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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Toxicokinetic assessment of the substance based on the available data
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
Not applicable
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Theoretical assessment taking all currrently available relevant information into account, based on the REACH Guidance: Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c Endpoint specific guidance. Since this is a theoretical assessment, the Klimisch value cannot be 1.
Objective of study:
other: Toxicokinetic assessment of the substance based on the available data
Qualifier:
according to guideline
Guideline:
other: ECHA Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance
Version / remarks:
Version 3.0; June 2017
Deviations:
not applicable
GLP compliance:
no
Type:
absorption
Results:
For risk assessment purposes, 100% is used for oral, dermal and inhalation absorption

Toxicokinetic assessment

Substances can enter the body via the gastrointestinal tract, the lungs, and the skin. In general, following oral administration, a compound is required to dissolve before adsorption can occur in the gastrointestinal tract. Benzyl trimethylammonium hydroxide (BTMAOH) is marketed as a 20% aqueous solution and as a 40 – 57% methanol solution. BTMAOH is highly soluble in water, therefore the substance will readily dissolve into the gastrointestinal fluids. Its low molecular weight may enable uptake via passive diffusion. However, the substance has a low partition coefficient which means that the substance is highly hydrophilic. This characteristic can hamper penetration through lipid membranes. BTMAOH dissociates in aqueous solutions in an OH-ion and a quaternary ammonium-ion. Due to the aqueous environment in the GI tract the substance will stay in ionized form. It is generally thought that ionized substances do not readily diffuse across biological membranes. Although its water solubility and its low molecular weight favour uptake, its low partition coefficient and its ionic form can hamper uptake. A toxicokinetic study with the benzyl trimethylammonium chloride (BMTAC), showed that uptake did not exceed 40% in rats and 15% in mouse in the GI tract (Sanders et al 1995, see below). Considering the quaternary ammonium ion is the same in BTMAOH, similar absorption rates could be expected. However, as BTMAOH is a corrosive it is likely to damage the GI tissues thereby increasing the absorption rate significantly. Therefore, for risk assessment purposes oral absorption of BTMAOH is set at 100%. Available oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

A toxicokinetic study with BTMAC showed wide distribution of the test item throughout the body in rat and mice (Sanders et al 1995, see below). Metabolism was minimal and most absorbed BTMAC was rapidly eliminated through the urine with no indication for bioaccumulation in tissues. BTMAOH is also expected to be widely distributed throughout the body based on its high water solubility and low molecular weight. Similar results in distribution are to be expected for BTMAOH compared to BTMAC as the structures contains the same cation.

The vapour pressure of pure BTMAOH was calculated to be low (9.5E-05 Pa) but considering BMTAOH is marketed as solution, aerosols could be formed. Therefore, it is assumed that BTMAOH can enter the respiratory tract. In case the substance reaches different regions of the lungs, high water solubility and low molecular weight in combination with the corrosive properties of BTMAOH will likely favour a high uptake in all lung regions. Therefore, for risk assessment purposes, the inhalation absorption of BTMAOH is set at 100%.

In case of skin contact with a solution of BTMAOH the quaternary ammonium ions will be binding to skin components thereby slowing absorption. In addition, the hydrophilicity of BTMAOH will limit the uptake via the skin. However, as BTMAOH is a corrosive the skin integrity will be negatively affected leading to an increased uptake. Once the skin surface is damaged, BTMAOH will be absorbed rapidly due to its low molecular weight and high water solubility. Based on the above data, for risk assessment purposes the dermal absorption of BTMAOH is set at 100%.

Reference: Sanders, J. M., Griffin, R. J., Burka, L. T., Matthews, H. B., Toxicokinetics of the cholinomimetic compound benzyltrimethylammonium chloride in the Male rat and mouse. Xenobiotica 1995; 25-3: 303-313.

Conclusions:
A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 100% (inhalation) and 100% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Description of key information

A toxicokinetic assessment was performed based on the available data of the substance. Based on the physical/chemical properties of the substance, absorption factors for this substance are derived to be 100% (oral), 100% (inhalation) and 100% (dermal) for risk assessment purposes. The bioaccumulation potential is expected to be low.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
100
Absorption rate - inhalation (%):
100

Additional information

Substances can enter the body via the gastrointestinal tract, the lungs, and the skin. In general, following oral administration, a compound is required to dissolve before adsorption can occur in the gastrointestinal tract. Benzyl trimethylammonium hydroxide (BTMAOH) is marketed as a 20% aqueous solution and as a 40 – 57% methanol solution. BTMAOH is highly soluble in water, therefore the substance will readily dissolve into the gastrointestinal fluids. Its low molecular weight may enable uptake via passive diffusion. However, the substance has a low partition coefficient which means that the substance is highly hydrophilic. This characteristic can hamper penetration through lipid membranes. BTMAOH dissociates in aqueous solutions in an OH-ion and a quaternary ammonium-ion. Due to the aqueous environment in the GI tract the substance will stay in ionized form. It is generally thought that ionized substances do not readily diffuse across biological membranes. Although its water solubility and its low molecular weight favour uptake, its low partition coefficient and its ionic form can hamper uptake. A toxicokinetic study with the benzyl trimethylammonium chloride (BMTAC), showed that uptake did not exceed 40% in rats and 15% in mouse in the GI tract (Sanders et al 1995, see below). Considering the quaternary ammonium ion is the same in BTMAOH, similar absorption rates could be expected. However, as BTMAOH is a corrosive it is likely to damage the GI tissues thereby increasing the absorption rate significantly. Therefore, for risk assessment purposes oral absorption of BTMAOH is set at 100%. Available oral toxicity data do not provide reason to deviate from the proposed oral absorption factor.

A toxicokinetic study with BTMAC showed wide distribution of the test item throughout the body in rat and mice (Sanders et al 1995, see below). Metabolism was minimal and most absorbed BTMAC was rapidly eliminated through the urine with no indication for bioaccumulation in tissues. BTMAOH is also expected to be widely distributed throughout the body based on its high water solubility and low molecular weight. Similar results in distribution are to be expected for BTMAOH compared to BTMAC as the structures contains the same cation.

The vapour pressure of pure BTMAOH was calculated to be low (9.5E-05 Pa) but considering BMTAOH is marketed as solution, aerosols could be formed. Therefore, it is assumed that BTMAOH can enter the respiratory tract. In case the substance reaches different regions of the lungs, high water solubility and low molecular weight in combination with the corrosive properties of BTMAOH will likely favour a high uptake in all lung regions. Therefore, for risk assessment purposes, the inhalation absorption of BTMAOH is set at 100%.

In case of skin contact with a solution of BTMAOH the quaternary ammonium ions will be binding to skin components thereby slowing absorption. In addition, the hydrophilicity of BTMAOH will limit the uptake via the skin. However, as BTMAOH is a corrosive the skin integrity will be negatively affected leading to an increased uptake. Once the skin surface is damaged, BTMAOH will be absorbed rapidly due to its low molecular weight and high water solubility. Based on the above data, for risk assessment purposes the dermal absorption of BTMAOH is set at 100%.

Reference: Sanders, J. M., Griffin, R. J., Burka, L. T., Matthews, H. B., Toxicokinetics of the cholinomimetic compound benzyltrimethylammonium chloride in the Male rat and mouse. Xenobiotica 1995; 25-3: 303-313.