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Description of key information

Short description of key information on bioaccumulation potential result:
No human data on toxico kinetic are available with Quaternary ammonium compounds, C12-14, even numbered,

alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). However, limited experimental animal data with analogue compounds exist. Read across is made to one study on basic kinetics (single oral gavage, 50 mg/kg bw) in the male rat with an analogue quaternary ammonium chloride compound ((14C labeled) N-Tridecyl-N, N-Dimethylhydroxyethyleneammonium chloride with a purity of >97%,). Additional read across is made to two studies on basic kinetics in the rat (both sex) with (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide in which one study was performed as single oral gavage study (50.7 mg/kg bw), the second one was performed as single dermal application study (5.2 mg/kg bw, ie. 0.097mg/cm2) with 72 hour nonocclusive exposure. From the study results no gender differences regarding the absorption, distribution, and elimination of radioactivity for rats that received either an oral dose or a dermal dose of (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide were apparent.
From all these data available it could be concluded that low bioaccumulation potential can be assumed for Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). Further, the direct dermal penetration potential for HYEQS is concluded to be about 4%.
Short description of key information on absorption rate:
No dermal penetration studies are available with Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). For the assessment read-across to the structural analogous compound (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide is made. After single dermal application to male and female rats under non-occlusive conditions skin absorption in the range of 3 - 4 % of the applied dose was determined.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - dermal (%):
4

Additional information

No human data on toxico kinetic are available with Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). However, limited experimental animal data with analogue compounds exist. Experimental data from one study on basic kinetics (single oral gavage, 50 mg/kg bw) in the male rat with the quaternary ammonium chloride compound ((14C labeled) N-Tridecyl-N, N-Dimethylhydroxyethyleneammonium chloride with a purity of >97%) is used. Additional read across is made to two studies on basic kinetics in the rat (both sex) with (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide in which one study was performed as single oral gavage study (50.7 mg/kg bw), the second one was performed as single dermal application study (5.2 mg/kg bw, ie. 0.097 mg/cm2) with 72 hour nonocclusive exposure. From the study results no gender differences regarding the absorption, distribution, and elimination of radioactivity for rats that received either an oral dose or a dermal dose of (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide were apparent.

From all these data available it could be concluded that low bioaccumulation potential can be assumed for Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). Further, the direct dermal penetration potential for HYEQS is concluded to be about 4%.

Although the tested substances are of shorter chain cuts as the substance to be assessed the use of experimental results with C8 Dimethyl Hydroxyethyl Ammonium Bromide is considered adequate. Based on the smaller molecular weight C8 Dimethyl Hydroxyethyl Ammonium Bromide is likely to have a higher permeability than C12-14, even numbered, alkyl(hydroxyethyl)dimethyl, chlorides. Percutaneous absorption is likely to decrease with increasing molecular weight. Furthermore it has to be taken into account that the rat skin usually shows a 2 -10 times higher permeability than pig skin, whereupon pig skin shares essential characteristics with human skin. [SCCNFP (2003)] This aspect has to be considered for the safety assessment.

Furthermore, the results for dermal absorption obtained with the C8 Dimethyl Hydroxyethyl Ammonium Bromide are supported by an assessment also for higher C-chain length materials (i.e. alkyl (C16, C18, C22) trimethylammonium chlorides, [SCCP 2007]. For this assessment experimental in vivo data with the structurally very similar laurtrimonium bromide (dodecyltrimethylammonium bromide or alkyl (C12) trimethylammonium chloride) in the rat were used as surrogate. Based on data of the in vivo dermal exposure (leave on application) to 0.90 mg/cm2 laurtrimonium bromide to rats the dermal adsorption leads to 3.15 %. These data on dermal absorption of 3.15 % were considered adequate and are an conservative approach as the smaller molecular weight of laurtrimonium bromide (alkyl (C12) trimethylammonium chloride) is likely to have a higher permeability than alkyl (C16, C18, C22) trimethylammonium chlorides and percutaneous absorption is likely to decrease with increasing molecular weight.

Taken into account that in the study with (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide (i.e. surrogate substance for Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS) the amount of radioactivity retained on /in the skin of the application site accounted for 4.60 % (males) and 6.33 % (females) the total amount of radioactivity adsorbed (inclusively the direct absorbed 4 %) could be seen as 10 % in a worst case. There were no apparent gender differences regarding the absorption, distribution, and elimination of radioactivity for rats that received an oral or dermal dose of (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide.

Discussion on bioaccumulation potential result:

No human data on toxico kinetic are available with HYEQS. However, limited experimental animal data exist. Read across is made to one study on basic kinetics (single oral gavage, 50 mg/kg bw) in the male rat with an analogue quaternary ammonium chloride compound ((14C labeled) N-Tridecyl-N, N-Dimethylhydroxyethyleneammonium chloride with a purity of >97%). In male rats during the 0-72 hours after oral dosing of 50 mg/kg of (14C labeled) N-Tridecyl-N, N-Dimethylhydroxyethyleneammonium chloride by gavage, urine, feces, expired air, and cage washings accounted for means of 12.77, 85.94, 0.42, and 0.515 % dose, respectively. Tissues contained a mean of 1.17 % at 72 hours. The majority excreted in the feces (i.e. 83.84 % dose) being excreted in the first 48 hours after dosing. The greatest mean concentrations of radioactivity were detected in the liver (0.935 µg/g), and gastro-intestinal tract (0.527 µg/g). Concentrations of radioactivity were 0.166, 0.203, and 0.254 µg/g in the pancreas, fat and kidneys, respectively. Concentrations in the muscle, heart, spleen, and lungs were between 0.083 and 0.092 µg/g. The lowest detectable concentrations were in the testes (0.033 µg/g) and the whole blood (0.024 µg/g). Concentrations of radioactivity in the bone, bone marrow and brain were below the limits of accurate measurement (<0.064, <0.299 and < 0.027 µg/g, respectively). The low concentration of radioactivity in the tissues (maximum 0.94 µg/g in the liver, and gastro-intestinal tract (0.527 µg/g)) at 72 hours is indicative of the low proportion of the dose being absorbed.

Additional read across is made to two studies on basic kinetics in the rat (both sex) with (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide in which one study was performed as single oral gavage study (50.7 mg/kg bw), the second one was performed as single dermal application study (5.2 mg/kg bw, ie. 0.097 mg/cm2) with 72 hour nonocclusive exposure. Urine, feces, expired air, and cage washes were collected at 24-hour intervals for 72 hours after dosing in both studies. Animals were sacrificed at 72 hours postdose and body fluids and selected tissues were collected. All collected samples were analyzed for total radioactivity.

Following the oral dose of the (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide, most of the radioactivity was excreted in urine (40.6 % in males, 43.8 % in females) and feces (52.5 % in males, 44.2 % in females). Less than 0.005 % of the radioactivity was detected in expired air. Most of the radioactivity was excreted within 24 hours postdose (i.e. 78.5% and 78% in males and females, respectively). Small amounts of radioactivity were retained in the carcass and all tissues combined, which accounted for 0.35 % for males and 0.27 % for females. The highest tissue residues (µg C14 -test substance equivalents/g) were detected in liver (1.09), kidneys (0.164), lymph nodes (0.079) for males,and liver (0.525), adrenals (0.176), lymph nodes (0.128), kidneys (0.067) salivary gland (0.041) and uterus (0.033) for females.

Following the 72 hours dermal exposure to 5 mg/kg bw (i.e. 0.0970 mg/cm2) of the (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide under nonocclusive conditions, for males, a total of 2.13 % and for females, a total of 3.42 % of the total radioactivity was directly absorbed then excreted or retained in the carcass and all examined tissues, combined. The amount of radioactivity retained on /in the skin of the application site accounted for 4.60% (males and 6.33% (females). There were no apparent gender differences regarding the absorption, distribution, and elimination of radioactivity for rats that received either an oral dose or a dermal dose of (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide.

From all these data available it could be concluded that low bioaccumulation potential can be assumed for Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS).

Discussion on absorption rate:

A dermal penetration study in male and female rats was performed with (14C labeled) C8 Dimethyl Hydroxyethyl Ammonium Bromide which can be used as read-across for assessment purposes due to the close chemical similarities to Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS). The results are discussed in Section 5.1.1 Summary and discussion of Basic Toxicokinetics. [Cross reference is made to Basic toxicokinetics.Absorp/ Dist.derm.41811.]

Following a 72 hour dermal exposure to 5 mg/kg bw (i.e. 0.0970 mg/cm2) of the labelled test material, up to 88 % of the applied radioactive dose was recovered in the subsequent skin washing fluid. For males a total of 2.13 % and for females, a total of 3.42 % of the total radioactivity was directly absorbed then excreted or retained in the carcass and all examined tissues, combined. About 4.6 and 6.3 % respectively, retained in and/or on the skin. There were no apparent gender differences regarding the absorption, distribution, and elimination of radioactivity for rats.

The direct dermal penetration potential of C8 Dimethyl Hydroxyethyl Ammonium Bromide is concluded to be about 4% and should serve as a worst case assumption to assess the Quaternary ammonium compounds, C12-14, even numbered, alkyl(hydroxyethyl) dimethyl, chlorides (HYEQS).