Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
and OECD 407 and METI
Deviations:
no
Remarks:
No deviations from protocol
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD (SD) rats (Charles River (UK))
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
corn oil
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: 10 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: 10 animals at 1000 mg/kg bw/day
Female: 10 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: 10 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
There were no unscheduled deaths, no clinical signs or
effects on sensory reactivity grip strength or motor
activity considered indicative of an effect of treatment.

The general appearance and behaviour of the animals were
unaffected by treatment.

Laboratory findings:
All animals receiving 1000 mg/kg/day showed post-dose
salivation. The salivation was present either immediately
after dosing or at the check performed after completion of
dosing the group and it had generally resolved by the last
check of the day (approx 3-4 hours post-dose).



No post dose signs were observed in animals receiving 15
mg/kg/day.

Effects in organs:
Treatment-related findings were seen in the liver and
thyroids of both sexes given 1000 mg/kg/day and in the
spleen of females of this dose group. They comprised

centrilobular or generalised hepatocyte hypertrophy in the
liver, follicular cell hypertrophy in the thyroids, and an
increased severity of haemosiderosis and increased incidence
of extramedullary haemopoiesis in the spleen. Centrilobular
or generalised hepatocyte hypertrophy was also seen in
several females given 150 mg/kg/day. Following a 2-week
recovery period, there was evidence of partial or complete
recovery from all changes.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
150 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

Any other information on results incl. tables

There were no unscheduled deaths, no clinical signs or effects on sensory reactivity grip strength or motor activity considered indicative of an effect of treatment. There were no toxicologically important bodyweight changes and food consumption was unaffected by treatment. Treatment resulted in lower group mean haematocrit and haemoglobin for females at 1000 mg/kg/day, increased group mean platelet counts for both sexes and activated partial thromboplastin times for males at 1000 mg/kg/day. At the end of the recovery period, general recovery from the previous changes in red blood cell parameters was evident, however higher than control platelet counts were still evident in females previously treated at 1000 mg/kg/day, though magnitude of difference was much less than during treatment. Higher group mean bilirubin and cholesterol and lower ALP, AST, glucose for both sexes and lower ALT in males, were recorded for animals receiving 1000 mg/kg/day. Males receiving 150 mg/kg/day also recorded lower AST and glucose compared with controls. In addition, higher than control group mean total protein, albumin, calcium and phosphorus and lower mean chloride and AG ratios were recorded for both sexes receiving 1000 mg/kg/day. No toxicologically important changes were recorded at the end of the recovery period, indicating general recovery from the previous effects of treatment. Lower group mean urinary protein was recorded for both sexes (dose related in females) receiving 1000 mg/kg/day and in females receiving 150 or 15 mg/g/day when compared with control. At the end of the recovery period, these values were considered similar to controls.

Higher than control adjusted group mean liver weights were recorded for both sexes at 1000 mg/kg/day and for females at 150 mg/kg/day. Group mean adjusted kidney weights were higher for females receiving 150 or 1000 mg/kg/day. At the end of the recovery period, higher than control group mean adjust liver and kidney weights were still evident in females previously treated at 1000 mg/kg/day though recovery was evident. Enlargement of the liver was seen in one male rat and all female rats treated at 1000 mg/kg/day. Treatment-related histopathological findings were seen in the liver and thyroids of both sexes given 1000 mg/kg/day and in the spleen of females of this dose group. They comprised centrilobular or generalised hepatocyte hypertrophy in the liver, follicular cell hypertrophy in the thyroids, and an increased severity of haemosiderosis and increased incidence of extramedullary haemopoiesis in the spleen. Centrilobular or generalised hepatocyte hypertrophy was also seen in several females given 150 mg/kg/day. Following a 2-week recovery period, there was evidence of partial or complete recovery from these changes.

Applicant's summary and conclusion

Conclusions:
Administration of Trimofix O by oral gavage to rats for 4 weeks followed by a 2 week recovery period at doses of 1000 mg/kg/day were associated with a number of differences from controls, which taken as a whole were considered to represent minor but generally reversible toxicity.
Treatment-related findings were also evident at 150 mg/kg/day, but the degree of difference and number of changes seen at this level was less than at 1000 mg/kg/day. Thus as good evidence of recovery was seen at 1000 mg/kg/day, 150 mg/kg/day was classed as the highest NOAEL on this study.
Executive summary:

Administration of Trimofix O by oral gavage to rats for 4 weeks followed by a 2 week recovery period at doses of 1000 mg/kg/day were associated with a number of differences from controls, which taken as a whole were considered to represent minor but generally reversible toxicity. Treatment-related findings were also evident at 150 mg/kg/day, but the degree of difference and number of changes seen at this level was less than at 1000 mg/kg/day. Thus as good evidence of recovery was seen at 1000 mg/kg/day, 150 mg/kg/day was classed as the highest NOAEL on this study.