2,4,6-trichloro-1,3,5-triazine

Endpoint summary

Description of key information

The toxicokinetics of Cyanuric chloride was assessed based on physico-chemical data and the available toxicological profile. The toxicokinetic profile of Cyanuric chloride is dominated by its chemical reactivity and rapid hydrolysis forming HCl and Cyanuric acid. Cyanuric chloride and its degradation products may be absorbed after oral, dermal or inhalation exposure and widely distributed throughout the body. The degradation products of Cyanuric chloride are its primary metabolites. Excretion of Cyanuric chloride and its degradation products is rapid and most likely via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetics of Cyanuric chloride

General

The following sections provide an overview of the toxicological profile of Cyanuric chloride and an analysis of the substance’s toxicokinetic behaviour. For the assessment of the toxicokinetic behaviour the high reactivity of Cyanuric chloride towards nucleopils and its hydrolytic instability leading to the release of Hydrogen chloride/Hydrochloric acid (HCl) and the final decomposition product Cyanuric acid must be considered. The increasing amount of acid compounds formed during hydrolysis is most likely responsible for the irritating and caustic effects of Cyanuric chloride.

Toxicological profile

Acute toxicity of Cyanuric chloride showed an oral LD50 of ca. 330 mg/kg bw and a dermal LD50 of >2000 mg/kg bw. The high acute inhalation toxicity of Cyanuric chloride (LC50=170 mg/m3/4 h) is likely to be secondary to its highly respiratory irritating properties. The compound is corrosive to the skin and to the eyes. In humans exposure due to accidental contamination to Cyanuric chloride causes irritation and caustic effects to the skin, eyes and respiratory tract. Cyanuric chloride is sensitizing to the skin. Asthma and contact dermatitis are also reported in humans.

In oral repeated dose studies Cyanuric chloride induced body weight loss and stomach erosion and ulceration. In a 21-day dermal study decreased body weight was reported at 150 and 500 mg/kg bw/day. Severe dermal irritation was seen at all dose levels tested. Since it cannot be excluded that the effects on body weight were secondary to stress by the treatment, no systemic NOAEL was derived. The LOAEL for local effects is 50 mg/kg bw/day. From a 90- day inhalation study of limited validity a NOAEC of 0.25 mg/m3/6 h (the highest concentration tested) for systemic toxicity was derived. The NOAEC for local effects in the respiratory tract of rats displaying intercurrent respiratory infection was found to be 0.05 mg/m3/6 h. In a human long term systemic and local inhalation study the effects of Cyanuric chloride were investigated in male employees working at a Cyanuric chloride production facility. In relation to external pulmonary reference values the results indicated no abnormalities of lung function parameters. When considering models with maximum estimates of pulmonary function loss, a long-term threshold value for cumulative exposure was identified. Using a representative model that described the estimated average loss, the result was a threshold band which offers a best value estimate 0.3 mg/m3-years.

In reproduction toxicity studies no signs of corrosive effects were noted in the GI-tract after oral application via drinking water of NHDT solution the first hydrolysis product of Cyanuric chloride.

In a mouse lymphoma forward mutation assay the mutagenic properties of Cyanuric chloride were tested in L5178Y mouse lymphoma cells with and without activation (aroclor induced rat liver S9 extract) in concentrations of 0, 1.56, 3.13, 6.25, 12.5 and 25μg/mL. Under the conditions of the study no mutagenicity was observed. Two Ames-Tests were performed with different tests strains. The S. Typhimurium TA97a, TA98, TA100 and TA102 showed negative results either with or without activation. In the second Ames-Test, using the S. Typhimurium TA 1535, TA1537, TA 98, TA100 and E.Coli, equivocal results were obtained. Two micronucleus assays and one sister chromatid exchange assay in the rat indicated that Cyanuric chloride was not mutagenic in vivo. The studies conclusively indicate that mutagenic effects by Cyanuric chloride or its degradation products are unlikely.

The results of carcinogenicity testing are not adequate for evaluation. For developmental toxicity an oral teratogenicity study is available. The NOAEL for maternal toxicity is 25 mg/kg bw. For developmental effects a NOAEL of 25 mg/kg bw was derived. In the 90-day inhalation toxicity study no effects on the gonads were found indicating no effects of Cyanuric chloride on fertility.

Toxicokinetic analysis of Cyanuric chloride

Cyanuric chloride is solid at room temperature with a molecular weight of 184.41 g/mol and an absolute density of 1.094 g/cm3 at 20°C. The substance has a melting point range from 146.5-147.5 °C. A water solubility of 440 mg/L and a log Pow of 2.14 were calculated for Cyanuric chloride. An experimental measurement of both endpoints is not possible due to hydrolytic instability of the substance. The vapour pressure was determined to be 0.6 hPa (20 °C). Cyanuric chloride hydrolyses rapidly via the di- and mono-chloro compound to Cyanuric acid thereby forming HCl. Furthermore, Cyanuric chloride reacts easily with nucleophils. These substance specific properties have to be considered when evaluating the toxicokinetic profile.

Absorption:

After oral, respiratory or dermal exposure Cyanuric chloride decomposes locally to Cyanuric acid under the formation of HCl via the di- and mono-chloro intermediates. It may also react with nucleophils such as amino- and/or thiol-group containing molecules. Thus, the absorption of the parent compound Cyanuric chloride may be limited. This is supported by the results of acute and repeated dose toxicity studies, where local irritating and or caustic effects were seen. Cyanuric chloride and its hydrolysis products are small molecules (molecular weight < 200 g/mol) with a log Pow between -0.35 and 2.14 indicating that gastro-intestinal absorption after oral exposure can occur.

Cyanuric chloride can be inhaled as dust or in smaller quantities as vapour due to its reduced ability to sublimate (vapour pressure < 5 hPa). The respiratory tract is probably the main route of exposure. It is most likely that Cyanuric chloride hydrolyses on the moist mucous membranes of the respiratory tract. Local irritation and corrosion effects may occur. Absorption is likely to be limited to degradation products. The substance characteristics (i.e. rapid hydrolysis, high reactivity) indicate that dermal absorption of the parent compound is limited. However, degradation products may be absorbed via the skin, if exposure conditions cause skin irritation/corrosion and consequently skin barrier damage. The skin sensitising properties of Cyanuric chloride further indicate dermal absorption of the parent substance and/or its degradation products.

Distribution: 

Due to the hydrolytic instability and chemical reactivity, distribution is likely limited to decomposition products or via binding to plasma proteins. For the degradation product Cyanuric acid a fast distribution with highest concentrations present in blood, liver and kidney 20 minutes after administration has been reported in rats treated orally with14C-Cyanuric acid (BG Chemie, 10/92). After six hours marginal radioactivity could be detected indicating a completely excretion of Cyanuric acid and no accumulation potential. The log Pow of Cyanuric chloride and its degradation products (between - 0.35 and 2.14) indicates that crossing of plasma membranes and intracellular diffusion is possible.

 

Metabolism and Excretion:

The metabolism of Cyanuric chloride is characterised by its hydrolytic instability and chemical reactivity. Therefore, the degradation products of Cyanuric chloride are most relevant. An oral 14C-metabolism study with rats demonstrated that Cyanuric acid is excreted unchanged primarily in the urine and only marginally via respiratory breathing or via faeces (BG Chemie, 10/92).In humans, more than 98 % of an orally administered dose of cyanuric acid is excreted unchanged in urine within 24 hours (Allen et al., 1982).

Furthermore, it can be assumed that Cyanuric chloride reacts with plasma proteins which undergo lysosomal degradation followed by excretion in the urine. This assumption is in the line with the sensitizing properties of Cyanuric chloride which requires a protein binding for the induction of immune response.

Summary 

The toxicokinetic profile of Cyanuric chloride is dominated by its chemical reactivity and rapid hydrolysis with the formation of HCl and finally, Cyanuric acid. Cyanuric chloride and its degradation products are expected to cause local irritation/corrosion effects and may be absorbed after oral, dermal or inhalation exposure. Following uptake the compounds are likely to be readily distributed throughout the body. The degradation products of Cyanuric chloride seem to remain mostly unchanged by metabolism. Excretion of Cyanuric chloride and its degradation products occurs rapidly and most likely via urine. There is no indication of biodegradation.

 

References

Allen LM, Briggle TV, Pfaffenberger CD (1982). Absorption and excretion of cyanuric acid in long-distance swimmers. Drug Metab Rev. 1982;13(3):499-516.

Berufsgenossenschaft der chemischen Industrie (BG Chemie), Toxikologische Bewertung – Cyanursäure, Nr 103, Ausgabe 10/92, 1993