Symclosene

Carcinogenicity

Description of key information

2 year carcinogenicity studies in rats and mice were carried out according to EU method B.33. Studies showed that the monosodium salt of cyanuric acid was non-oncogenic by the oral route.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed to GLP and guideline

Qualifier:

according to guideline

Guideline:

EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)

GLP compliance:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Portage, Michigan, USA
- Age at study initiation: ~5 weeks old
- Weight at study initiation: males: 87.0 - 164.0 g; females 72.0 – 141.0 g
- Housing: wire mesh cages
- Diet: ad libitum
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 71 ± 1.3
- Humidity (%): 59 and 61 ± 8.2 and 7.9
- Photoperiod : Illumination provided 12 hours per day

Route of administration:

oral: drinking water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Fresh drinking water solutions were prepared 3 times weekly. The appropriate amount of test article was dissolved in tap water and mixed using a motor propellor. Solutions were preapred at concnetrations of 0.4, 1.2, 2.4 and 5.375 mg active s-triazinetriol per ml tap water to provide dosing solutions of 400, 1200, 2400 and 5375 ppm. The pH of the preapred drinking water solutions was adjusted to 7.4 at 25C using glacial acetic acid and/or sodium hydroxide.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

ad libitum

Remarks:

Doses / Concentrations:
0, 400 ppm, 1200 ppm, 2400 ppm, 5375 ppm (males ~ 25, 76, 154, 371 mg/kg bw/d; females ~ 42, 129, 266, 634 mg/kg bw/d).
Basis:

No. of animals per sex per dose:

Low dose group: 80/sex
Mid dose, mid-high dose and high dose groups : 100 /sex/dose level
Tap water control: 100/sex
Sodium control: 80/sex
Controls:
Tap water control: 100/sex
Sodium control: 80/sex

Control animals:

other: Vehicle (tap water), Sodium control (sodium hippurate)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly



BODY WEIGHT: Yes
- Time schedule for examinations: Recorded weekly, beginning with the pretest period, for the first 14 weeks of study and once every 2 weeks thereafter


FOOD CONSUMPTION: Yes
- Time schedule for examinations: recorded weekly for the first 14 weeks of the study, every 2 weeks thereafter

WATER CONSUMPTION AND COMPOUND INTAKE : Yes
- Time schedule for examinations: Weekly


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months
- Animals fasted: Yes
- How many animals: 10 rats/sex/group
- Parameters checked: total and differential leukocyte count, erythrocyte count, haemoglobin, haematocrit, platelet count, reticulocyte count, haematological indices mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCH).


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 6, 12, 18 and 24 months
- Animals fasted: Yes
- How many animals: 10 rats/sex/group
- Parameters checked: sodium, potassium, chloride, calcium, phosphorous, osmolality, alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, blood urea nitrogen, creatinine, total protein, albumin, globulin (calculated), cholesterol and glucose.


URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12, 18 and 24 months
- Animals fasted: Yes
- Parameters checked: colour and appearance, microscopic examination of sediment, volume, osmolality, pH, protein, glucose, occult blood, nitrites, bilirubin, ketones, urobilinogen, sodium, potassium, chloride, magnesium, phosphorous, calcium, urea nitrogen, creatinine and pH (meter).


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes all animals received a complete post mortem.
Organs: external examination; contents of the abdominal, thoracic and cranial cavities were examined both in situ and after removal and dissection. Adrenal, all gross lesions, all tissue masses, brain (fore-, mid-, and hind-), cecum, colon, duodenum, esophagus, eye and contiguous Harderian gland, heart with coronary vessels, ileum, jejunum, kidneys, liver (3 sections) lung and mainstream bronchi, lymph nodes (medistinal, mesenteric and regional), mammary gland, ovaries, pancreas, peripheral nerve (sciatic), pituitary, prostate / corpus and cervix uteri, mandibular salivary gland, skeletal thigh muscle, skin, spinal cord (cervical and thoracic), spleen, sternum bone marrow, stomach, testis with epididymus, thymus, thyroid and parathyroid, tongue, trachea, ureter, urinary bladder, whole head (including nasal, oral and otic tissue) and Zymbal’s gland.

HISTOPATHOLOGY: Yes a full tissue compliment was prepared for all animals in control and high dosage groups. Sections of the following organs from animals in the 400 ppm, 1200 ppm, 2400 ppm groups sacrificed at 6, 12and 18 months and all animals which died or were sacrificed in extremis between 0 and 24 months of study: adrenal, heart, kidneys, liver, ovaries, spleen, testes, ureter, urinary bladder, tissue masses and gross lesions. Gross lesions and tissue masses were microscopically examined for animals in the 400 ppm, 1200 ppm, 2400 ppm dose groups which survived to terminal sacrifice

Statistics:

Body weights and food consumption (weekly for weeks 1 – 4, quarterly thereafter) organ weights, (absolute and relative to body weights, interim and terminal sacrifices) clinical laboratory values (6, 12, 18 and 24 months prior to interim and terminal sacrifices) were analysed by Bartlett’s test for homogeneity of variance and analysis of variance (one-way classification). Treatment groups were compared to the control group and to the sodium control group by sex, using the appropriate t-statistic (equal or unequal variance) as described by Steel and Torrie and Ostle. Dunnett’s multiple comparison tables were used to determine significance. All statistical tests were two-tailed. Survival data and data on time to neoplastic lesion were analysed using the computer program of Thomas, Breslow and Gart. Statistical procedures included in this program are the Kaplan-Meier and standard methods for computing survival curves, Cox’s test for linear trend in proportions and both Cox’s test and Gehan-Breslow’s generalized Kruskall-Wallis test for comparing survival distributions. Data on time to neoplastic lesion were analysed for all benign tumours, all malignant tumours, all tumours combined and for individual type that appeared in two or more animals in the high dose group.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Red urine was observed for 5375 ppm group males (week 1 – 62) and appeared to be test article related and correlated with the high incidence of urinary bladder calculi. Decreased defecation and / or no faeces occurred more frequently for 5375 ppm group males (week 1 – 62) and a slightly higher incidence of yellow material (anogenital region, ventral surface, ventral abdomen, hindlimb) for 2400 and 5375 ppm female groups (weeks 14 – 39) and for the male rats in the 5375 ppm group (weeks 1 – 52). In weeks 14 – 52 some male rats in the 5375 ppm group were noted to feel cold to the touch.


BODY WEIGHT AND WEIGHT GAIN:
Male control and treatment withdrawal rats were similar in weeks 63 – 104. The body weight of the withdrawal rats was also similar to their respective male groups not placed on compound withdrawal. Group mean body weights of female rats receiving 2400 and 5375 ppm after withdrawal were higher compared to group mean body weights of female control withdrawal animals and non withdrawal females receiving 2400 and 5375 ppm


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Values of control and treatment withdrawal animals were similar in weeks 63 – 104.


WATER CONSUMPTION AND COMPOUND INTAKE:
Water consumption of male and female treatment groups and the sodium control group was higher than those of the control group. The increased water consumption appeared dose related. No definite trends in water consumption of the compound withdrawal group was evident. Average water consumption (weeks 63 – 104) of male and female 2400 ppm and 5375 ppm withdrawal groups was higher than those of male and female control groups during the recovery period. Male and female 5375 ppm withdrawal groups showed decreased average water consumption as compared to non withdrawal male and female 5375 ppm groups in weeks 63 – 104.



HAEMATOLOGY:
No significant treatment related effects were observed


CLINICAL CHEMISTRY
No results of pathologic significance were observed

URINALYSIS
No significant treatment related effects were observed

ORGAN WEIGHTS
There were no test article related organ weight variations in the treatment groups at any of the interim or terminal sacrifices.


GROSS PATHOLOGY
Calculi in the kidney (pelvis) or urinary bladder, hydronephrosis, hydroureter, blood in urine and distention of urinary bladder were test article related in male rats from the 5375 ppm group sacrificed at the 6 month interim, died / sacrificed in extremis during the 0 – 12 month period of the study. Urolithiasis was the primary lesion. None of the rats at 12, 18 or 24 months or any rat that died / sacrificed in extremis during the 12 – 24 month periods showed any test article effects.

HISTOPATHOLOGY: NON-NEOPLASTIC
No evidence of a test article related carcinogenic effect was observed in any tissues or organs examined microscopically from male or female rats from any of the experimental groups. A non neoplastic change of questionable toxicological significance occurred in the kidneys of a small number of female rats from the 5375 ppm group, which died or were sacrificed in extremis during the period 6 – 12 months.
Urinary tract lesions were probably related to the presence of urinary tract calculi. These lesions included hyperplasia of the urinary bladder epithelium, acute cystitis and haemorrhage in the bladder wall, which correlated with macroscopic observations of bladder calculi. Almost all test-article related urinary tract lesions were limited to male rats from the 5375 ppm group which died, were sacrificed in extremis or were electively sacrificed in the first 12 months of study with most occurring in animals which died or were sacrificed in extremis. Hydroureter was sometimes associated with bladder calculi, some dilated ureters were also inflamed and hemorrhagic. Test article related kidney lesions consisted of tubular nephrosis in some rats from the 5375 ppm group which died or were sacrificed in extremis during the period 6 - 12 months. Calculi were noted in the bladders of some affected males, no calculi were found in any of the affected females. Test article related urinary tract lesions only occurring in the first 12 months of study suggests that some males by the nature of their urinary tract structure were more prone to obstruction and succumbed early. Occurrence of bladder epithelial hyperplasia and associated test article related bladder lesions in rats which did not have grossly evident calculi is consistent with a calculus based mechanism. Calculi which were transiently present but which were small enough to pass on the urine stream would cause irritation during their residence in the bladder. Uremia due to urinary tract obstruction by calculi was the probable cause of death in animals in which calculi could not be passed.
Heart lesions in 5375 ppm males which died or were sacrificed in extremis during the first 12 months of study also had urinary bladder calculi and or distention at necroscopy suggesting that the heart lesions were of uremic etiology, secondary to urinary tract obstruction.
An increased incidence of splenic hemosiderosis in male rats of the 5375 ppm group was possibly test article related but did not correlate with any alteration in clinical pathologic parameters.

Dose descriptor:

NOAEL

Effect level:

ca. 154 mg/kg bw/day

Sex:

male

Dose descriptor:

NOAEL

Effect level:

ca. 266 mg/kg bw/day

Sex:

female

Conclusions:

No evidence of test article related carcinogenic effect was observed in any tissues or organs examined microscopically from male or female rats of any test group.

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study performed to GLP and guideline

Qualifier:

according to guideline

Guideline:

EU Method B.33 (Combined Chronic Toxicity / Carcinogenicity Test)

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Kingston, New York, USA.
- Age at study initiation: 6 weeks
- Weight at study initiation: males 15.5-21.1 g; females 14.6-18.5 g
- Housing: Stainless steel wire mesh cages
- Acclimation period: 13 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70± 4
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: drinking water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
For the treatment groups monosodium cyanurate was screened and double ground in a mortar and pestle to achieve a fine powder. The required amount of compound for the high dose group was weighed on an Arbor 126 electronic balance and transferred to a carboy which was then filled to the required volume with water. The mixture was stirred for approximately 2.5 hours until complete dissolution was achieved The solution mixed at the high dose level was used as the stock solution for dilutions required for the lower dose group. The pH was adjusted to 7.4 for all study groups using glacial acetic acid or sodium hydroxide as necessary. Fresh test and control solutions were prepared and presented twice weekly throughout the study.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Monosodium cyanurate was analyzed for cyanuric acid concentration. Two samples were analyzed weekly from approximately 1 through 7 and one samples was analyzed weeky from approximately weeks 9 through 105.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

ad libitum

Remarks:

Doses / Concentrations:
0, 100, 400, 1200, 5375 ppm as cyanuric acid (males: ~24, 97, 307, 1520 mg/kg bw/d; females: ~ 26, 100, 315, 1580 mg/kg bw/d)
Basis:

No. of animals per sex per dose:

Low dose group: 80/sex
Mid dose, mid-high dose and high dose groups : 100/sex/dose level
Tap water control: 100/sex
Sodium control: 80/sex

Control animals:

other: Vehicle (tap water), Sodium control (sodium hippurate)

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Three times daily
- Cage side observations checked included. Mortality and moribundity


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Recorded weekly from study initiation through week 14, and biweekly thereafter.


FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: ecorded weekly from study initiation through week 14, and biweekly thereafter.


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Twice each week at four and three-day intervals


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to initiation and after weeks 52 and 104.
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes (overnight)
- How many animals:10 mice per sex
- Parameters checked: Hematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, erythrocyte morphology, reticulocyte count, myeloid / erythroid ratio (bone marrow smear).


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: rior to initiation and after weeks 52 and 104
- Animals fasted: Yes (overnight)
- How many animals:10 mice per sex
- Parameters checked: blood urea nitrogen.


URINALYSIS: Yes
- Time schedule for collection of urine: 26, 52, 78 and 104 weeks
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (overnight)
- Parameters checked: Colour and appearance, volume, osmolality, pH, protein, glucose, blood, ketones, bilirubin, microscopic examination of sediment, zinc, copper, magnesium, chloride, inorganic phosphate, calcium, urea nitrogen, potassium, sodium, urobilinogen.


NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: mice used for clinical pathology including urinalysis and the weeks 27, 53 and 79 interim sacrifices. All surviving animals at week 105 were euthanized and examined. Animals which were found dead or sacrificed in extremis during the study were necropsied.

ORGANS: the external surface, all orifices, cranial cavity, carcass, external surface of the brain and spinal cord (performed post fixation), the nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera, the cervical tissues and organs.

HISTOPATHOLOGY: all preserved tissues from animals that were found dead or sacrificed in extremis as well as all control and high dose animals at terminal sacrifice were examined. Preserved tissues included all gross lesions and tumours, brain (at least 3 levels from the fore- mid- and hind-brain), pituitary, salivary gland, heart, thymus, thyroid with parathyroids, lung (2 corneal sections including all lobes and mainstream bronchi), trachea, esophagus, stomach, duodenum, jejunum, ileum, colon, cecum, adrenals, pancreas, gallbladder, liver (at least 2 lobes), urinary bladder, ureter with left and right identified, testes with epididymides, prostate, ovaries, corpus and cervix uteri, spleen, lymph nodes (all grossly enlarged, or otherwise abnormal nodes, nodes draining known and suspected tumour sites and nodes which show no gross abnormalities from other sites) skin, sciatic nerve, mammary gland, Zymbal’s gland (if present), bone (including marrow) from sternum or femur, skeletal muscle attached to tibio-femoral joint, spinal cord (2 levels), three coronal sections though the head (to include nasal cavity, paranasal sinuses, tongue, oral cavity, nasopharynx and middle ear, carcass and remaining viscera.
For animals surviving to study termination coronal sections of the head were examined microscopically from 10 animals per sex from each group. The kidneys, ureters, urinary bladder and gross lesions from 10 mice per sex from high dose and control groups at interim sacrifices were also examined microscopically. The tissues were processed by embedding in Paraplast®, sectioning and staining with hematoxylin and eosin.

Statistics:

Cumulative survival data through week 104 were analyzed using the National Cancer Institute Package. Groupwise comparisons were based on an analysis of all groups using the highest concentration of sodium hippurate that occurred on study.
Food and water consumption, body weight and growth rates, haematology (except leukocyte differentials and morphology), serum chemistry, urine chemistry and organ weight data were tested using Levene’s test for homogeneity of variance. If the variances proved to be homogenous, the data were analyzed by one-way ANOVA. If the variances proved to be heterogeneous, a series of transformations was performed until variance homogeneity was achieved, namely log10, square (X2), square root (X½), reciprocal (1/X), angular (arcsine X½) and rank, in that order. If one of the transformations was effective in achieving variance homogeneity, ANOVA of the transformed data was performed. If ANOVA of either untransformed or untransformed data was significant, the Games and Howell modification of the Tukey-Kramer honestly significant difference test was used for group mean comparisons. If ANOVA was not significant, the analysis was complete. If none of the transformations were effective in achieving variance homogeneity, the Terpstra-Jonckheere nonparametric test for trend and Kruskall-Wallis nonparametric one-way ANOVA and pairwise group comparisons were performed. Levene’s test, ANOVA, the Terpstra-Jonckheere test and the Kruskall-Wallis test were evaluated at the 5.0% one tailed probability level. Group comparisons by the Games and Howell test or the Kruskall-Wallis test were evaluated at the 5.0% and 1.0% two-tailed probability levels.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Increased incidences of swollen / enlarged abdomens were noted for the 1200 or 5375 ppm and the sodium control males beginning week 15 and continuing throughout the study. The incidences in the 5375 ppm males continued to be higher than the sodium control males. In the 100 and 400 ppm group males, the incidence of swollen / enlarged abdomens was similar to the control group.
In females, swollen / enlarged abdomens were observed less frequently than in the males, but after week 27 the incidences in groups treated with 1200, 5375 ppm and the sodium control were slightly higher than the control group females for several weeks.
A slightly increased number of occurrences of rough hair coat were noted in groups treated with 1200, 5375 ppm and the sodium control. Sporadic findings of tissue masses were observed in all groups of females except 1200 ppm, although the incidence was low and did not exceed 3.3% of the number of surviving females of groups at any given interval. Tissue masses were not observed in any of the male groups.



BODY WEIGHT AND WEIGHT GAIN
Female mean body weights of groups treated with 400, 1200 or 5375 ppm or the sodium control, were almost exclusively lower than control group for the first 24 weeks of the study. The mean body weight of the high dose (5375 ppm) group females were consistently lower than control through weeks 78, while by week 24, body weights in the 400 ppm and 1200 ppm groups were similar to the control group. Mean body weights were slightly higher in the sodium control group females than the control group females.
Significantly lower mean absolute body weights at weeks 13 and 26 in the 5375 ppm dose females compared to the control group were noted. Mean growth rates were significantly lower in the groups treated with 400, 1200, 5375 ppm and the sodium control compared to the control group from initiation to week 26.
At week 52 no statistically significant differences were noted in the body weights or growth rates of control and cyanurate treated females.
No significant differences were noted in the male body weights. The mean body weights of males in the high dose and sodium control groups fell below the mean body weight values of the control group for several weeks between weeks 28 and 78


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption: slightly decreased food consumption was noted most weeks during the first 26 weeks in the cyanurate treated females and in the cyanurate treated males during the first 13 weeks. Statistically significant lower mean total food consumption was observed for 5375 ppm dose males and females at 13 and 26 weeks and in males at 52 weeks.
The food consumption was higher for the 5375 ppm dose males than for the sodium control group males. For the females, food consumption was generally lower for the high dose group than for the sodium control group for the first 13 weeks and was comparable for those two groups after week 13. The food consumption in sodium control males was significantly lower than the control group.



WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
Mean water consumption was consistently higher for the 5375 ppm dose males and females compared to the control group. Water consumption was also generally increased for the sodium control group males and females. Water lost within the sipper tube as well as the additional handling / agitation contributed to the significantly increased mean water consumption values for the high dose group. 5375 ppm dose males mean water consumption was significantly higher than the control group mean value when the procedures were the same and 1200 ppm treated males were generally higher (occasionally significantly) than in the control group after week 10.

HAEMATOLOGY:
No significant differences between the control and treated groups and no indications of compound related effects were noted.


CLINICAL CHEMISTRY:
A statistically higher blood urea nitrogen level was noted in the sodium control females at termination. As the values for all female groups at week 53 and all male groups at weeks 53 and 105 were comparable this was not considered biologically important


URINALYSIS:
Mean urine sodium concentrations and excretion values were significantly higher in the 5375 ppm dose and sodium control females than the control group. At weeks 27, 79 and 105 the mean sodium values for the sodium control group females were generally higher than for the 5375 ppm dose females although at week 53 the mean sodium values for the two groups were similar. Slight to moderate increases were also noted in the mean sodiumconcentrations and excretion values of the males. The mean urine sodium excretion values of the 5375 ppm dose group were slightly lower than the sodium control males. The mean sodium concentrations were similar in the two groups at weeks 79 and 105, the high dose group values were less than the sodium control




ORGAN WEIGHTS:
Although there were statistically significant differences between the control group and the test groups on the ovary, heart, brain and kidney weights, these effects are considered incidental and unrelated to treatment due to lack of dose relationship and / or the effect at subsequent intervals.


GROSS PATHOLOGY:
No distinct compound related trends were observed

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic evaluation failed to reveal compound related histomorphologic alterations. Spontaneous disease lesions and incidental findings were noted but were of the expected frequency for mice of this age and strain and occurred without relationship to treatment. In the urinary system, the kidneys from all groups had lesions consistent with chronic nephropathy. There was a significant decrease in focal pituitary hyperplasia in the 5375 ppm group and the sodium control group compared to the control group. There was increased congestion in the mesenteric lymph node in the 5375 ppm group and the sodium control group compared to the control group females although this probably has little biological significance. Microscopic evaluation of tissues from mice receiving high doses of monosodium cyanurate failed to reveal specific treatment related histopathologic alterations consistent with the results of the 27, 53 and 79 week interim sacrifices.

Dose descriptor:

NOAEL

Effect level:

ca. 1 520 mg/kg bw/day

Sex:

male

Dose descriptor:

NOAEL

Effect level:

ca. 1 580 mg/kg bw/day

Sex:

female

No treatment-related effects on survival, clinical pathology (except urine sodium), organ weights, gross pathology, and histopathology were observed.

Apparent treatment-related effects on clinical signs (swollen/enlarged abdomens), body weights, food consumption, and urine sodium were generlly observed in both sexes treated with monosodium cyanurate at higher levels and in the sodium control group. The significance of these responses, however is unclear in terms of monosodium cyanurate treatment. These effects may well be the result of treatment with high levels of sodium, although the magnitude effect was generally more pronounced in the high-dose monosodium cyanurate group than in the sodium control group. The increased water consumption observed in the high-dose females appeared to be due to technical procedures rather than to treatment. The effect in the high-dose males appeared, at least in part to also be due to technical procedures although the possibility of a treatment related effect cannot be totally excluded.

Conclusions:

Monosodium cyanurate was not found to be oncogenic in mice

Endpoint conclusion

Dose descriptor:

NOAEL

154 mg/kg bw/day

Justification for classification or non-classification

In both studies, under the experimental conditions, there is no evidence of carcinogenic potential of the test material

Additional information

Two carcinogenicity drinking water studies with monosodium cyanurate monohydrate (77.4 - 77.5% CYA) were performed, one in the rat and the other in the mouse. In both studies there is no evidence of carcinogenic potential of the test material. The lowest NOEL derived was that in male rats 154 mg/kg bw/day (Blair M 1985) due to test substance related urinary tract lesions which occurred in the first half of the study. At the highest dose, the test substance precipitated in the urinary bladder. No treatment related effects were observed in the study performed with mice.