Amines, C12-14-branched alkyl, dodecylbenzenesulfonates (1:1)

Endpoint summary

Description of key information

In accordance with REACH Annex VIII, Section 8.8.1, an assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information has been conducted.

Toxicological Information

Acute Toxicity: The test item was not acutely toxic via the oral route with no mortality, clinical or overt toxicity reported and reported LD50 > 2000 mg/kg (OECD 423).

Local Toxicity:  Non-corrosive to the skin and eyes, but irritating to skin (category 2) and eye (category 2) following in vitro studies (OECD 431, 439, 437 and 492).  In a local lymph node assay (OECD 429) the test item did elicit a Stimulation Index ≥ 3 when tested at ≥ 10 % w/v with SI values of 17.22, 24.00 and 25.16 in the 10, 25 and 50 % w/v test groups, respectively.  Local irritation was observed in the form of slight erythema, no signs of systemic toxicity or abnormal observation at necropsy were reported following the LLNA study. The test item was therefore considered to be a category 1 sensitiser under the conditions of the test.

Sub-acute study - OECD 422: Oral gavage exposure at up to 500 mg/kg/day was not well tolerated in rats.  Key clinical findings were; at 500 mg/kg bw/day lower mean body weight, total litter loss in two females, centrilobular hepatocyte hypertrophy and/or increased hepatocellular glycogen of the liver, thyroid follicular cell hypertrophy, non-glandular stomach, epithelial hyperplasia and orthokeratotic hyperkeratosis decreased lymphocyte cellularity in the cortex and medulla of the thymus, adrenal cortical hypertrophy with adrenal enlargement. Observations at mid or high dose included; dose-dependent incidence of stillborn pups, lower mean body weights were evident in pups. Other observations were: urogenital staining, wet abdominal fur, salivation, piloerection, changes in body posture, dose related increase in ataxia, high stepping, walking on toes, slow deliberate movements, and incidences of rears in male. Mean adjusted liver, thyroid, and kidney weights were increased, increased glucose, cholesterol calcium, inorganic phosphate, and urine output.  In all dose groups, mottled and/or pale discoloration in the liver, discoloration in kidney, thick and/or raised focus, epithelial hyperplasia and orthokeratotic hyperkeratosis were recorded in the stomach, as were follicular cell hypertrophy of the thyroid, centrilobular hepatocyte hypertrophy, nephropathy and hyaline droplets, with increased gradings. These observations demonstrate test item gastrointestinal (GI) tract absorption, transformation/metabolism, distribution and elimination/excretion (ADME). Parameters in liver and kidney are indicative of hepatic metabolism and renal elimination.

Absorption

The molecular weight of constituents is low i.e. in the range of 129 - 270 g/mol, it’s n-octanol/water partition coefficient is 3.0, melting point of - 20 °C, boiling point of 160 °C, water solubility of 16 mg/L, and vapour pressure 0.00208 Pa at 20 °C with surface tension of 33.9 mN/m are suggestive of favourable absorption via oral and limited uptake via dermal or inhalation routes. Absorption from the gastro-intestinal tract and the respiratory tract epithelium: absorption of the test item is likely to be mainly via passive diffusion to into portal circulation with delivery into the liver i.e. first pass metabolism and relatively high pulmonary uptake. Although the test item’s properties coupled with the irritation potential makes uptake from the dermal route possible, as a UVCB substance with potentially variable molecular weight and surface tension of 33.9 mN/m, the test item transfer between the stratum corneum and the epidermis would be restricted, therefore overall systemic uptake via this route could be limited. This is demonstrated by the lack of significant systemic and local toxicity from in vivo sensitisation study on the test item. Based on the vapour pressure and the boiling point of the substance, uptake via inhalation route is limited. Some percentage of the parent compound is expected to remain in the GI tract and would be eliminated via faeces and bile, this is supported by the observed epithelial hyperplasia and orthokeratotic hyperkeratosis observed in the stomach.

Distribution

The substance has physicochemical properties (mainly n-octanol/water partition coefficient, surface tension, high water solubility) indicating that test item uptake will be through aqueous pores or be carried through the epithelial barrier by the bulk passage of water into the liver, though limited by the varied molecular weight, as penetration is enhanced due to its surface activity. This means limited distribution of the parent compound systemically and the subsequent half-life of the parent compound in blood plasma is reduced. Based on the water solubility, a wide distribution of the absorbed substance is expected as it can easily be taken up into circulatory system as demonstrated by the nephropathy syndrome which is associated with α2u globulin accumulation in hyaline droplets, a condition not relevant to humans.  This is supported by the clinical observations of increased kidney weight, adrenal cortical hypertrophy with adrenal enlargement. and changes in renal functions such as cholesterol calcium, inorganic phosphate, and urine output. Distribution of the parent compound is expected in the GI tract as demonstrated by the clinical effect in the stomach.

Metabolism

Amine metabolism is mainly through the liver via phase I and II enzymes as demonstrated by increased liver weight and centrilobular hepatocyte hypertrophy in the liver in both sexes following subacute exposure to the test item. For alkyl amine derivative; possible route of metabolism would involve oxidative deamination by the monoaminooxidases produced ammonia and alkylamine aldehyde derivative which could undergo further oxidative reaction headed by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH to produced more polar metabolites such as carboxylic acid derivative. For the dodecylbenzenesulfonates derivative, desulfonation reaction via hydrolysis of the linear alkylbenzene sulphonate by enzymes such as sulfolysaes resulting into phenolic and acidic derivatives as well as sulphite.

Excretion

The n-Octanol/water partition coefficient (log Pow = 3.0) suggest potential accumulation of this substance in fatty tissues after absorption from the GI tract, however, this is not expected to be significant based on the solubility and molecular weight of the test item.  Based on the molecular structure, solubility and irritating tendency, it means availability of the absorbed substance into the circulatory system is rapid making it readily available for biotransformation into conjugated metabolites which are easily eliminated via urine. Elimination is assumed to be rapid, therefore no potential for bioaccumulation is to be expected. The observed clinical changes in stomach, liver, kidney would confirm metabolism is rapid and urine as the most probably route of excretion. Unabsorbed parent compound is expected to be eliminated via faeces and bile.

Conclusion

The substance has physicochemical properties with favourable ADME. Exposure via the oral route is most favourable and therefore the substance is expected to be widely distributed with limited absorption/distribution following inhalation or dermal exposure.  Based on the log Pow = 3.0, surface tension and water solubility, systemic bioaccumulation is not significant as the parent compound is rapidly metabolized to more polar substance which is readily elimination via urine.  The clinical signs observed following oral sub-acute exposure support oral absorption of the test item and clinical signs reported in liver and kidney are demonstrative of distribution, biotransformation and elimination of the test item. It can be concluded that the toxicokinetic of the test item does not pose significant toxicological concern.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100