:          

* NOAELoral,systemicrat = 100 mg/kg bw/d

Step 2)Modification of starting point:

* Correction for differences in absorption between oral and inhalation routes

Due to the low vapour pressure , the potential for generating vapour and thus the risk of inhaling the substance is minimal. In the event that aerosols or particulates are inhaled, the pulmonary physiology and clearance dynamics would largely favour the oral absorption rather than the inhalation. Therefore, based on the physico-chemical properties of fatty nitriles and their derivatives, the default factor of 2 in case of oral to inhalation extrapolation seems unjustified and is reduced to 1.

* Correction for respiratory volume between rat and human : 1/ 0.38 m3 /kg bw

* Correction for activity driven differences of respiratory volumes in workers compared to workers in rest: 6.7 m3/10 m3

Correctedinhalation, systemicNOAEL = 100 x 1.76 = 176 mg/m3

Step 3) Assessment factors:

* Interspecies: 1 No correction is made for differences in body size, because extrapolation is based on toxicological equivalence of a concentration of a chemical in the air of experimental animals and humans. Animals and humans breathe at a rate depending on their caloric requirements and this was already taken into account into step 2.The default factor for "remaining differences" is not considered scientifically justified. Analysis of various data sets have revealed that for workers a factor of 3 may be appropriate and that potential residual interspecies differences is largely accounted for already in the assessment factor for intraspecies variability (ECETOC 2010).

* Intraspecies : 3 (ECETOC 2010, see the above mentioned justification)

* Exposure duration: 6 (extrapolation from a subacute exposure to a chronic exposure)

* Dose response : 1 (the starting point for DNEL calculation is a NOAEL)

* Quality of database: 1 (there is no reason to assume a special concern)

DNEL Valuebased on theCorrectedinhalation, systemicNOAEL = 176 mg/m3

= 176 /(3 x 6 x 1x 1) = 9.7 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

N-benzyl-N-C16-18(even numbered) -alkyl-N-methyl-C16-18(even numbered) -alkyl-1-aminium chloride, commonly referred Benzyl-dihydrogenated-methyl ammonium chloride (BDHTMAC) is not used in the consumer sector. DNELs derivation for the general population is therefore not necessary and not required.