1,3-Benzenediamine, 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-

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: Annex V

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: Rat (Wistar)

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

propylene glycol

Details on oral exposure:

Method of administration:
oral 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 50 mg/kg bw/day
Male: 5 animals at 150 mg/kg bw/day
Male: 5 animals at 450 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 450 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
There were no clinical signs noted over the 28-day
observation period that were considered to be of
toxicological relevance.


Salivation was observed among all group 4 (high dose)
animals from week 3 onwards. This clinical sign is often
noted in rats of this age and strain following oral gavage
and considered to be related to multiple intra-oesophageal
intubation and/or irritant or bad taste of the test
substance. Moreover, no microscopic correlates were found.
Alopecia of various body parts was noted among all high dose
animals during the study. Macroscopic examination confirmed
alopecia of some body parts on some occasions only.
Although microscopic examination supported the macroscopic
observations, evidence of stuctural abnormalities of the
skin/subcutis were absent. Therefore, alopecia was
considered to have a mechanical cause (e.g. rubbing or
excessive grooming caused by the stress of treatment),
rather than being a toxicological event. Incidental findings
that were noted included a missing apex of the tail of one
group 4 female and breathing rales among two high dose
males. These signs are occasionally noted at this incidence
observed in similar studies. Therefore, these findings were
considered to be of no toxicological significance.


No clinical signs were noted among control animals, and
group 2 and 3 animals (50 and 150 mg/kg, respectively).


Functional Observations

No changes were observed in hearing ability, pupillary
reflex, static righting reflex and grip strength in the
animals treated with STI571 D6, when compared to control
animals.

The variation in motor activity did not indicate a relation
with treatment.


Low sensor readings of one control group male and high
sensor readings of one group 2 female were high when
compared to control data of similar studies. Based on the
incidence of these deviating values, they were considered to
have occurred by chance and not to be of toxicological
relevance.

Laboratory findings:
Haematology



No toxicologically significant haematological changes were
observed.


Clinical Biochemistry


Alanine aminotransferase (males and females) and aspartate
aminotransferase (males) activity values were increased in
the high dose group by 70-90% and 70% respectively,
Bilirubin values were increased from 50 mg/kg/day onwards
among females (by upto 115%) and among high dose males (by
upto 170%). High dose males also showed increased urea and
glucose values. In addition, females showed increased
cholesterol values from 150 mg/kg/day onwards, and also
increased potassium, creatinine, inorganic phosphate and
total protein values, and decreased chloride values at 450
mg/kg/day.

Effects in organs:
Macroscopic Examination


An enlarged liver was seen in two high dose males (in one
case accompanied by an accentuated lobular pattern) and in
one male dosed at 150 mg/kg/day. In addition, one high dose
male and female showed an enlarged spleen.


Alopecia (confirming in-life alopecia of the respective
animals), albeit occurring in a dose-related manner, was
considered to be of no primary toxicological significance
(see Clinical Signs). Other findings among control and/or
treated animals included red discolouration of and/or
enlarged mandibular lymph nodes, and red foci or
discolouration of the thymus and/or lungs. The incidence of
these findings did not distinguish treated from control
animals, and were considered to be within the background
pathology for rats of this age and strain used for this type
of study. These abnormalities were therefore considered
changes of no toxicological significance.


Organ Weights


Absolute and relative liver weights were statistically
significantly increased at 150 mg/kg/day and above. Also,
decreased absolute and relative thymus weights and increased
absolute and relative spleen weights were found for high
dose females. These changes also achieved statistical
significance.




Microscopic Examination


Hepatocyte hypertrophy and single cell necrosis/apoptosis
were observed in males from all treatment groups and at 150
mg/kg/day and above in females. Bile duct proliferation,
consistent with clinical chemistry findings associated with
cholestasis, was observed at 150 mg/kg/day and above in
males and in high dose females.


In the kidney, hyline droplet nephropathy was observed, in
males only, in all treatment groups. Granulolymphocytic
inflammation of the medullopapilliary region was observed in
5/10 animals at the high dose only. Isolated instances of
tubular necrosis were also noted at 150 mg/kg/day and above.


A dose dependent increase in the incidence and severity of
hyperplasia of the urinary bladder urothelium with
lymphocytic infiltration of the submucosa and muscluaris was
also noted at 150 mg/kg/day and above.



Treatment-related microscopic findings were noted in the
liver, urinary bladder and kidneys, in the spleen of animals
dosed at 150 mg/kg and above and in the thymus at 450
mg/kg only.


Other microscopic findings recorded were considered to be
within the normal range of background pathology encountered
in Wistar rats of this age and strain and occurred at
similar incidence and severity in control and treated rats.

Effect levels

Dose descriptor:

NOEL

Effect level:

< 50 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