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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
histopathology limited to kidneys and urinary tract
Principles of method if other than guideline:
The 59 day study was designed to evaluate the toxicity of s-triazinetriol monosodium salt (cyanuric acid, monosodium salt) to rats and to establish dosage levels to be used in a 13 week toxicity study.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): s-triazinetriol monosodium salt (cyanuric acid, monosodium salt) equivalent to 77.34% CYA.
- Substance type: fine white powder

Test animals

Species:
rat
Strain:
other: Charles River CD® rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan, USA
- Age at study initiation: ~ 3 weeks
- Weight at study initiation: Males: 84 – 100 g, Females: 84 – 101 g
- Housing: wire-mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-70
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: A suitable amount of the test compound was dissolved in tap water, on a stir plate to yield test solutions. The pH of the test solutions was adjusted to 7.2-7.6 (using sodium hydroxide and glacial acetic acid) and the solutions aged for 4 days in vented containers at room temperature. Before the test solutions were offered to the animals, the pH was readjusted to 7.2 - 7.6, if necessary. Fresh test solutions were prepared twice a week, 4 days prior to administration.


Duration of treatment / exposure:
28 days extended to 59 days
Frequency of treatment:
Continuous
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Dose / conc.:
400 ppm
Remarks:
males - 49 mg/kg bw/day; females - 65 mg/kg bw/day
Dose / conc.:
1 200 ppm
Remarks:
males - 141 mg/kg bw/day; females - 264 mg/kg bw/day
Dose / conc.:
2 000 ppm
Remarks:
males - 260 mg/kg bw/day; females - 370 mg/kg bw/day
Dose / conc.:
4 000 ppm
Remarks:
males - 521 mg/kg bw/day; females - 717 mg/kg bw/day
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily/7 days a week


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly


BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly


FOOD CONSUMPTION: Yes
- Time schedule for examinations: Weekly



WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Three times a week


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of study (week 9)
- How many animals: all animals
- Parameters checked: haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and reticulocyte count.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study (week 9)
- How many animals: all animals
- Parameters checked: glucose, cholesterol, blood urea nitrogen, total bilirubin, creatinine, total protein, albumin, alkaline phosphatase, serum glutamic oxaloacetate transamine, serum glutamic pyruvic transaminase, calcium, lactic dehydrogenase, phosphorous, sodium, potassium, chloride, globulin, (calculated) and osmolarity


URINALYSIS: Yes
- Time schedule for collection of urine: end of study (week 9)
- Metabolism cages used for collection of urine: Yes
- Parameters checked: colour and appearance, volume, osmolality, specific gravity, pH, protein, glucose, occult blood ketones, bilirubin, nitrite, urobilinogen, microscopic examination of sediment, sodium, potassium, chloride, phosphorous, calcium, creatinine, urea nitrogen


Sacrifice and pathology:
GROSS PATHOLOGY: : All gross lesions, adrenals, eye, trachea, duodenum, jejunum, ileum, cecum, colon, ureters, brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, submaxilliary salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, spleen, heart, lungs with bronchi, aorta, gonads, uterus, prostate, urinary bladder, gall bladder (mouse), mesenteric lymph node, peripheral nerve, bone marrow, skin, mesenteric lymph node, sternum, skeletal thigh muscle, peripheral nerve

HISTOPATHOLOGY: Microscopic examination of hematoxylin and eosin stained sections of ureters, urinary bladders and Buoin’s fluid fixed kidneys for all animals in the control group, s-triazinetriol monosodium salt treated groups. Histopathology was not performed on terminal sacrifice animals treated with the chlorinated compounds.
Statistics:
All statistical analyses compared the treatment groups of each compound with the control group, by sex.
Body weights (weeks 4 and 8), water consumption (weeks 4 and 8), haematological, biochemical and urinalysis parameters (day 59) and absolute and relative organ weights (terminal sacrifice) were compared by ANOVA. Dunnett’s multiple comparison tables were used to judge significance of difference.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
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

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
> 521 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No evidence of toxicity reported
Dose descriptor:
LOAEL
Effect level:
717 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No evidence of toxicity reported
Dose descriptor:
NOAEL
Effect level:
521 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No evidence of toxicity reported
Dose descriptor:
NOAEL
Effect level:
717 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No evidence of toxicity reported

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Haematology:

All values were within the normal range.  Occasional values were statistically significant, although the absolute differences were small. Albumin, globulin and serum protein values were slightly elevated in high dose males which may be suggestive of hemoconcentration, although water consumption and urine volume were normal.

Clinical chemistry:

All values were within the normal range. Occasional values were statistically significant, although the absolute differences were small.  Glucose values for males and females at the 4000 ppm dosage level were significantly greater than the control values, although the difference between the high dose and control values was not.  All values were within the normal range for this laboratory

Urinlaysis:

Urine values were within the normal range, except for urea nitrogen which was significantly decreased in female rats at 1200 ppm and in both male and female rats at 4000 and 8000 ppm, by around 50%.

Organ weights:

No statistically significant organ weight variations of livers and kidneys were noted

Gross and histopathology:

No gross or microscopic lesions of treatment-related significance were noted

Applicant's summary and conclusion

Conclusions:
LOAEL (CYA) >521 mg/kg bw/d (males); >717 mg/kg bw/d (females)
NOAEL (CYA) 521 mg/kg bw/d (males); 717 mg/kg bw/d (females)