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Key value for chemical safety assessment

Effects on fertility

Description of key information

A 3-generation reproductive study using monosodium cyanurate (equivalent to EU Method B.35) showed no biologically detrimental effect on the reproductive potential of the parents or on the growth and development of the offspring.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test guideline (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to
Guideline:
EU Method B.35 (Two-Generation Reproduction Toxicity Test)
GLP compliance:
yes
Species:
rat
Strain:
other: Charles River CD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, USA.
- Housing: Wire mesh cages
- Diet : ad libitum
- Water: ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 50 ± 15%
- Air changes (per hr): 10-11
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: drinking water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
A factor of 1.2979 was utilized in dosage calculations to adjust for the base composition (77.05%) of cyanuric acid in the test article. The appropriate amounts of the sodium salt of cyanuric acid (s-triazinetriol) were dissolved in tap water, utilizing a motor driven propeller, to permit administration at concentrations of 400, 1200 and 5375 ppm of s-triazinetriol. Each test solution was adjusted to a pH of 7.4 at approximately 25°C using glacial acetic acid or a 1% sodium hydroxide solution. The amounts of acid or base used were recorded. Fresh test solutions were prepared twice each week.

Details on mating procedure:
- M/F ratio per cage: 1 male per two females
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug and or vaginal smear referred to as day 0 of gestation
- After 7 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- The F0 and F1 parents were mated twice to produce 'a' and 'b' offspring, the F2 parents were mated once to produce the F3 offspring
Duration of treatment / exposure:
Exposure period: Treatment was initiated at 36 days of age to the F0 generation and at 21 days of age to F1 and F2 parents of both sexes. Test solution was administered until termination of each generation
Premating exposure period (males): F0: minimum 100 days (14 weeks) of treatment, F1 and F2: minimum 120 days of treatment.
Premating exposure period (females): F0: minimum 100 days (14 weeks) of treatment, F1 and F2: minimum 120 days of treatment.
Frequency of treatment:
Ad libitum
Remarks:
Doses / Concentrations:
400, 1200 and 5375 ppm (males F0 ~35, ~100, ~470 mg/kg bw/d; F1 ~36, ~110, ~500 mg/kg bw/d; F2 ~40, ~110, ~485 mg/kg bw/d; females, F0 ~64, ~185, ~950 mg/kg bw/d; F1 ~63, ~190, ~910 mg/kg bw/d; F2 ~65, ~195, ~970 mg/kg bw/d)
Basis:

No. of animals per sex per dose:
12 males 24 females / dose level
Control animals:
other: Vehicle (tap water), Sodium control (sodium hippurate 8056 ppm)
Details on study design:
The concentration of sodium hippurate was selected to permit the administration of an equal concentration of ionic sodium as that contributed by the test article at the high dose level.

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice each day
- Cage side observation included signs of overt toxicity, changes in general appearance, behaviour and mortality.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION: Yes
- Time schedule for examinations: Weekly except during mating mating periods


Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 / F3 offspring:
The number and sex of pups, stillbirths, live births, presence of gross anomalies, weight gain, physical or behavioural abnormalities, pup survival through weaning, pup weight at birth and specified intervals during lactation.



Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals
- Maternal animals: All surviving animals


HISTOPATHOLOGY:
Gonads and gross lesions

ORGAN WEIGHTS:
Adrenal glands, brain, heart, liver, ovaries (2), spleen, testes, epididymides (2) and thyroid.
Postmortem examinations (offspring):
SACRIFICE
- All F1b and F2b pups not selected as parents. All F3 pups retained after weaning.



ORGAN WEIGHTS:
Adrenal glands, brain, heart, liver, ovaries (2), spleen, testes, epididymides (2) and thyroid.

HISTOPATHOLOGY:
F1b and F2b pups (5/sex from control, high dose and sodium control) and F3 (5/sex/group) as follows: adrenals, aorta, bone (tibia with marrow), brain (longitudinal section), colon, duodenum, esophagus, eyes, heart, ileum, jejunum, kidney, liver, lungs, lymph node (mesenteric), mammary gland, ovaries, pancreas, pituitary, peripheral nerve, prostate, salivary gland, seminal vesicles, skeletal muscle, skin (with cervical lymph node), spleen, stomach, testes (with epididymis), thymus, thyroid (with parathyroids), thrachaea, urinary bladder, uterus, cervix, all the gross lesions, tissue masses, spinal cord and ureter
Statistics:
Analysis compared the treated groups to the control and sodium control groups and the control and sodium control groups were compared to each other. The parental body weights by sex were analyzed by one-way analysis of variance, Bartletts test for homogeneity of variances and the appropriate t-test (for equal or unequal variances). In all generations analyses were conducted at one week prior to the first mating, one week prior to the second mating and at termination of the generation. In addition, analyses were conducted at initiation of the F1 and F2 generations. Male and female indices were compared using the Chi-square test criterion with Yates' correction for 2 x 2 contingency tables and/or Fishers exact probability test. The proportion of live pups at birth per total number born and the survival indices at lactation days 4, 7, 14 and 21 were compared by the Mann-Whitney U-test. The mean numbers of liveborn pups per litter and mean body weights of pups were analyzed by one-way analysis of variance, Bartletts test for homogeneity of variances and the appropriate t-test (for equal or unequal variances). Organ weights by sex were analyzed by one-way analysis of variance, Bartlett's test for homogeneity of variances, and the appropriate t-test (for equal or unequal variances).
Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
MALES:
Appearance, behaviour and mortality: 2 control, 2 high-dose and 1 sodium control males failed to survive to scheduled sacrifice. One male control and one male in the high dose groups were sacrificed in extremis. All deaths and sacrifices occurred between weeks 11 and 34. Surviving animals showed no biologically significant effects.
Body weights: no biologically significant effects were observed.
Food consumption: no effects.
Water consumption: no treatment effect was presumed.

FEMALES:
Appearance, behaviour and mortality: no effects.
Body weights: no biologically significant effects were observed.
Food consumption: no effects.
Water consumption: an increase in high dose females was observed.
Dose descriptor:
NOAEL
Effect level:
ca. 470 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse treatment-related effects observed.
Dose descriptor:
NOAEL
Effect level:
ca. 950 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse treatment-related effects observed.
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
effects observed, treatment-related
F1 MALES:
Appearance, behaviour and mortality: one male in each of the high dose and sodium control groups failed to survive to scheduled sacrifice. Surviving animals showed no biologically significant effects.
Body weights: a slight to moderate increase in the high dose and sodium control groups were observed.
Food consumption: no effects.
Water consumption: no treatment effect was presumed.

F1 FEMALES:
Appearance, behaviour and mortality: one female from each of the control, low and mid dose and sodium control groups between week 38 and 63 exhibited no overt clinical signs prior to death. One control group female was sacrificed in extremis during study week 61. Surviving animals showed no biologically significant effects.
Body weights: a slight to moderate increase in the high dose and sodium control groups were observed.
Food consumption: no effects.
Water consumption: an increase in high dose and sodium control females was observed.

F2 MALES:
Appearance, behaviour and mortality: one 400 ppm male died during week 98. Two males in the 5375 ppm group died, one at week 83, one at week 100. Surviving animals showed no biologically significant effects.
Body weights: no biologically significant effects were observed. An increased incidence of calculi in the urinary bladder in the 5375 ppm males was related to the test article.
Food consumption: no effects.
Water consumption: no treatment effect was presumed.

F2 FEMALES:
Appearance, behaviour and mortality: one 400 ppm female died immediately prior to initiation of the generation. One female died in the sodium control group on day 20. Surviving animals showed no biologically significant effects.
Body weights: a slight to moderate increase in the mid dose group was observed.
Food consumption: no effects.
Water consumption: an increase in high dose and sodium control females was observed.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No adverse treatment-related effects observed.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
910 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse treatment-related effects observed.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 110 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
gross pathology
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
ca. 970 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse treatment-related effects observed.
Reproductive effects observed:
not specified

S-triazinetriol had no significant effect on survival, appearance or behaviour including nesting and nursing behaviour.  No cross generational trends indicative of a test article effect on parental body weight was noted, nor was food consumption affected.  A consistent cross generational trend of increased water consumption was noted in high dose females, which in the F1 and F2 generations was accompanied by a concurrent increase in sodium control female values, although the role of increased sodium intake versus that of cyanuric acid is unclear. 

The survival, general appearance, behaviour, mean body weights and food and water consumption of retained F3 pups were uniform in all study groups.  Treatment with s-triazinetriol at concentrations of 5375 ppm or less did not induce significant fluctuations in reproductive or litter parameters.  Fertility indices, gestation length, litter size, pup survival to weaning and pup weights at parturition and throughout lactation of treated groups, including the sodium control were comparable to those of the controls.  An increased incidence of calculi in the urinary bladder in 5375 ppm F2 males was related to the test article.  The findings with respect to female water consumption in the high-dose group and the post-mortem urinary bladder findings in the high-dose F2 males had no biologically detrimental effect on the reproductive potential of the parents or on the growth and development of the offspring

Conclusions:
No biologically detrimental effect on the reproductive potential of the parents or on the growth and development of the offspring.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There were no treatment related effects on the fertility of the parent generation. Fertility indices, gestation length, litter size, pup survival to weaning and pup weights at parturition and throughout lactation of treated groups, including the sodium control were comparable to those of the controls. An increased incidence of calculi in the urinary bladder in 5375 ppm F2 males was related to the test article. The findings with respect to female water consumption in the high-dose group and the post-mortem urinary bladder findings in the high-dose F2 males had no biologically detrimental effect on the reproductive potential of the parents or on the growth and development of the offspring.

Effects on developmental toxicity

Description of key information

Two pre-natal developmental toxicity studies are available. One performed in rabbits (Rodwell 1990) and another in rats  (Laughlin 1982)

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
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:
EU Method B.31 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Species:
rat
Strain:
other: Charles River CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: ~ 12 weeks
- Weight at study initiation: 219 – 288 g
- Housing: Wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 15 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 69
- Humidity (%): 36-68
- Air changes (per hr): 12.2-12.5
- Photoperiod: 12 hour light/dark


Route of administration:
oral: gavage
Vehicle:
other: 4% carboxymethyl cellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The appropraite amount of test article was weighed and suspended in the vehicle, 4% carboxymethyl cellulose, using a tissue homogenizer. The test article was prepared daily at concentrations of 1, 5 and 25% to permit administration at dosage levels of 200, 1000 and 5000 mg/kg/day at a constant volume of 20 ml/kg.

Details on mating procedure:
- Impregnation procedure:cohoused
- If cohoused:
- M/F ratio per cage: One male to one female
- Proof of pregnancy: vaginal smear referred to as day 0 of gestation
Duration of treatment / exposure:
days 6-15 post-mating
Frequency of treatment:
daily
Duration of test:
20 days
Remarks:
Doses / Concentrations:
200, 1000, 5000 mg/kg bw
Basis:

No. of animals per sex per dose:
25
Control animals:
other: Vehicle control and Sodium control (sodium hippurate) at 1118 and 5590 mg/kg/day
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality and once daily for clinical signs of toxicity on days 6 through 20 of gestation.


BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 6, 9, 12, 15, 18 and 20. Due to an error, two females in the 200 mg/kg group were weighed on gestation days 0, 5, 8, 11, 14, 17 and 20.



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter
Statistics:
All statistical analyses compared the treatment groups and the sodium control groups to both the vehicle control group and the untreated control group with the level of significance at p<0.01. In addition all statistical analyses compared the untreated control group with the vehicle control group at the same level of significance. The male to female fetal sex distribution and the number of litters with malformations were compared using the Chi-square test criterion with Yates' correction for 2 x 2 contingency tables and/or Fishers exact probability test as described by Siegal to judge significance of differences.
The number of early and late resorptions and postimplantation losses were compared by the Mann-Whitney U-test as described by Siegal and Weil to judge significance of differences.
The mean number of viable fetuses, total implantations, corpora lutea and mean fetal body weights were compared by analysis of variance (one-way classification), Bartlett's test for homogeneity of variances and the appropriate t-test (for equal or unequal variances) as described by Steel and Torrie using Dunnets multiple comparison tables to judge significance of differences.
Details on maternal toxic effects:
Details on maternal toxic effects:
11 females in the high dose sodium control group (5590 mg/kg/day) died between days 8 and 16 of gestation. Survival was 100% in all other groups.The mean maternal body weight in the high dose sodium control group was slightly reduced when compared to the control group.
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
A decrease was noted in the mean gravid uterus weights only in the high dose sodium control group. There were no treatment related differences in the number of viable foetuses, post implantation losses, total implantations and corpora lutea, the foetal sex distribution or in the mean foetal body weight or crown-rump length in the test groups when compared to the vehicle control groups. In the high dose sodium group mean foetal body weight and mean foetal crown-rump length were decreased compared to the vehicle control and untreated groups. An increased mean post implantation loss and a corresponding slight reduction in the mean number of foetuses were also noted in the high dose sodium group. These factors in the low dose sodium group were comparable to those in the vehicle control.
There was no dose dependent or statistically significant difference in the total number of litters with malformed foetuses in the monosodium cyanurate groups when compared to both the vehicle control and the untreated control group. In the high dose sodium control group an increased incidence of malformation in foetuses and litters were due primarily to an increased incidence of bent ribs in this group. In the high dose (5000 mg/kg) group the percentage of foetuses with variations in sternaebrae no. 1, 2, 3 and / or 4 unossified or vertebra reduced in ossification was increased when compared to the control. Additionally the high dose sodium control group also had sternebrae no. 5 and 6 unossified, entire sternum unossified or skull reduced in ossification. No such variations were observed in the low dose sodium group.
Dose descriptor:
NOAEL
Effect level:
5 000 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Monosodium cyanurate did not produce a teratogenic response when administered orally by gavage to rats at a dose level of 5000 mg/kg/day or less. Various effects were found in the high dose sodium control group. In addition there was an increased incidence of malformed foetuses in litters from the high dose sodium control group, namely bent ribs.
Endpoint:
developmental toxicity
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:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc. Denver, PA. USA
- Age at study initiation: 6 ½ to 7 months
- Weight at study initiation: 3 to 5 kg
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 28 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 61-70
- Humidity (%): 40-60
- Photoperiod: 12 hr light/12 hr dark


Route of administration:
oral: gavage
Vehicle:
other: 1% methyl cellulose in water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was ground by a mortar and pestle and sieved through a 40 mesh sieve prior to weighing. A specified amount of the test material for each group was then weighed out into a calibrated beaker. A sufficient amount of the vehicle was added and the mixtures were stirred to suspend the test material. An appropriate amount of the vehicle was added to obtain the desired concnetrations. The suspensions were stirred with a magnetic stir bar until homogenous. Dosing solutions were prepared weekly and stored in the refrigerator, Each suspension was stirred for 30 minutes prior to daily dispensing for dosing and continuously during dosing.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A sample of the vehicle and each dosage suspension was analyzed on the first day of dosing and near the end of the dosing period for verification of dosage concentration.
Details on mating procedure:
- Impregnation procedure: artificial insemination
Duration of treatment / exposure:
days 6-18 post insemination
Frequency of treatment:
daily
Duration of test:
29 days
Remarks:
Doses / Concentrations:
50, 200 and 500 mg/kg bw
Basis:

No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Maternal examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: clinical signs of toxicity including physical or behavioural abnormalities. Mortality checks were performed twice daily.



BODY WEIGHT: Yes
- Time schedule for examinations: Gestation day 0, 6, 9, 12, 15, 19, 24 and 29


FOOD CONSUMPTION: Yes
- Time schedule for examinations: Daily during gestation.



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29



Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
Statistics:
Statisitcal analyses were perforemd by a Digital Vax 11/730 computer. All analyses were two-tailed with a minimum significance level of 5%. One way analysis of variance followed by Dunnetts test was used to analyze maternal and fetal data inclufing body weights, food consumption, number of viable fetuses, implantation sites and corpora lutea. Mann-Whitney U test was used to compare post-implantation loss, dead fetuses, and resorptions. Fetal sex ratios were analyzed using the Chi-square test. Fishers Exact test was used to analyze the incidence and number of fetal malformations and variations utilizing the dam (litter) as the experimental unit.
Details on maternal toxic effects:
Details on maternal toxic effects:
One female at the 500 mg/kg level and two females at the 50 mg/kg group aborted on gestation days 22, 24 and 26 days respectively. No treatment related clinical signs of toxicity or statistically significant difference in body weights were observed during the study. No treatment related gross abnormalities were observed. Slight body weight losses or lack of body weight gains appeared to parallel slightly smaller sizes of litters and reduced proportion of males in litters at 200 and 500 mg/kg bw/d.
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
At the 500 mg/kg level there was a statistically significant increase in post-implantation loss, primarily related to one dam with 7 late resorptions. A statistically significant difference in the foetal sex ratio at the 50 mg/kg level was considered incidental, although non significant reductions occurred at higher dose levels. No treatment related differences were noted in gravid uterus weight, foetal body weight or foetal malformation data
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No treatment related statistically significant clinical signs of toxicity or difference in body weights were observed during the study. Maternal toxicity (body weight gain, food consumption) was claimed at 200 and 500 mg/kg levels. This was in parallel with a slight reduction in numbers of foetuses/litter and changes in sex ratio of foetuses. There was no evidence of developmental toxicity in the absence of maternal toxicity
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Maternal Toxicity:

In a study conducted by Rodwell (1990) one female at the 500 mg/kg level and two females at the 50 mg/kg group aborted on gestation days 22, 24 and 26 days respectively.  A slight reduction in bodyweight was observed and appeared to correspond with a slight reduction in litter size. However no treatment-related clinical signs of toxicity or gross abnormalities were observed.

In the study conducted by Laughlin (1982),11 females in the high dose sodium control group (5590 mg/kg/day) died between days 8 and 16 of gestation.  Survival was 100% in all other groups. The mean maternal body weight in the high dose sodium control group was slightly reduced when compared to the control group.

Developmental Toxicity/ Teratogenicity:

Rodwell (1990), showed that there was a statistically significant increase in post-implantation loss at the 500 mg/kg level. This was primarily related to one dam with 7 late resorptions.  No treatment related differences were noted in gravid uterus weight, foetal body weight or foetal malformation data.

In the study conducted by Laughlin (1982), treatment-related effects such as a reduction in group mean foetal body weight and mean foetal crown-rump length and an increase in post-implantation losses were observed in the high-sodium dose group. In the low sodium dose group these parameters were found to be comparable to the controls. In addition there were some incidences of foetal malformations in the high dose group only.

Justification for classification or non-classification

In the rat teratogenicity study, monosodium cyanurate administered by gavage did not produce a teratogenic response at a dose of 5000 mg/kg bw/day or below. In the rabbit teratogenicity study, via oral exposure, the NO(A)EL maternal toxicity based on the statistical significance of the toxicological observations is 500 mg/kg bw/day. However, there was no evidence of developmental toxicity in any of the treated groups. Hence the NO(A)EL for developmental toxicity was assessed to be at least 500 mg/kg bw/day.

Oral exposure of monosodium cyanurate in the rat fertility study did not produce any consistent effects on reproductive parameters or offspring toxicity; therefore 5375 ppm (470 - 500 mg/kg bw/day for males and 910 - 970 mg/kg bw for females) is assessed as the NOEL for CYA for reproductive and offspring effects. Under the test conditions, the NO(A)EL for adult toxicity of the monosodium cyanurate is 5375 ppm (males = 470 mg/kg bw/day, females 910 mg/kg/day) with the exception of F2males where the NOEL = 1200 ppm (190 mg/kg/day). This is based on the related incidence of calculi in the urinary bladders of high dose animals seen at the highest dose level. On this basis no classification is warranted for cyanuric acid.