Registration Dossier

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:
other: Meets the criteria for classification as Reliable without restriction according to Klimisch et al (1997)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Annex V
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
other: Rat CD
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
other: 1% aqueous methylcellulose
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 150 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 1.5 mg/kg bw/day
Male: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 150 mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 1.5 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:
Clinical observations:
One female receiving 150 mg/kg/day died during Week 1 of
treatment. The death of this animal was attributed to
treatment with the test substance. One control female died
during the routine bleed in Week 4 of treatment; the death
of this animal was incidental.

Black staining of the cage tray paper was seen in animals
receiving 150 mg/kg/day during Weeks 1 and 2 of treatment.
Pallor of the skin was seen in mose males and females
receiving 150 mg/kg/day.

Overall bodyweight gain , food consumption and food
conversion efficiency was low in males receiving 150
mg/kg/day in comparison with the controls. A less marked
effect on weight gain was seen from Week 2 in males
receiving 1.5 or 15 mg/kg/day.

In comparison with the controls, water consumption was high
in females receiving 15 mg/kg/day and in all animals
receiving 150 mg/kg/day.

Laboratory findings:
Markedly low packed cell volumes, haemoglobin concentrations
and erythricyte counts, slightly low mean cell haemoglobin
concentrations, slightly high mean cell haemoglobin content
and high mean cell volumes were seen in animals receiving
150 mg/kg/day. Macrocytes, polychromasia and anisocytosis
were also seen in animals receiving 150 mg/kg/day.

Markedly high bilirubin, high cholestrol and high protein
concentrations were seen in animals receiving 150 mg/kg/day;
slightly high albumin concentrations were seen in males
receiving 150 mg/kg/day.

Effects in organs:
Analysis of organ weights revealed high spleen weights in
animals receiving 150 mg/kg/day, high liver weights in
females which received 1.5 or 15 mg/kg/day and males and
females given 150 mg/kg/day and high kidney weights
(absolute or bodyweight relative) in most treated groups.
Amongst animals receiving 150 mg/kg/day macroscopic
examination showed dark thyroid s, dark kidneys, swollen or
dark spleens and pale skin. Dark thyroids were also seen in
females receiving 50 mg/kg/day.

Periacinar hepatocytic hypertrophy was seen in males and
females given 150 mg/kg/day; extramedullary haemopoiesis in
the liver was seen in females given 150 mg/kg/day. An
increase in incidence and severity of proximal tubular
vacuolation and necrosis was seen in the kidneys of treated
females and in two males given 150 mg/kg/day. Congestion and
haemosiderosis of the spleen was seen in males and females
given 150 mg/kg/day. Follicular hyperplasia of the thyroid
was seen in males and females given 150 mg/kg/day. Brown
pigment deposition was seen in the Kupffer cells of the
liver, tubular epithelium of the kidney and follicular cells
and follicular colloid of the thyroid in males and females
given 150 mg/kg/day; brown pigment in follicular cells of
the thyroid only was seen in males and females given 15
mg/kg/day.

Effect levels

Dose descriptor:
NOAEL
Remarks:
toxicity observed at lowest dose
Sex:
male/female
Basis for effect level:
other: Observations of a minimal nephrotoxic change in a single female given 1.5 mg/kg/day prevented the establishment of a No-Observed -Effect-Level in this study
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Observations of a minimal nephrotoxic change in a single female given 1.5 mg/kg/day prevented the establishment of a No-Observed -Effect-Level in this study

Applicant's summary and conclusion

Conclusions:
Classified as: Xn - harmful