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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
and EC Commission directive 92/69/of July 31, 1992, Part B: Methods for the determination of Toxicity; Toxicity after 28-day administration (oral); Official Journal of the European Communities No. L 383, pp. 136-139, 1992
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Purity: 99.9%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Breeder: Dr. Karl Thomae GmbH, Biberach/Riss, FRG
age of 39 days (males) or 38 days (females)
The rats were identified by ear tattoo.
The rats were housed singly in type DK 111 stainless steel wire mesh cages supplied by Becker & Co., Castrop-Rauxel, FRG (floor area about 800 cm2). Underneath the cages, waste trays were fixed containing absorbent material (type 3/4 dustfree embedding, supplied by SSNIFF, Soest, FRG).
The motor activity measurements were conducted in Polycarbonate cages with wire Covers from Ehret, Emmendingen, FRG (floor area about 800 cm2) and small amounts of absorbent material (see above) .
The animals were housed in a fully air-conditioned room. Central air-conditioning guaranteed a range of 20 - 24°C for temperature and 30 - 70% for relative humidity. The day/night rhythm was 12 hours (12 hours light from 06.00 a.m. - 06.00 p.m., 12 hours dark from 06.00 p.m. - 06.00 a.m.). Deviations from these ranges did not occur.
The food used was ground Kliba maintenance diet rat/mouse/hamster meal, supplied by Klingentalmühle AG, Kaiseraugst, Switzerland. Food and
drinking water (from water bottles) were available ad libitum.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
20 ppm
Remarks:
1.5 mg/kg bw/day in males, 1.9 mg/kg bw/day in females
Dose / conc.:
100 ppm
Remarks:
7.3 mg/kg bw/day in males, 9.2 mg/kg bw/day in females
Dose / conc.:
600 ppm
Remarks:
38.9 mg/kg bw/day in males, 84.0 mg/kg bw/day in females
No. of animals per sex per dose:
Control and high dose group consisted of each 13 animals per sex; low and mid dose group consisted of each 8 animals per sex.
Control animals:
yes

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1.5 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: reduced water consumption, mild anaemia, leucocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of Serum proteins and cholesterol, substance-related changes in thyroid and spleen
Dose descriptor:
NOAEL
Effect level:
1.9 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: reduced water consumption, mild anaemia, leucocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of Serum proteins and cholesterol, substance-related changes in thyroid and spleen

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In conclusion, the following substance-related effects were seen:

600 ppm (38.9 mg/kg bw/day in males, 84.0 mg/kg bw/day in females)

- impairment of water consumption in males and females - impairment of food consumption in males and females

- impairment of body weight, resulting in reduced values of 16.9%/17.3% [males/females] on day 28

- impairment of food efficiency in males and females

- increases in platelets, total bilirubin, total protein, globulins, cholesterol and urinary specific gravity in both sexes

- dark yellow discoloration of the urine specimens in both sexes

- increases in albumin and urinary blood in the males - increases in white blood cells, lymphocytes, alanine aminotransferase, sodium, inorganic phosphate and thyroid stimulating hormone (TSH) in the females - decreases in hemoglobin, alkaline phosphatase, urea, triglycerides and urinary volume in both sexes - decreases in red blood cells, creatinine, glucose and thyroxin (T4) in the females

- vacuolization of the follicular epithelial cells of the thyroid glands of male and female rats

- increased extramedullary hematopoiesis in the spleen of male and female rats

100 ppm (7.3 mg/kg bw/day in males, 9.2 mg/kg bw/day in females)

- slight impairment of water consumption in males

- increases in total protein, albumin, globulins and cholesterol in the males

- increases in platelets and thyroid stimulating hormone (TSH) in the females - decreases in hemoglobin and triglycerides in the females - increased extramedullary hematopoiesis in the spleen of male and female rats

20 ppm (1.5 mg/kg bw/day in males, 1.9 mg/kg bw/day in females)

- no substance-related changes

Applicant's summary and conclusion

Conclusions:
NOAEL: 20 ppm (equivalent to 1.5 and 1.9 mg/kg/day for males and females, respectively.
Executive summary:

In a GLP drinking water study according to OECD Guideline 407, groups of male and female Wistar rats received 20, 100 or 600 ppm of the test substance (purity unknown) for 4 weeks, followed by a recovery period of 2 weeks. The groups consisted of 13 animals per sex in the control and high dose treatment and of 8 animals per sex in the other treatments. The 20, 100 and 600 ppm values correspond to 1.5, 7.3 and 38.9 mg/kg bw in males and 1.9, 9.2 and 84.0 mg/kg bw in females, respectively.

In high dose treatment, following effects were observed: impairment of the food and water consumption and of the food efficiency; reduced body weight, mild anaemia, leucocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of serum proteins and cholesterol, substance-related changes in thyroid and spleen. In the mid dose, slight impairment of water consumption in males, increases in total protein, albumin, globulins and cholesterol in the males, increases in platelets and thyroid stimulating hormone (TSH) in the females, decreases in haemoglobin and triglycerides in the females and increased extramedullary haematopoiesis in the spleen of male and female rats were observed. In the low dose, no substance related effects were observed. In the recovery period, the effects were not fully reversible in animals of the high dose treatment. Therefore, the NOAEL is identified as 20 ppm corresponding to 1.5 mg/kg bw in males and 1.9 mg/kg in females.