[No public or meaningful name is available]

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: Method B7 of Commission Directive 96/54/EC OECD Guidelines for Testing of Chemicals No 407 "Repeated Dose 28 Day Oral Toxicity Study in Rodents" (Adopted 24 July 1995).

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: rat, Sprague-Dawley Crl: CD(R) IGS BR Strain

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: polyethylene glycol 400.

Details on oral exposure:

Method of administration:
gavage.

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 15 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 500 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 500 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
Mortality:

Three males and one female high-dose group animals were
found dead between Days 4 and 8. Following the reduction of
the high-dose a further male was found dead on the morning
of Day 12. There were no further deaths until the morning of
Day 28, when one male treated with 150 mg/kg/day was found
dead. There were no further unscheduled deaths.


Clinical Observations:

Among the high-dose animals that survived the treatment,
isolated incidences of transient increased salivation
following dosing, ataxia and hunched posture were detected
amongst high-dose females. Both sexes at the high-dose
showed instances of increased respiration. No clinical
signs were observed in the remaining treatment groups.
Findings observed prior to death in decendent animals were
confined to one high-dose male that showed ataxia and
hunched postureon the day prior to death and a further high-
dose male that showed pilo-erection, hunched posture and
dehydration, alsoon the day prior to death. The remaining
high-dose male andfemale and the one decendent male treated
with 150 mg/kg/day displayed no clinical signs prior to
death.


Animals treated with 150 or 15 mg/kg/day showed no clinical
signs of toxicity throughout the study period.


Behavioural Assessment:

Open field assessments from Week 1 onwards highlighted
instances of ataxia, tiptoe gait, hunched posture and
increased respiration amoung high-dose animals of either
sex, these signs supported those seen clinically during the
study period. No such observations were reported for 150 or
15 mg/kg/day animals.


Functional Performance Tests:

Males treated with 150 mg/kg/day showed a statistically
significant reduction (p<0.05) in motor activity during the
final 20 percent of the trial period compared with controls.



Sensory Reactivity Assessments:

No treatment-related effects were detected.


Bodyweight:

Low mean weight gains were apparent in all male treatment
groups during the first week of the study with a similar
trend continuing among males with 150 and 15 mg/kg/day over
the following weeks, achieving statistical significance in
males treated with 150 mg/kg/day at Week 1 and Week 2 and
for males treated with 15 mg/kg/day at Week 2. Bodyweight
gains in high-dose females and in females treated with 150
or 15 mg/kg/day were similar to the controls.


Food Consumption:

A reduction in food consumption was detected in high-dose

males and in males treated with 150 mg/kg/day in comparison
with controls throughout the study period. Food efficiences
in these animals remained largely unaffected. Food
consumption and food efficiency in high-dose females, 150
mg/kg/day females and in both sexes treated with 15
mg/kg/day remained unaffected throughout the treatment
period.


Water consumption:

Daily visual inspection of water bottles revealed no overt
intergroup differences.

Laboratory findings:
Haematology:

Animals of either sex treated with the high-dose or with 150
mg/kg/day showed a trend towards reduced platelet counts.
In group 4 surviving males there was an increase in white
blood cells and lymphocytes.


Blood Chemistry:

Surviving high-dose animals showed an increase in aspartate
aminotransferase and alanine aminotransferase in comparison
to the controls. There were no other changes detected in the
blood chemical parameters measured.

Effects in organs:
Organ Weights:

There was a possible trend towards elevated liver weights
(absolute and relative to bodyweight) in high-dose animals
and animals treated with 150 mg/kg/day but the intergroup
differences did not achieve statistical significance. No
such effect was apparent at 15 mg/kg/day.


Necropsy:

No treatment related macroscopic abnormalities were detected
in the animals necropsied at study termination. Decedent
high-dose animals showed gastric changes consistent with
irritation accompanied in all decedents by dark areas on all
lobes of the lungs, dark or pallid liver, lungs, thymus and
kidneys. These latter findings were consistent with
congestive tissue changes occurring post mortem.


Histopathology. Treatment related histopathology was
observed for:


Liver: Centrilobular necrosis was observed in premature
death animals treated at the high-dose or at 150 mg/kg/day,
but not among any animals surving the dose period.
Hepatocyte necrosis was associated with bile duct
proliferation in two animals. Higher severity grades of
mononuclear cell infiltration were also seen among premature
death animals. In addition, generalised hepatocyte
enlargement was seen in relation to treatment for two high-
dose females and for several rats of either sex dosed at 150
mg/kg/day. One male rat dosed at 15 mg/kg/day also
demonstrated hepatocyte enlargement, but this condition does
occasionally appear spontaneously among control rats and
was probably unrelated to treatment at the 15 mg/kg/day dose
level.


Kidneys: Vacuolation of the proximal tubular epithelium was
observed in premature-death high-dose male animals, but not
among surviving animals of either sex in this group. One
male rat dosed at 150 mg/kg/day was similarly affected. This
is probably a treatment-related effect. In addition, the
incidence and/or general severity of cortico-medullary
mineralisation were lower for high-dose female rats or
females dosed at 150 mg/kg/day.


Urinary Bladder: Vacuolation of the proximal epithelium was
observed in high-dose female, and possibly high-dose male
animals. Similar effects were also seen for rats of either
sex dosed at 150 mg/kg/day and for one female control rat.


Adrenal Glands: Higher severities of vacuolation of cortical
cells were observed in relation to treatment for high-dose
female rats and those females dosed at 150 mg/kg/day. A
similar effect was not observed for male rats.


Stomach: Treatment related acanthosis and hyperkeratosis of
the epithelium of the forestomach were observed for high-
dose female rats. One female rat dosed at 150 mg/kg/day was
similarly affected and two male rats at this treatment level
demonstrated hyperkeratosis.


Ovaries: Higher severities of vacuolation of corpora luteal
cells were observed as a treatment related effect for high-
dose female rats or at 150 mg/kg/day.


All of the remaining morphological changes were those
commonly observed in laboratory maintained rats of the age

and strain used.

Effect levels

Dose descriptor:

NOAEL

Effect level:

15 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