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Key value for chemical safety assessment

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Toxicokinetics:

There are three key toxicokinetic studies investigating the absorption, distribution, metabolism and excretion of the test substance (dodecyl dimethyl amine oxide, AO, radiolabelled with C-14) following either oral or dermal administration in animals and man (Procter & Gamble study 13708 (1975), P&G study 21376 (1978) and P&G study 21910 (1979)].

Methodology

Two C-14 radio-labelled versions of the test substance were used in the toxicokinetic studies:
[methyl-14C]-dodecyldimethylamine and [1-dodecyl-14C]-dodecyldimethylamine. The toxicokinetics of the radiolabelled test substance was studied in rats, mice and rabbits and also in human volunteers. 

Rats were orally dosed with radiolabelled test substance at either 1, 40 (bile duct cannulated rats) or 100 mg/kg and at 22 mg/kg for an intraperitoneal dose. Rabbits were orally dosed with radiolabelled test substance at 1 mg/kg. Following dosing stainless steel animal metabolism cages were employed to separate and collect expired carbon dioxide, urine and faeces for up to 72 hours post dose and tissues and organs were collected for analysis at the termination of the experiment. 

The radiolabelled test substance was administered topically to rats (10 mg to 18 cm2), mice (1 mg to 6 cm2) and rabbits (10 mg to 40 cm2). The animals were restrained or fitted with collars to restrict oral ingestion of the test substance. Expired carbon dioxide, urine and faeces were collected for up to 72 hours post dose and tissues and organs were collected for analysis at the termination of the experiment.

Humans orally took 50 mg of radiolabelled test substance in water and expired carbon dioxide (up to 72 hours post-dose), excreta (up to 144 hours) and blood samples were collected. For the human dermal study, 10 mg of the radiolabelled test substance in 0.5 mL of water was topically applied to a 60 cm2 area of forearm skin and left on the skin for 8 hours. At 8 hours, the skin was repeatedly swabbed and subsequently tape-stripped to remove any dose remaining in the stratum corneum. Expired carbon dioxide (up to 72 hours post-dose) and excreta (up to 144 hours) were collected for analysis.

Absorption, distribution and excretion

The major conclusions on absorption, distribution and excretion that could be drawn from the oral TK studies in rats are:

·        The test substance is rapidly (Tmax1.5 hours) and readily absorbed following oral administration (>80%).

·        Microbial metabolism by gastrointestinal flora does not play a major role in the oral absorption and excretion of the test substance.

·        Biliary excretion is a minor excretory route (<5%).

·        The test substance is rapidly excreted (~75% within 24 hours).

·        The test substance is extensively metabolised and excreted primarily in urine, but also initially (first 12 hours) as CO2 (proportions depend upon the position of the C-14 tracer).

·        There were no major differences in the route (urine vs expired CO2) or rate of excretion of dose between the 1 and 100 mg/kg dose levels.

·        The test substance (or its metabolites) is widely distributed throughout the body with the highest proportions remaining primarily in the excretory organs (liver, stomach, kidneys and lungs) at 72 hours after dosing. The reproductive organs also contained similar proportions of dose at 72 hours after dosing to the kidneys/stomach.

The absorption, distribution and excretion of the radiolabelled test substance in the rabbit after oral administration was very similar to the rat, with a blood Tmax of 1.5 hours, most of the radioactivity excreted in the urine, approximately 30% as expired carbon dioxide and less than 10% in the faeces.

The absorption, distribution and excretion of the radiolabelled test substance in humans after oral administration were also similar to the rat although an incomplete mass balance was obtained (69% and 80% recoveries). Over half of the recovered radioactivity was detected in the urine and approximately a quarter measured in the expired carbon dioxide indicating a very high (>75%) oral absorption of dose. Almost the entire recovered dose was rapidly excreted within the first 24 hours and a blood Tmaxof 1 hour was seen.

The major conclusions on absorption, distribution and excretion that could be drawn from the dermal TK studies in rats, mice and rabbits are:

·        The test substance is slowly absorbed following dermal application (approximately 5% per day was consistently excreted in urine up to 72 hours post dose) with approximately 50% of dose still remaining at the dose site 72 hours after dosing (rats).

·        Approximately 20% of the dose was absorbed and excreted (up to 72 hours) following dermal application with a further ~20% recovered from the carcass/cage wash which may have been due to contamination of the applied dose (rats).

·        The overall distribution of dose was very similar between rats and mice; however, the rabbit excreted twice as much dose (~46%).

·        The rate of penetration (flux) of the test substance through rabbit, rat and mouse skin was calculated to be 12.8, 6.0 and 1.7 nmol/hour/cm2respectively.

The major conclusions on absorption, distribution and excretion that could be drawn from the dermal TK study in man are:

·        More than 92% of the applied topical dose was removed from the dose site after 8 hours.

·        Less than 0.2% of dose was detected in the stratum corneum.

·        A very small percentage (~0.2%) of dose was estimated to have been absorbed.

·        The rate of penetration (flux) of the test substance though human skin was estimated to be <0.2 nmol/hour/cm2.

Whist the absorption, distribution and excretion of the radiolabelled test substance following oral administration was very similar in the test animals; rats, rabbits and mice to man, this was not the case following dermal dosing. Results from these studies indicate that the dermal absorption of the test substance is a magnitude lower in man than the test animals. Whilst it is often seen that the dermal absorption of many test substances is greater in animals than man, the magnitude of difference from these studies is greater than would be expected. It is quite likely that the extent of absorption seen from the animal studies was compromised by oral absorption (licking of the test site) and by external contamination of the animal carcasses. As such, the extent of absorption of dose following the animal dermal studies may be an over estimate. A major difference in the study design for the human dermal absorption work was that the dose was only left on the application site for 8 hours, whereby it was swabbed and tape stripped; whereas in the animal studies it was left on the application site for 72 hours. Since the animal studies showed that the dermal absorption of the dose was very slow (approximately 5% per day) this may be another explanation as to the extent of the differences seen. However, if following human dermal exposure to the test substance the skin is thoroughly washed at the end of a working day, then the assumption that only a small proportion of dose is absorbed and that 90% or more of the dose would be removed by washing would appear reasonable.

Based on the recovery of 92 % of the applied topical dose of amine oxide from the test site in humans a value of 8 % is used in the risk assessment to model worse case systemic exposure via the dermal route.

Metabolism

The test substance was extensively metabolised after oral administration as shown by at least 10 metabolites characterised in urine in addition to a substantial proportion of dose completely biotransformed to CO2. There were several different pathways of metabolism proposed:

·        Oxidative degradation of the alkyl side chain by ω-oxidation to form a carboxylic acid followed by the loss of two-carbon fragments by sequential β-oxidation. This route of metabolism is frequently observed in similar substances to the test substance.

·        Hydroxylation of the alkyl side chain at a position four or five carbons from the end of the chain.

·        Reduction of the amine oxide group to the parent amine.

Qualitatively, the metabolic profiles (from urine) were similar for rat, rabbit and man but quantitatively there were differences. The identity of the major human metabolite of the test substance was proposed as N-methyl-4-aminobutyric acid N-oxide (~60% of urinary profile). This metabolite was also the most abundant metabolite in rabbit urine but not for rats. The major metabolite in rats resulted from hydroxylation of the side chain. The proportion of this metabolite in rat urine doubled when the dose of the test substance was increased from 1 to 100 mg/kg. Another substantial (~30%) metabolite seen in rats, rabbits and humans was proposed to be N,N-dimethyl-4-aminobutyric acid. The presence of this metabolite would indicate that a dodecyldimethylamine (DDA) was a likely metabolic intermediate. Further examination of the urinary metabolic profiles indicated that the rat excreted >12% of the dose as long-chain compounds (at least half of these were C-hydroxylated amino-alcohols), which was in contrast to the rabbit and man. As such, it appears that the metabolism of the test substance by the rabbit is closer to that of man than the rat.