WHO FOOD ADDITIVES SERIES: 52

First draft prepared by

Mr J. Fawell
Buckinghamshire, England

Sodium dichloroisocyanurate is the sodium salt of a chlorinated hydroxytriazine and is used as a source of free available chlorine (in the form of hypochlorous acid, HOCl) for the disinfection of drinking-water. Sodium dichloroisocyanurate can be manufactured either as the anhydrous salt or as the dihydrate. It has not been evaluated previously by the Committee. At its present meeting, the Committee considered the safety of sodium dichloroisocyanurate in relation to its possible use as a disinfectant for drinking-water in emergency situations, and for routine use in some water supplies.

When sodium dichloroisocyanurate is added to water, it is rapidly hydrolysed to release free available chlorine, establishing a complex series of equilibria involving six chlorinated and four non-chlorinated isocyanurates. As free available chlorine is consumed by reaction with organic material in the water, chloroisocyanurates will rapidly dissociate and continue to release free chlorine. Conventional chlorination of drinking-water with elemental chlorine gives rise to a number of by-products as a result of the reaction of free available chlorine with natural organic matter. The safety of these by-products has been addressed by WHO, with the development of guidelines for drinking-water quality. The use of sodium dichloroisocyanurate as a source of free available chlorine is not expected to lead to greater production of such by-products than does the use of elemental chlorine.

In contact with saliva of about pH 7.0, chlorinated isocyanurates react extremely rapidly such that, at the concentrations required to deliver free available chlorine at the levels typically used in drinking-water, no detectable chlorinated isocyanurate remains. The material that reaches the gastrointestinal tract is, therefore, the unchlorinated cyanuric acid (Oxychem, 1997, 2000). The relevant toxicological studies cited refer to this compound.

2.1.1 Sodium dichloroisocyanurate

No information was available.

2.1.2 Sodium cyanurate

Rats

In a study in which groups of five male rats and five female rats were given an intravenous bolus dose of ¹⁴C-labelled sodium cyanurate of 5 mg/kg bw, the compound was rapidly distributed through the body, with an elimination half-time of 30–40 min. Other groups were given a dose of 5 mg/kg bw or 500 mg/kg bw, by gavage. At a dose of 5 mg/kg bw, the cyanurate was almost completely absorbed and the peak blood concentrations occurred 15–30 min after administration. The elimination half-times were 30–40 min after the intravenous dose and 40–60 min after the oral dose. Eighty-five per cent and 80% of the administered dose in males and females respectively was excreted in the urine as the parent compound. At the peak blood concentration, cyanurate was distributed between plasma and blood cells in equal proportions.

As part of the same study, another group received oral doses of sodium cyanurate of 5 mg/kg bw per day for 14 days and were given an equivalent dose of ¹⁴C-labelled sodium cyanurate on day 15. This produced a similar excretory profile to that in animals given a bolus dose by oral or intravenous administration, with most of the radioactivity being excreted in the urine within 6 h and only very small amounts being detected after 24 h, faecal excretion representing about 5% of the administered dose.

The pattern of excretion following a single oral bolus dose of 500 mg/kg bw was different, with 70% and 55% of the administered dose in males and females respectively appearing in the faeces. The peak blood concentration occurred 60 min after dosing and the elimination half-time was 122–148 min, but with most of the cyanurate being excreted in urine within 24 h. All of the radioactivity could be accounted for as cyanurate except in animals receiving either multiple doses or a single dose of 500 mg/kg bw, when <0.5% of the radioactivity excreted was not cyanurate and was excreted before the 24-h time point. It was not possible to identify the substance responsible, but the authors suggested that its appearance might be a consequence of microbial action. No radioactivity was exhaled as ¹⁴CO₂.

After 7 days, the level of radioactivity in the tissues was undetectable or at the limits of detection (Barbee et al., 1983, Chadwick et al., 1983).

Dogs

In a study of similar design in dogs, groups of four males and four females were given radiolabelled cyanurate as a single intravenous dose of 5 mg/kg bw or a single oral dose of 5 or 500 mg/kg bw. Blood samples were collected at regular intervals from two males and two females and faeces and urine were collected from a further two males and two females. At the completion of the collection period, the animals from which faeces and urine had been collected were killed and 14 tissues and the remains of the carcass were analysed for residual radioactivity. An additional group of two males and two females was given unlabelled cyanurate orally at a dose of 5 mg/kg bw per day for 14 days and an equivalent dose of radiolabelled cyanurate on day 15.

Most of the radiolabelled cyanurate was excreted in the urine within 12 h, with minor amounts appearing after 24 h in all the animals receiving a dose of 5 mg/kg bw. In three of the animals receiving multiple doses, between 6% and 13% of the administered dose was excreted in the faeces, while in the other animals no more than 2% was excreted by this route. Animals receiving a dose of 500 mg/kg bw excreted between 27% and 86% of the administered dose in the faeces and the remainder in the urine. The elimination half-life was 1.5–2.0 h for both doses. However, there was some difficulty in determining the elimination kinetics, which the authors ascribed to continued absorption from the gastrointestinal tract. There was no evidence from blood kinetics for a slower elimination phase.

All of the excreted material was present as unchanged cyanurate. The residual level of radioactivity in all tissues was below the sensitivity of the method used. The total recovery in excreta ranged from 81% to 100%, with a mean of 93%; recovery in faeces was negligible for animals receiving the low dose (Barbee et al., 1984, Chadwick et al., 1982).

These data are supported by a study in rats receiving [¹⁴C]cyanuric acid by oral administration; more than 99% of the radioactivity in urine comprised the parent substance. These authors also showed that no systemic radioactivity could be detected after percutaneous exposure (Inokuchi et al., 1978).

Humans

Absorption and excretion of cyanuric acid has been studied in long-distance swimmers exposed by swimming in pools disinfected with chlorinated isocyanurates, and in two volunteers given an unspecified solution of cyanuric acid orally. More than 98% of the administered dose was recovered unchanged in urine after 24 h. The half-life of excretion was about 3 h (Allen et al., 1982).

In contact with saliva at about pH 7.0, chlorinated isocyanurates react extremely rapidly such that, at the concentrations required to deliver free available chlorine at the levels typically used in drinking-water, no detectable chlorinated isocyanurate remains. The material that reaches the gastrointestinal tract is, therefore, the unchlorinated cyanuric acid. The relevant toxicological studies cited refer to this compound.

2.2.1 Acute toxicity

(a) Sodium dichloroisocyanurate

The acute oral LD₅₀ for sodium dichloroisocyanurate (dihydrate) in rats was 1823 mg/kg bw (95% CI, 1479–2166 mg/kg bw), the acute oral LD₅₀ in males and females being 2094 and 1671 mg/kg bw respectively. The acute dermal LD₅₀ in rabbits was >5000 mg/kg bw (Gargus, 1984, 1985).

(b) Sodium cyanurate

The acute oral toxicity of sodium cyanurate and cyanuric acid in mice, rats and rabbits is reported to be between 1500 mg/kg bw and 10 000 mg/kg bw. The available data are summarized in Table 1.

Table 1. Acute oral toxicity of cyanuric acid and sodium dichloroisocyanurate

From Tice, R. (1997) (all references cited in this publication)

LLD, lowest lethal dose

2.2.2 Short-term studies of toxicity

(a) Sodium dichloroisocyanurate

In early, limited studies in rats, sodium dichloroisocyanurate was administered in the drinking-water to groups of five male and five female rats, at a concentration of 0, 400, 1200, 4000 or 8000 mg/l (equivalent to 50, 150, 500 or 1000 mg/kg bw per day) for 59 days. Mortality, laboured breathing, reduced body weight and a reduction in water consumption were observed in the groups receiving concentrations of 4000 or 8000 mg/l. Water consumption was also reduced in the groups receiving sodium dichloroisocyanurate at a concentration of 400 or 1200 mg/l. No histopathology was carried out, but animals in the group receiving 8000 mg/l exhibited an increased incidence of gastrointestinal bleeding at necropsy, although the site of bleeding was not identified. The NOEL was reported as 50 mg/kg bw per day in males and 130 mg/kg bw per day in females (Hammond et al., 1986).

In a subsequent study in which rats were given sodium dichloroisocyanurate in the diet at a concentration of 0, 2000, 6000 or 12 000 mg/kg of feed (equivalent to 0, 100, 300 or 600 mg/kg bw per day) for 13 weeks, body weights and food consumption were reduced in the groups receiving sodium dichloroisocyanurate at 6000 and 12 000 mg/kg of feed. Relative liver and kidney weights were also increased in these groups. No other treatment-related changes, including histopathological changes, were reported. The NOEL was 2000 mg/kg feed (100 mg/kg bw per day) (Hammond et al., 1986).

(b) Sodium cyanurate

Groups of 25 male and 25 female B6C3F₁ mice received drinking-water containing sodium cyanurate at a concentration of up to 5375 mg/l (the limit of solubility at pH 7.0), equivalent to 0, 252, 522 or 1500 mg/kg bw per day, for 13 weeks. Control groups were given either sodium hippurate at a concentration of 7769 mg/l (sodium control), or tap water. Five animals of each sex from each group were killed after 6 weeks; all other animals were killed after 13 weeks. All animals were subjected to clinical pathological, gross pathological and histopathological examinations, and organ weights were measured. Increased water consumption was noted in the group receiving a dose of cyanurate of 1500 mg/kg bw per day. Absolute and relative ovarian weights showed a dose-related increase, which was significant in the groups given doses of 522 and 1500 mg/kg bw per day, but the same finding was observed in the sodium control group. The only compound-related change reported was the occurrence of bladder calculi in two males in the group given the highest dose, 1500 mg/kg bw per day. The NOEL was 1792 mg/l (equivalent to 522 mg/kg bw per day) (Serota et al., 1982).

Groups of Charles River rats were given drinking-water containing sodium cyanurate at a concentration of 896, 1792 or 5375 mg/l, equivalent to 72, 145 or 495 mg/kg bw per day, for 13 weeks. Forty rats of each sex were assigned to each group receiving doses of 145 and 495 mg/kg bw per day and to a control group receiving tap water. Twenty-four rats of each sex were assigned to the group receiving 72 mg/kg bw per day and to a sodium control group receiving sodium hippurate (1792 mg/l). Measurement of haematological and biochemical parameters, and urine analysis were undertaken before the commencement of exposure and then at intervals of 2 weeks. Four males and four females from both control groups and from the group receiving 495 mg/kg bw per day were killed at weeks 2, 4, 6, 8, and 10 and the remainder of the animals were killed at week 13. Organ weights were measured and examinations of gross pathology and histopathology, with particular attention being paid to the kidney and urinary tract, were carried out on all animals. A number of male rats in the group given a dose of 495 mg/kg bw per day (weeks 6 and 8, 1/4; week 10, 2/4; week 13, 4/20) and one male from the group given a dose of 145 mg/kg bw per day at week 13 had epithelial hyperplasia of the bladder. The NOEL was 896 mg/l (72 mg/kg bw per day) in males and 1792 mg/l (495 mg/kg bw per day) in females. No treatment-related effects were observed in the kidney or in any other tissue (Rajasekaran et al., 1981).

2.2.3 Long-term studies of toxicity and carcinogenicity

(a) Sodium dichloroisocyanurate

No long-term studies of toxicity and carcinogenicity are available for sodium dichloroisocyanurate.

(b) Sodium cyanurate

Groups of 80 male and 80 female Charles River CD1 rats were given drinking-water containing sodium cyanurate at a concentration of 400, 1200, 2400 or 5375 mg/l, equivalent to about 0, 26, 77, 154 or 371 mg/kg bw per day, for a period of 2 years. An additional 20 rats of each sex per group were treated for 63 weeks and maintained until 104 weeks to examine recovery from any recorded changes. There were two control groups, a tap water control group and a sodium control group given 7768 mg/l of sodium hippurate. Ten animals were killed at 6, 12 and 18 months. Measurement of haematological and clinical chemistry parameters, urine analysis, examinations of gross pathology, histopathology and measurement of organ weights were performed on all animals in the control group and in the group receiving a dose of 371 mg/kg bw per day. More restricted examinations of pathology were performed for the other groups, although tissues were retained for subsequent examination if necessary. There were a number of changes in organ weights that were not consistent. At 12 months, the absolute and relative thyroid and parathyroid weights in males given doses of sodium cyanurate of 154 and 371 mg/kg bw per day were significantly lower (p <0.05) than those of the negative controls. There appeared to be no substance-related increase in tumour incidence.

Lesions of the urinary tract and heart were reported in males at the high dose. These were reported to occur mostly in the first 12 months of the study and were more frequent in animals that died or were killed because they were moribund. Nine of the 11 males with heart lesions receiving a dose of 371 mg/kg bw per day that died or were killed in the first year of the study also showed calculi in and distension of the bladder. Although urinary calculi were not found in all animals showing urinary tract lesions and cardiovascular lesions, it was postulated that a number of these calculi had been lost in fixation and an expert panel observed calculi fragments in a number of histological slides (Cohen et al., 1999). Since urolithiasis was more frequent in males than in females at the high dose and as the urethra is longer in males, the urinary tract lesions would be consistent with the presence of calculi. The authors of the study report considered that the urinary lesions, consisting of hyperplasia, bleeding and inflammation of the urinary bladder epithelium, inflamed ureters and renal tubular nephrosis were probably related to calculi, and that the acute myocarditis, necrosis and vascularmineralization were secondary to uraemia caused by the urinary tract lesions. There was an increased incidence of splenic haemosiderosis in the males receiving the high dose in the first year of the study. There was also a slight reduction in survival in the males given a high dose when compared to the negative control. Haematological and clinical chemistry parameters and urine analysis were reported to be unremarkable. There was a dose-related increase in water intake in the treated and sodium control groups, which was attributed to increased sodium intake. Water consumption in the groups maintained until week 104 returned to normal after cessation of treatment. The NOEL was 2400 mg/l (equivalent to 154 mg/kg bw per day) (International Research and Development Corporation, 1985).

In a similar 2-year study in which groups of 100 male and 100 female B6C3F₁ mice were given drinking-water containing sodium cyanurate at a concentration of 0, 100 (80 animals of each sex), 400, 1200 or 5375 mg/l (equivalent to about 0, 30, 110, 340 or 1523 mg/kg bw per day). A group of 80 males and 80 females was given sodium hippurate as a sodium control. Measurement of haematological and clinical chemistry parameters and urine analysis was carried out for 10 males and 10 females from each group before the start of treatment and at weeks 26, 52, 78 and 104. Ten males and 10 females from each group were sacrificed after weeks 27, 53 and 79 and, together with the animals participating in the studies of clinical pathology, were subjected to necropsy. Tissues were collected and the urinary tract and gross lesions from the control group and from the group receiving the high dose were subjected to histopathological examination. All animals found in extremis throughout the study were sacrificed and also subjected to gross and histopathological examination. At the termination of the study, in week 105, all remaining animals were sacrificed, subjected to gross pathological examination and the tissues collected into fixative. All of the tissues from the control group and the group receiving the high dose were subjected to examination by microscopy.

Survival was similar in all groups. There were no significant differences in body weights for males. Although body weights were generally lower in females in groups receiving sodium cyanurate at doses of 110, 340 or 1523 mg/kg bw per day and in the sodium control group, compared to the water control group up to week 24, the only significant difference was for the group receiving the high dose, at weeks 13 and 26. There was a dose-related increase in water consumption above that in the control group receiving water only in both males and females, but water intake was highest in the sodium control group. There were no treatment-related changes in haematological or clinical chemistry parameters, or urine analysis. Distended or enlarged abdomens were noted in males in the groups receiving the high and intermediate doses and in the sodium control group compared to the water control group, beginning at week 15. A similar effect was observed in females, but with a lower frequency. There were no treatment-related changes in the incidence of tumour or histopathological lesions at any dose (Serota et al., 1986).

2.2.4 Reproductive toxicity

(a) Sodium dichloroisocyanurate

In a study in which sodium dichloroisocyanurate was administered by gavage to pregnant mice of strain dd on days 6–15 of gestation at doses of 0, 25, 100 or 400 mg/kg bw per day, about 50% mortality was observed in animals receiving the high dose and reduced body weight was observed in the survivors. There were no signs of fetotoxicity, but delayed ossification associated with maternal toxicity was observed in the group receiving the high dose. This appeared to be an effect of the reaction of chlorine with the gastrointestinal tract (Tani et al., 1980).

(b) Sodium cyanurate

Groups of 25 pregnant Charles River COB and CD rats given sodium cyanurate at a dose of 0, 200, 1000 or 5000 mg/kg bw per day, by gavage, on days 6–15 of gestation, showed no signs of toxicity and no effects were reported in the off-spring. Two sodium control groups given sodium hippurate at doses of sodium equivalent to 1000 and 5000 mg/kg bw per day were also included in the study. There were no deaths except in the group receiving a high dose of sodium, in which 11 animals died, although the cause of death was not determined. Fetotoxic effects were also seen in this group (Laughlin et al., 1982).

In a study of teratology in which Dutch belted rabbits were given sodium cyanurate by gavage at a dose of 0, 50, 200 or 500 mg/kg bw per day on days 6–18 of gestation, maternal toxicity reflected by dose-related body-weight loss, was observed at doses of 200 and 500 mg/kg bw per day. Small decreases in mean fetal weight and crown–rump length were observed at 500 mg/kg bw per day, but these were not statistically significant (Consultox Laboratories Ltd, 1974).

In study of teratology in which groups of 20 pregnant New Zealand White rabbits were given doses of of sodium cyanurate of 0, 50, 200 or 500 mg/kg bw per day on days 6–18 of gestation, no maternal toxicity was observed. Animals in the groups receiving doses of 200 and 500 mg/kg bw per day showed reduced body-weight gain or slight body-weight loss on days 12–19 of gestation. An increased incidence of postimplantation loss was observed in the group given 500 mg/kg bw per day, although this was within the range of historical controls. There was an increased incidence of hydrocephaly in the group receiving 500 mg/kg bw per day (number of cases of hydrocephaly, 3, 0, 3 and 9 per group, respectively), but there was no apparent difference in the number of litters affected (1, 0, 2 and 2 litters affected per group, respectively). Hydrocephaly is not an uncommon finding in this strain of rabbits and although it normally occurs at a lower incidence, it is not considered to be a treatment-related effect (Rodwell, 1990).

Drinking-water containing sodium cyanurate at a concentration of 400, 1200 or 5375 mg/l (equivalent to about 26, 77, or 100 mg/kg bw per day) was given to three generations of Charles River CD rats. Control groups were given either tap water or a solution of sodium hippurate, 8056 mg/l, as a sodium control. For each generation, 12 males and 24 females were selected using randomized procedures. The F₀ generation was mated only after a minimum of 100 days of treatment and the F₁ and F₂ parents were only mated after at least 120 days of treatment. The ₀ and F₁ parents were mated twice to produce a and b litters and the F₂ parents were mated once to produce the F₃ offspring. As with other studies, an increase in water consumption was noted in females given the high dose; this was also noted in females of the F₁ and F₂ generations in the sodium control groups. There were no consistent effects reported for the offspring and no effects on reproduction were reported that could be associated with the administration of sodium cyanurate. There were treatment-related calculi observed in the bladder in males of the F₂ generation in the group receiving the high dose (100 mg/kg bw per day). These were associated with epithelial hyperplasia or chronic cystitis in three of the affected animals. The NOEL for reproductive effects was identified by the authors as 100 mg/kg bw per day (Aldridge et al., 1985).

2.2.5 Genotoxicity

Sodium cyanurate was not found to have mutagenic activity, either in the presence or absence of exogenous metabolic activation, in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, at a concentration of up to 10 000 µg/ plate, or in mouse lymphoma cells, at a concentration of up to 2000 µg/ml. Neither did it induce sister chromatid exchanges in Chinese hamster ovary cells in vitro at a concentration of up to 1500 µg/ml. No effects were observed in an assay for cytogenetic alterations in bone marrow of rats in vivo at a dose of 5000 mg/kg (Gridley & Ross, 1980; Kirby et al., 1981; Sharma, 1981; Stewart, 1981; Hammond et al., 1983).

2.2.6 Special studies: Immunotoxicity

Dichloroisocyanurate was not found to be a skin sensitizer in guinea-pigs (Mappes, 1984).

Although sodium dichloroisocyanurate is widely used as a disinfectant for swimming pools, it appears that no specific studies on the effects of this substance in humans have been carried out, apart from an early study on absorption and excretion in long-distance swimmers. In this study, absorption and excretion of cyanuric acid was studied in long-distance swimmers exposed by swimming in pools disinfected with chlorinated isocyanurates, and in two volunteers given a solution of cyanuric acid to drink (see also section 2.1). No correlation was found between excretion of cyanuric acid and urinary concentrations of gamma-glutamyl transpeptidase, measured as a potential marker of nephropathy (Allen et al., 1982).

A typical concentration of free available chlorine used for the treatment of drinking-water is 1 mg/l and normally the objective would be to achieve a residual of available chlorine of between 0.2 and 0.5 mg/l. As anhydrous sodium dichloroiso-cyanurate contains about 63% free available chlorine, a solution of sodium dichloroisocyanurate of 1.6 mg/l (or of the dihydrate, 1.8 mg/l) is equivalent to a solution of free available chlorine of 1 mg/l. Drinking-water becomes increasingly unpalatable as concentrations of free chlorine increase above this level. However, to overcome initial chlorine demand, disinfection using sodium dichloroisocyanurate might require higher initial doses, but not greater than double these quantities (i.e. 3.2 mg/l), according to WHO estimates. For emergency disinfection of raw or pre-treated (settled, coagulated, and/or filtered) drinking-water supplies (lakes, rivers, wells, etc.), sodium dichloroisocyanurate would be introduced to achieve an initial concentration of available chlorine of 10 mg/l and to maintain a concentration of 1 mg/l.

The default intakes of drinking-water currently used by WHO are 2 l per day for adults, 1 l per day for a 10-kg child, and 0.75 l per day for a 5-kg bottle-fed infant. WHO also recognizes that higher rates of intake may occur in some tropical countries. These intakes include water consumed in the form of juices and other beverages containing tap water (e.g. coffee), but no chlorinated isocyanurate would remain in these beverages. Thus, the daily intake of the dissociation products of sodium dichloroisocyanurate from the consumption of water by adults, children and infants, assuming a maximum application of sodium dichloroisocyanurate of 3.2 mg/l, would be equivalent to 6.4, 3.2, and 2.4 mg/person per day, expressed as sodium dichloroisocyanurate, respectively. Given that 1 mole of sodium dichloroisocyanurate corresponds to 1 mole of cyanuric acid (the ultimate product of the application of sodium dichloroisocyanurate), ingestion of cyanuric acid is estimated to be 0.06 mg/kg bw per day for adults, 0.19 mg/kg bw per day for children, and 0.28 mg/kg bw per day for a bottle-fed infant (WHO, 1993, WHO, 2000; Oxychem, 2003).

In studies in which ¹⁴C-labelled sodium cyanurate was administered in multiple doses of 5 mg/kg bw to rats, the sodium cyanurate was extensively absorbed and excreted unchanged in the urine, mainly within about 6 h. Only 5% of the administered dose was detected in the faeces and the radiolabel was not exhaled as ¹⁴CO₂. In a similar study in dogs, between 2% and 13% of ¹⁴C-labelled sodium cyanurate was excreted unchanged in the faeces and the remainder in the urine, mainly within 12 h. In two human volunteers given a solution of cyanuric acid of unspecified concentration, >98% of the cyanurate was recovered unchanged in the urine after 24 h. The elimination half-life was 40–60 min in the rat, 1.5–2.0 h in the dog and about 3 h in humans.

Both sodium dichloroisocyanurate and sodium cyanurate have low acute oral toxicity.

In 13-week studies in mice given drinking-water containing sodium cyanurate at a concentration of up to 5375 mg/l (equivalent to 1500 mg/kg bw per day), the only compound-related effect reported was the occurrence of bladder calculi in males receiving the highest dose. In a similar study in Charles River rats, 1/28 males in the group receiving sodium cyanurate at a concentration of 1792 mg/l (equivalent to 145 mg/kg bw per day) and 7/28 males in the group receiving the highest dose (equivalent to 495 mg/kg bw per day) showed epithelial hyperplasia of the bladder.

In a 2-year study, Charles River CD1 rats were given drinking-water containing sodium cyanurate at a dose estimated as 26, 77, 154 or 371 mg/kg bw per day, with control groups receiving drinking-water containing an equivalent amount of sodium hippurate, or untreated drinking-water. Survival was slightly lower in the group receiving the highest dose compared to the control group receiving untreated drinking-water, but not the control group receiving sodium hippurate. There was no substance-related increase in tumour incidence. Multiple lesions of the urinary tract (calculi and hyperplasia, bleeding and inflammation of the bladder epithelium, dilated and inflamed ureters and renal tubular nephrosis) and cardiac lesions (acute myocarditis, necrosis and vascular mineralization) were reported in males that died during the first year of the study and that were receiving a dose of 371 mg/kg bw per day. No toxicologically significant treatment-related effects were observed at 154 mg/kg bw per day, which was considered to be the NOEL in this study. In a similar 2-year study in which B6C3F₁ mice received a dose of sodium cyanurate equivalent to 30, 110, 340 or 1523 mg/kg bw per day, survival was similar in all groups and there were no treatment-related changes in the incidence of tumours or other histopathological lesions.

There were no signs of toxicity in adult animals and no effects reported in the offspring of groups of Charles River COB and CD rats given sodium cyanurate at doses of 0, 200, 1000 or 5000 mg/kg bw per day, by gavage, on days 6–15 of gestation. In studies in pregnant rabbits, either Dutch belted or New Zealand White, in which a dose of 0, 50, 200 or 500 mg/kg bw per day of sodium cyanurate were administered by gavage on days 6–18 of gestation, a small reduction in body-weight gain was observed in the groups receiving the two highest doses on days 12–19 of gestation in New Zealand White rabbits only, but compensatory body-weight gains were made by the end of the study. An increased incidence of post-implantation loss, which was within the historical control range, was also observed in this strain at 500 mg/kg bw. The Committee considered that these effects were not significant and there were no other effects that were considered to be related to treatment.

Three generations of Charles River CD rats were given drinking-water containing sodium cyanurate at an estimated dose of 26, 77 or 100 mg/kg bw per day, with control groups receiving untreated drinking-water or sodium hippurate. There were no treatment-related effects on reproductive parameters in the P₀, F₁ and F₂ generations or on offspring of the F₁, F₂ or F₃ generations.

Sodium cyanurate was not genotoxic in four different tests.

The Committee concluded that studies of the toxicity of sodium cyanurate were appropriate for assessing the safety of sodium dichloroisocyanurate, because any residues of intact sodium dichloroisocyanurate in drinking-water would be rapidly converted to cyanuric acid on contact with saliva. Sodium cyanurate did not induce any genotoxic, carcinogenic or teratogenic effects.

The NOEL for sodium cyanurate derived from the 2-year study in rats was 154 mg/kg bw per day, equivalent to 220 mg/kg bw per day as anhydrous sodium dichloroisocyanurate. With the application of an uncertainty factor of 100, a tolerable daily intake of anhydrous sodium dichloroisocyanurate of 0–2.0 mg/kg bw per day for intake from drinking-water treated with sodium dichloroisocyanurate for the purpose of disinfection was determined by the Committee.

The no-adverse-effect levels in the reported studies are summarized in Table 2.

Table 2. NOAELs for sodium dichloroisocyanurate and sodium

NA, not applicable

Aldridge, D., Schardin, J.L., Blair, M., Kopplin, J.R. & Richer W.R. (1985) Three-generation reproductive study in the rat with sodium salt of cyanuric acid (s-triazinetriol), (Report no. 497-001). Unpublished report from the International Research and Development Corporation. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Allen, L.M., Briggle, T.V. & Pfaffenberger, C.D. (1982) Absorption and excretion of cyanuric acid in long-distance swimmers. Drug Metab. Rev., 13, 499–516.

Barbee, S.J., Cascieri, T., Hammond, B.G., Inoue, T., Ishida, N., Wheeler, A.G., Chadwick, M., Hayes, D., MacCauley, M. & McComish, A. (1983) Metabolism and disposition of sodium cyanurate. Toxicologist, 3, 60.

Barbee, S.J., Cascieri, T., Hammond, B.G., Inoue, T., Ishida, N., Wheeler, A.G., Chadwick, M., Hayes, D., MacCauley, M. & McComish, A. (1984) Metabolism and disposition of sodium cyanurate. Toxicologist, 4, 92 (Meeting abstract).

Cascieri, T., Barbee, S.J., Hammond, B.G., Inoue, T., Ishida, N., Wheeler, A.G. & Schardein, J.L. (1983) Absence of teratogenic response in rats with monosodium cyanurate. Toxicologist, 3, 45 (Meeting abstract).

Chadwick, M., Hayes, D., McComish, M. et al. (1982) Disposition and metabolism of 14C-labelled sodium cyanurate in dog: Report No. C-86329. Unpublished report from Arthur D Little, Inc. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Chadwick, M., Hayes, D., Branfman, A. et al. (1983) Disposition and metabolism of ¹⁴C-labelled sodium cyanurate in rat: Report No. C-86329. Unpublished report from Arthur D Little, Inc. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Cohen, S.M., McKinney, L., Wagner, B.M., Weil, C., Goodman, J.I., Lotti, M., Portoghese, P. & Bernard, B.K. (1999) An evaluation of the long-term toxicity/carcinogenicity of sodium isocyanurate. Unpublished report to Occidental Chemical Corporation, February 25, 1999, provided to U.S. EPA and assigned MRID No. 44834403. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Consultox Laboratories Ltd. (1974) Monosodium cyanurate teratogenicity study in the rabbit: CL 73:101:899, (Cited in USEPA Reregistration eligibility document for chlorinated isocyanurates 1992). Unpublished report. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Gargus J.L., Phips N.G. & Ralph J.A. (1985) Acute oral toxicity study in rats dichlorocyanuric acid, sodium salt, dihydrate (Final report. Project No. 2291-100). Unpublished report from Hazleton Laboratories America provided to the US EPA and assigned MRID No. 150953. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

Gargus J.L. Phipps, N.G. & Gluck S.E. (1984) Acute dermal toxicity study in rats dichlorocyanuric acid, sodium salt, dihydrate, (sodium dichloro-s-triinetrione) Final report. Project No 2291-101. Unpublished report from Hazleton Laboratories America provided to the US EPA and assigned MRID No. 150954. Submitted to WHO by the Industry Ad Hoc Committee on Isocyanurates.

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    See Also:
       Toxicological Abbreviations