1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

No data on absorption, distribution, metabolism and excretion of triallyl isocyanurate are available.

According to REACh, the human health hazard assessment shall consider the toxicokinetic profile (Annex I). However, generation of new data is not required as the assessment of the toxicokinetic behaviour of the substance should be performed to the extent that can be derived from the relevant available information (REACh Annex VIII, 8.8.1).

Qualitative information on toxicokinetic behaviour can be derived taking into account the information on the chemical properties of the compound as well as data obtained in a basic dataset.

 

Absorption

The observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this will not provide any quantitative information.

Asingle dose oral toxicity test of triallyl isocyanurate in rats revealed LD50 values of 707 mg/kg bw for male and 812 mg/kg bw for female rats (2003-0758-FGT). The animals that died showed hypoactivity, gait disturbance, tremors and convulsions. Histopathology revealed erosions or ulcerations in the forestomach.Since acute oral toxicity was observed with triallyl isocyanurate, absorption of the compound via the gastrointestinal tract (at least to some extent) has evidently occurred.

 

No GLP study according to current OECD Guidelines on dermal acute toxicity is available. Bidnenko, 1969 reported,that dermal application of triallyl isocyanurate for 2 hours caused general toxic effects including death of rats. According to the method by Behrens and Schlosser a LD50 value of 2750 mg/kg bw was calculated. The study revealed dermal acute toxicity and indicates bioavailability of triallyl isocyanurate after dermal application. However, against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of less magnitude, presumably due to lower dermal uptake in contrast to oral absorption.

 

Triallyl isocyanurate has a comparably very low vapour pressure of 0.00017 Pa at 20 °C (2002-0726-DKP); subsequently the calculated vapour saturation threshold is ca 0.00002 mg/L. No information on inhalation toxicity of triallyl isocyanurate as vapour is available. However, an inhalation study with triallyl isocyanurate on synthetic calcium silicate (content of 74% triallyl isocyanurate) was performed (1978-0306-FKT). Rats were exposed to the particles (mass median diameter: 1.2 – 3.5 µm) for 4 hours. No animals died up to and including the maximum attainable concentration of 1.86 mg triallyl isocyanurate on calcium silicate/L. However, at the maximum dose clinical signs of toxicity like sporadic salivation and irregular respiration and lethargy immediately following exposure have been noted. Thus, triallyl isocyanurate is likely to be also absorbed, if inhaled.

 

To be absorbed, the substance has to cross biological membranes, either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is dependent on compound properties such as molecular weight, lipophilicity, or water solubility. In general, low molecular weight (MW ≤ 500 g/mol) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of triallyl isocyanurate is relatively low with 249.27, favouring oral absorption of the compound. Dermal uptake can be seen to be moderate at this molecular weight level (<100: dermal uptake high; >500: no dermal uptake). This is supported by the determined log P value being 2.2 (2003-0624-DNP), being advantageous for oral, respiratory and dermal absorption. In addition, the good water solubility of 3.5 g/L (2011-0060-DKP) leading to a ready dissolving of the compound in the gastrointestinal fluids favours oral absorption. Also for dermal uptake, sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis. In the respiratory tract, the compound would readily diffuse into in the mucous lining. However, very hydrophilic substances might be retained in the mucous in the upper respiratory tract and transported out by mucociliary activity.

 

According to QSAR predictions obtained from the Danish (Q)SAR database (2005), gastrointestinal absorption of triallyl isocyanurate is presumed to be 100 %.

The dermal permeability constant Kp of triallyl isocyanurate was estimated to be 0.00198 cm/h using the QSAR published by Potts and Guy (1992) and taking into account the log Pow and molecular weight. Further on the maximum flux Imax (Imax = Kp [cm/h] x water solubility [mg/cm³]) was calculated similar to the approach taken by Kroes et al. (2007) and yielded in a value of 6.947 µg/cm²/h for triallyl isocyanurate. This flux value can be assigned to a moderate dermal absorption of 50% (Mostert and Goergens, 2011).

 

Rarely, exogenous compounds (e.g. similar to a nutrient) may be taken up via a carrier mediated or active transport mechanism. However, prediction in this direction is not generally possible. Active transport (efflux) mechanisms also exist to remove exogenous substances from gastrointestinal epithelial cells thereby limiting entry into the systemic circulation. From physicochemical data, identification of substances ready for efflux is not possible.

 

Distribution

Some information or indication on the distribution of the compound in the body might be derived from the available physico-chemical and toxicological data. Once a substance has entered the systemic circulation, its distribution pattern is likely to be similar for all administration routes. However, first pass effects after oral exposure influence the distribution pattern and distribution of metabolites is presumably different to that of the parent compound.

The smaller a molecule, the wider is its distribution throughout the body. Membrane-crossing substances with a moderate log P and molecular weight will be able to cross the blood-brain and blood-testes barrier and reach the central nervous system (CNS) or testes, respectively. However, due to the high water solubility, penetration of triallyl isocyanurate through these barriers is presumably limited.

From the toxicological studies, the predominant target organs after repeated exposure to triallyl isocyanurate were identified to be liver, spleen, organs of the immune system like lymph nodes and thymus, as well as the kidney (2003-0756-FGT; Komsta et al., 1989). Thus, distribution throughout the body – a least to some extend – can be presumed. There is no indication of CNS effects or effects on spermatogenesis, thus no conclusion regarding blood-brain or – testes barrier penetration can be drawn.

 

Bioaccumulation

Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, highly lipophilic (log P > 4) compounds tend to have longer half-lives. Thus, they potentially accumulate within the body in adipose tissue, especially after frequent exposure (e.g. at daily work) and the body burden can be maintained for long periods of time. After the stop of exposure, the substance will be gradually eliminated dependent on its half-life. During mobilization of fat reserves, e.g. under stress, during fasting or lactation, release of the substance into the serum or breast milk is likely, where suddenly high substance levels may be reached.

After dermal exposure, highly lipophilic compounds may persist in the stratum corneum, as systemic absorbance is hindered.

Substances with log P values of ≤3 would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate during continuous exposures. Triallyl isocyanurate is moderately lipophilic and thus unlikely to accumulate in adipose tissue during 8 h-workday scenarios.

 

Metabolism

Prediction of compound metabolism based on physico-chemical data is very difficult. Structure information gives some but no certain clue on reactions occurringin vivo. It is even more difficult to predict the extent of metabolism along different pathways and species differences possibly existing.

Evidence for differences in toxic potencies due to metabolic changes can be derived for instance fromin vitrogenotoxicity tests conducted with or without metabolic activation.

Regarding thein vitrogenotoxicity of triallyl isocyanurate, some chromosomal aberration studies revealed a positive outcome with metabolic activation only, which could be interpreted as a hint on some toxification effect. However, positive results were obtained at special experimental set-ups and at precipitating or cytotoxic dose levels. Thus, the relevance of the positive test outcomes is strongly questionable.

Based upon chemical structure, hydrolysis would be the most likely means of metabolism of triallyl isocyanurate (Parkinson, 1996).

 

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product.

According to Rozman and Klaassen (1996) hydrolysis of triallyl isocyanurate will be followed by elimination in the urine.

 

References:

Kroes et al., 2007.Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients.Food Chem Toxicol 45:2533-2562

Mostert and Georgens (2011) Dermal DNEL setting: using QSAR predictions for dermal absorption for refined route-to-route extrapolation. The Toxicologist: 107

Potts and Guy, 1992.Predicting skin permeability. Pharm Res 9:663-669

 

Parkinson, A. 1996. Biotransformation of Xenobiotics. In: Casarett & Doull’s Toxicology: The Basic Science of Poisons. 5th ed. Klaassen, C.D., Ed. The McGraw-Hill Companies, Inc., New York, NY; pp. 113-186 as cited in Triallyl Isocyanurate [1025-15-6] Review of Toxicological Literature. Prepared for Errol Zeiger, NIEHS, Research Triangle Park, North Carolina, USA. Submitted by Raymond Tice, Integratory Laboratory Systems, Inc., Research Triangle Park, North Carolina, USA. July 1998

 

Rozman, K.K., and Klaassen, C.D. 1996.Absorption, distribution, and excretion of toxicants.In: Casarett & Doull’s Toxicology: The Basic Science of Poisons. 5th ed. Klaassen, C.D., Ed. The McGraw-Hill Companies, Inc., New York, NY; pp. 113-186 as cited in Triallyl Isocyanurate [1025-15-6] Review of Toxicological Literature. Prepared for Errol Zeiger, NIEHS, Research Triangle Park, North Carolina, USA. Submitted by Raymond Tice, Integratory Laboratory Systems, Inc.Research Triangle Park, North Caroline, USA. July 1998