CNPU

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral

Adequacy of study:

other information

Data source

Reference

Reference Type:

other: Body responsible for the test

Title:

Unnamed

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: 96/54/EG, B.7; OECD 407 (1995)

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: rat, Wistar Rj:WI (IOPS Han.)

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: diet

Details on oral exposure:

Method of administration:
oral

Duration of treatment / exposure:

Test duration: 28 days

Frequency of treatment:

Dosing regime: 7 days/week

No. of animals per sex per dose:

Male: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 1.5 mg/kg bw/day
Male: 5 animals at 9.7 mg/kg bw/day
Male: 5 animals at 39.1 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 1.6 mg/kg bw/day
Female: 5 animals at 10.9 mg/kg bw/day
Female: 5 animals at 42.7 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
No mortality occurred during the study period and no
clinical signs were recorded in either sex.

At 500 ppm mean body weights were reduced in males between

4 % and 13 % (not statistically significant) throughout the
study compared to controls. At the end of treatment the
overall mean body weight gain was reduced by 27 %
(statistically significant). In females, body weight
parameters were unaffected by treatment. Mean food
consumption in males was reduced between 9 % and 20 %
throughout the study. In females, mean food consumption was
reduced between 7 and 8 % throughout the study, when
compared to controls.

No test substance-related effects were detected during
neurotoxicity assessment including extraploratory locomotor
activity, open field observation, sensory reactivity and
grip strength.

Laboratory findings:
There were no test substance-related effects on haematology,
clinical biochemistry and urinalysis data at termination of
the treatment which could be considered of biological
significance.

Effects in organs:
In males treated at 500 ppm, mean absolute and relative
testis weights were statistically significant reduced
between 59 % and 65 %, and mean absolute and relative
epididymides weights between 29 % and 38 %, when compared

to controls.

At necropsy atrophic/small and/or soft testis and
atrophic/small epididymides were found in all males at

500 ppm and in one male at 120 ppm.

Test substance-related lesions were observed in the brain,
testis, epididymis and kidneys at 500 ppm. In the brain,
minimal to moderate cerebella demyelisation was observed in
3/5 males and 3/5 females. In the testis, marked diffuse
tubular degeneration (bilateral) with loss of germ cells,
multinucleated giant cells and sloughing of germ cells were
seen in all males. Correlating to these findings relevant
changes were noted in the epididymis of the same animals.
There were marked to severe oligospermia (bilateral) and
exfoliated germ cells (bilateral) in all males. Minimal
tubular hyaline droplets were found in the proximal tubules
of the kidneys in 3/5 males. Accumulation of hyaline
droplets in kidney tubules was known as a species and
sex-specific phenomenon of hydrocarbon nephropathy, which
results from the excessive accumulation of alpha 2µ-globulin
in renal proximal tubular epithelial cells. Alpha
2µ-globulin is found only in the proximal tubular epithelium
of adult male rats. This effect was considered not to
represent serious damage to health, as defined by the
criteria given in the Council Directive 67/548/EEC (Annex
VI).

Effect levels

Dose descriptor:

NOAEL

Effect level:

42.7 mg/kg bw/day (nominal)

Basis for effect level:

other: original NCD unit is mg/kg/day.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Classified as: Xn - harmful