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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: according to information in OECD SIDS (2002)
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 10 weeks old, both sexes
- Weight at study initiation: 335-364 g for males, 233-263 g for females

IN-LIFE DATES:
- Treatment period, Males: 49 days (14 days before mating and 35 days including 14 days for mating)
Treatment period, Females: 40-46 days (from 14 days prior to mating to day 3 of lactation.)
- Frequency of treatment: Daily
- Post treatment observation period: 1 day
- Duration of test, Males: 50 days
Duration of test, Females: From 14 days prior to mating to day 4 of lactation.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
for injection
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
- Treatment period, Males: 49 days (14 days before mating and 35 days including 14 days for mating)
- Treatment period, Females: 40-46 days (from 14 days prior to mating to day 3 of lactation.)
Frequency of treatment:
Daily
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
Post-treatment observation period: 1 day
Observations and examinations performed and frequency:
Clinical observations performed and frequency:
- Clinical signs: Twice a day (just before and after administration)
- Body weight, Males: Twice a week
Body weight, Females: Twice a week for pre-mating and mating period, 0, 7, 14, 21st day of pregnancy and 0, 4th day of lactation period.
- Food consumption, Males: Twice a week for pre-mating period and after a mating period end.
Food consumption, Females: Twice a week for pre-mating period, 2, 9, 16, 21st day of pregnancy and 4th day of lactation period.

Hematological examinations (only for males):
Red blood cell count, white blood cell count, platelet count, hemoglobin concentration, hematocrit value, differential leukocyte counts,
protrombin time, activated partial thromboplastin time, fibrinogen, mean corpuscular volume, mean corpuscular hemoglobin,
mean corpuscular hemoglobin concentration, reticulocyte count.

Blood chemical examinations (only for males):
Total protein, albumin, A/G ratio, blood urea nitrogen, creatinine, glucose, total cholesterol, total bilirubin, triglyceride, sodium, potassium,
chloride, calcium, inorganic phosphorus, alkaline phosphatase, AST, ALT, gamma-GTP.

Urinary examinations (only for males): Urinalysis was conducted just before the termination of treatment, and the following items were examined:
Volume, specific gravity, color, pH, protein, glucose, ketone body, bilirubin, occult blood, urobilinogen, urinary sediments.


This study was conducted to examine both repeated dose toxicity and  reproductive/developmental toxicity as an OECD screening combined study
(OECD 422 test guideline).  Therefore, hematological and blood chemical examinations, and urinalysis  for females were not performed.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, see below
WEIGHING OF ORGANS: Yes, see below
HISTOPATHOLOGY: Yes, see below

- Terminal sacrifice, Males: Killed on the day after the treatment period.
Terminal sacrifice, Females: Killed on day 4 of lactation. Females with no delivery were killed 4 days after the delivery expected date.
Females with no copulation were killed at the end of the mating period.

- Gross pathology: All rats received a full macroscopic examination  with tissue collection.

- Organs Weights: The following organs were weighed at necropsy:
Brain, pituitary, thyroids, heart, thymus, liver, spleen, adrenals, kidneys, testes, epididymides, ovaries.

- Histopathology: The following organs were microscopically observed for the control and 1000 mg/kg bw/day groups:
Brain, pituitary gland, thyroids, heart, thymus, liver, spleen, adrenals, kidneys, testes, epididymides, ovaries,
lung, trachea, pancreas, salivary glands, esophagus, stomach, duodenum, jejunum, ileum, caecum, rectum,
colon, lymph node, bladder, uterus, vagina, parathyroids, spinal cord, sciatic nerve, eyes, Harderian glands,
mammary gland,  bone marrow, seminal vesicle, prostate.
In addition, liver and spleen (male only) were also examined for the 30, 100 and 300 mg/kg bw/day groups.
Other examinations:
Reproductive and developmental toxicity parameters (addressed in separate endpoints).
Statistics:
Dunnett's test was used for numerical data.
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
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
examined only in males
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
examined only in males
Urinalysis findings:
no effects observed
Description (incidence and severity):
examined only in males
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
only in 2 females, no effect in males
Histopathological findings: neoplastic:
not examined
Details on results:
Histopathology
Males:  No treatment-related abnormality was observed.
Females:  Very slight (marginally positive) extramedullary hematopoiesis in the liver was noted in two female animals of the 1000 mg/kg bw/day group.
Key result
Dose descriptor:
NOEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: NOEL = highest dose tested. NOEL (instead of NOAEL stated by OECD SIDS) seems more appropriate, because OECD SIDS states: "No treatment related abnormality up to 1000 mg/kg bw/day in parental males."
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: NOAEL = highest dose tested. Very slight extramedullary hematopoiesis in the liver in two parental females at 1000 mg/kg bw/day was statistically not significant, therefore not adverse.
Key result
Critical effects observed:
no
Conclusions:
There were no treatment related effects in male rats up to 1000 mg/kg bw/day. The only treatment related effect in females was very slight (marginally positive) extramedullary hematopoiesis in the liver in two female animals of the high dose group (1000 mg/kg bw/day). This finding was considered not to represent an adverse effect, because it did not differ statistically significantly from controls. Therefore, for treated male animals the no observed effect level (NOEL) was estimated to be 1000 mg/kg bw/day and for treated female animals the no observed adverse effect level (NOAEL) was estimated to be 1000 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Treatment with THEIC over ca. 45 days did not induce any adverse effects in the OECD 422 study.

 

Read across of THEIC with cyanuric acid (EC No. 203-618-0, CAS No. 108-80-5) regarding subchronic repeated dose oral toxicity testing was warranted by very similar physico-chemical, ecotoxicological and toxicological properties of both substances and the lack of any adverse effects of THEIC in the available studies. Therefore, the conduct of a subchronic toxicity study with THEIC in the rat would not have provided relevant additional information regarding its toxicological hazard.

For cyanuric acid, sodium salt, WHO/JECFA established a Tolerable Daily Intake level (TDI) of 1.54 mg/kg bw/day. This TDI was based on a broad toxicology data set including a number of reproduction, developmental toxicity and combined chronic toxicity/carcinogenicity studies with cyanuric acid, sodium salt in various species.

Justification for classification or non-classification

In the OECD 422 Study, it was demonstrated that treatment with THEIC at doses up to and including 1000 mg/kg/day for approximately 45 consecutive days did not induce any adverse effects. In addition, THEIC did not induce any adverse effects in any of the other toxicity or ecotoxicity studies. Read-across from study results obtained with cyanuric acid, sodium salt was also favourable and, in view of a TDI of 1.54 mg/kg bw/day, gave no indication of relevant toxicity. Therefore, THEIC does not warrant any classification regarding repeated exposure according to European classification rules [REGULATION (EC) 1272/2008].