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EC number: 229-722-6
CAS number: 6683-19-8
Adequate repeated-dose toxicity studies predating GLP but performed
similar to OECD guidelines 409 and 453 are available. A 3-month feeding
study in beagle dogs revealed no relevant toxicological effects and a
NOEL of 10000 ppm was derived. In a chronic feeding study in rats a NOEL
of 3000 ppm was derived based on an intermittent reduction in body
weight gain at the high dose level. Since the toxicological relevance of
this finding is doubtful the NOAEL can be set at 10000 ppm.
MINIMUM ACHIEVED DOSAGE (Table 1)
The mean intake of test substance (mg/kg body weight/day) during the 104
week treatment period
During the complete histopathological investigation performed in 1985
(see above), the following additional observations were reported:
The incidence of pancreatic islet cell adenomas, in male rats from the
10,000 ppm dosage group was slightly above that of the control
group (Table 1 ). However, the increase was not statistically
significant (Appendix 2) and considered unlikely to be of biological
importance. No effect was seen in female rats. The incidence and
distribution of other neoplasms in this study were within the normal
tumour profile for laboratory maintained rats of this strain. Briefly:
mammary tumours were common in females; pituitary tumours in both sexes;
with a lower incidence of subcutaneous tumours predominantly in males.
No treatment-related changes were detected. Spontaneous changes were
recorded for many organs and were within the normal background range for
rats of this strain, in this laboratory. Among the more common lesions
were: renal progressive glomerulo-nephrosis with parathyroid hyperplasia
and associated metastatic mineralisation in the aorta, heart and
stomach; and occasional osteodystrophia fibrosa of the sternum;
myocardial fibrosis-predominantly in males; foci of altered hepatocytes;
periportal hepatocyte vacuolation - predominantly in females;
vacuolation of the adrenal cortex; cystic degeneration and haemorrhage
of the adrenal cortex - predominantly in females; extra-medullary
haemopoiesis in the spleen - mainly in females; and mammary secretory
activity/galactoceles - also predominantly in females.
FACTORS CONTRIBUTORY TO DEATH
For animals dying, or killed in a moribund condition during the course
of the study, the pathologist attempted to ascertain the major factor(s)
responsible for each individual rat. None of these factors were
considered to be treatment-related. Common factors were pituitary and
mammary tumour - especially in females, subcutaneous tumours in males,
and renal disease - especially in males.
Commercial samples of the test item were investigated for repeated dose
toxicity in feeding studies performed with rats and dogs. The chronic
feeding study in rats is valid with the following restrictions: Feed
analysis was performed, but no details for accuracy of preparation,
homogeneity and stability were reported. Not all biochemical parameters
as required by OECD testing guideline 453 were measured. Some of the
histopathological examinations were performed 10 years after the
finalization of the study. The study was performed prior to GLP
requirements. Overall, it is considered suitable to serve as key study.
Groups of 50 male and 50 female CFY rats, a hysterectomy-derived strain
of Sprague-Dawley origin, were fed the test substance admixed in the
diet at concentrations of 1000, 3000 or 10000 ppm for 104 weeks. A
control group received plain diet. All rats were examined daily for
signs of ill-health and toxicity. All rats found dead, or killed for
humane reasons, were subjected to detailed macroscopic examination. The
weight of each rat was recorded at weekly intervals for the first twelve
weeks and at four-weekly intervals thereafter. The quantity of food
consumed by each cage of rats was recorded and the mean weekly intake
calculated. Ophthalmoscopy, urinalysis, hematology and blood chemistry
were investigated after 13, 26, 52, 78 and 103 weeks. On completion of
the treatment period, all surviving rats were killed by carbon dioxide
euthanasia and subjected to autopsy procedures following
There were no overt signs of reaction to treatment and the survival
rates among treated rats were comparable with those of the controls.
Between weeks 24 and 52, bodyweight gain of males receiving 10000 ppm
was significantly lower than that of the controls (P<0.05), although
subsequent performance was comparable with that of the controls. Between
weeks 80 and 104, bodyweight gain of males receiving 1000 ppm was
significantly higher than that of the controls, although since this
finding was not dose related in degree it is of doubtful biological
significance. With the exception of a small decrease in the total mean
food intake among all treated rats between weeks 53 and 80, food intake
was not disturbed by treatment. Some minor statistically relevant
changes were seen during urinalysis, hematology and blood chemistry,
however these changes occurred only occasionally, and all values
obtained were within normal limits for the strain of rat employed and
therefore considered of no toxicological relevance. Macroscopic
examination of decedents and rats killed after 104 weeks of treatment
showed pathology which was common to animals from control and treated
groups. Although differences from control values in adrenal, thyroid and
kidney weights attained levels of statistical significance, the
differences were related to the intergroup disparity in bodyweight and
were not dose related in degree. It was, therefore, concluded that the
differences were of no toxicological significance and probably arose
fortuitously. During microscopic analysis, no morphological abnormality
or variation from normal was seen in any of the tissues examined which
was considered to be due to the administration. The NOEL was set at 3000
ppm, corresponding to 135 mg/kg for females and 166 mg/kg for males.
Since the findings reported for the high dose are of no toxicological
relevance, a NOAEL of 10000 ppm can be derived, corresponding to 446
mg/kg body weight for males and 547 mg/kg body weight for females.
For subchronic exposure, three studies are available. Two of them were
performed at a laboratory that is known to have falsified study reports
(Industrial Bio-Test lab, 1966a+b). These reports are excluded from the
hazard assessment, noting that the results are consistent with the
findings of the valid studies. The feeding study with beagle dogs is
sufficiently well performed and reported to serve as key study. It was
performed under a quality assurance program. The following deviations to
OECD testing guideline 409 were noted: Homogeneity of the test substance
formulation was not determined and not all required organ weights were
determined. Parasitic infection was reported throughout the population.
The test item caused no adverse effects at any test dose level; the NOEL
is determined to be ≥ 10000 ppm (302 mg/kg body weight for males and 343
mg/kg body weight for females).
The overall low toxicity is supported by the absence of findings in the
carcinogenicity study in mice.
Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for
classification purposes under Regulation 1272/2008. As a result the
substance is not considered to be classified for repeated dose toxicity
under Regulation (EC) No. 1272/2008.
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