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EC number: 433-400-2 | CAS number: -
Tab. 2: Blood chemistry (mean data of males): Ca in mmol/l
This study in rats was conducted to determine the oral toxicity of the test item when administered by gavage over a period of 4 weeks, to estimate a No-Observable-Adverse-Effect level (NOAEL), and to evaluate reversibility, persistence of, or delayed occurrence of potential toxic effects after a 4-week recovery period.
The test item CA 2342 A (Intermediate of CGA 293343), suspended in the vehicle, was administered by daily gavage at dose levels of 0, 10, 100, 300 and 1000 mg/kg body weight (groups 1, 2, 3, 4, 5 and 6, respectively), to albino rats (Hanlbm:WIST), 5 animals per sex and dose group (experimental group A) and, additionally at the control and high dose level, 5 animals per sex for recovery evaluation (experimental group B). Clinical signs, body weight, food consumption, water consumption, and mortality were monitored throughout the study for all animals. Neurotoxicologic investigations were performed weekly (detailed clinical observations) and at weeks 4 and 8 (functional observational battery, motor activity). Hematological, blood chemistry, and urine analyses were performed at the end of the treatment period on all animals, and at the end of the recovery period on animals of experimental group B. At sacrifices, animals were examined macroscopically and organ weights were recorded. Organs and tissues were collected and prepared for histopathological evaluation.
In life observations, body weight, food consumption, hematology, organ weights and necropsy
None of the animals died. Clinical observations. body weight development, food consumption, hematology profile, and organ weights were not affected by treatment. No treatment-related necropsy findings were observed.
Observations and functional tests conducted as part of the Careful Clinical Observations and Functional Observational Battery, motor activity measurements, as well as, histological examination of peripheral and central nervous system tissues, eyes and muscles evidenced absence of a neurotoxic potential of the test item.
Mean water consumption of the male and female high dose group (1000 mg/kg bw per day) was significantly increased throughout the whole treatment period. During the recovery period, water consumption declined in both sexes to normal values.
Treatment resulted in higher plasma urea levels at 100, 300 and 1000 mg/kg bw per day with higher creatinine levels at 1000 mg/kg bw per day in males and females. In addition, a disturbance of the electrolyte balance was in evidence with lower values for sodium recorded for males and females at 100, 300 and 1000 mg/kg, and lower values for chloride recorded for males and females at 1000 mg/kg and for males at 100 and 300 mg/kg. Males at 1000 mg/kg also had minimally lower values for calcium and females at 300 and 1000 mg/kg had minimally lower potassium levels. Following a 4-week recovery period, normal values were recorded for the above parameters except for calcium that remained at a lower level in males.
At the end of the treatment period, males at 1000 mg/kg excreted a larger urine volume. Following the 4-week recovery period, the urine excreted by previously treated rats was similar to that excreted by the respective controls.
Microscopically, hepatocellular hypertrophy was increased in dose groups 4 and 5 of either sex, but not after 4-week recovery.
The changes seen on some blood chemistry parameters (at dose levels of CA 2342 A of 100 mg/kg and above) point to influencing the renal function. In addition, adaptive changes of the liver were observed. Reversibility was demonstrated for all changes within a 4-week treatment free period except for calcium blood levels in males. Due to the irreversibility in males, a No-Observable-Adverse-
Effect Level (NOAEL) of 300 mg/kg body weight per day is defined for males and 1000 mg/kg body weight per day for females.
Remarks on GHS classification
For a classification as Category 2 STOT-RTD (specific target organ toxicity, repeated dose toxicity), both UN-GHS and EU-GHS (CLP) are using as guidance values for the 28 days oral chronic toxicity test a cut-off value of 300 mg/l (daily gavage) as observed effect level. Since the single observed irreversible health effect, the calcium blood level in males, occured at a higher dose only, GHS classification does not apply for chronic oral toxicity of CA 2342 A. This is also supported by section 22.214.171.124 in the GHS and CLP documents, where it is stated that small changes in blood chemistry would not justify classification.
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