Pheco

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: EEC-Directive 92/69 B.7

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: rat / Wistar Crl:(WI)BR

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: 1% Aqueous carboxymethyl cellulose

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 mg/kg bw/day
Male: 5 animals at 15 mg/kg bw/day
Male: 5 animals at 60 mg/kg bw/day
Male: 5 animals at 300 mg/kg bw/day
Female: 5 animals at mg/kg bw/day
Female: 5 animals at 15 mg/kg bw/day
Female: 5 animals at 60 mg/kg bw/day
Female: 5 animals at 300 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
300 mg/kg:

Lethargy, ventro-lateral recumbency, hunched posture,
uncoordinated movements, quick breathing, piloerection,
ptosis, watery discharge from the eyes, brown/red staining
of the snout and dark yellow discolouration of urine.

It was noted that female rats were more affected than male
rats and the majority of symptoms was observed during the
first 10 days.

Other signs noted in treated and control groups were
considered not to present a sign of toxicity.

Laboratory findings:
Haematology:

Effects were noted on red blood cell parameters among
animals of all treated groups. A statistical significance
and a dose relationship was established in most cases.

60 or 300 mg/kg (M+F):

decreased red blood cell count, haemoglobin, haematocrit (in
300 mg/kg/day increased in M) and mean corpuscular
haemoglobin concentration. Increased mean corpuscular
volume, mean corpuscular haemoglobin and red cell
distribution width.


Decrease in red blood cell count was very large at 300 mg/kg
(50% of control values).


Increased total white blood cell count and differential
neutrophil counts (M/F) at 300 mg/kg.

Polychromatic appearance of erythrocytes, increased number
of normoblasts were seen and lymphocytes were small in size.

The latter effects were slight at 60 mg/kg and pronounced at
300 mg/kg.


At 15 mg/kg a decrease in red blood cell count (F),
haemoglobin (M+F) and haematocrit (F) was seen. Also an
increase in red blood cell distribution width (M) was seen.


Other findings were within the range of historical data.


Clinical biochemistry:

300 mg/kg:

Extremely high values for bilirubin (M+F).

Increased urea and albumin and decreased alkaline
phosphatase were found in males.


Other findings were considered to be of no toxicological
relevance, since values remained within the normal range.

Effects in organs:
Body weight:

Decreased b.w. was noted at 300 mg/kg (M+F), also the
b.w.-gain was decreased.

This effect was slight in the 60 mg/kg group.


Macroscopic examination:

300 mg/kg: spleen dark red in colour and enlarged (M+F).

Liver and kidneys were dark red discoloured (M+F).

60 mg/kg: spleen dark red in colour and enlarged (M+F).

15 mg/kg: spleen discolouration (1M).


Organ weights:

Spleen:b.w.-ratios were increased (M+F) at 60 and 300 mg/kg.

A slight increase was also noted at 15 mg/kg. A dose
response relationship was detected.

Kidney:b.w.-ratios were increased in males at all dose
levels in a dose related manner.

Liver:b.w.-ratios increased (M+F) at 300 mg/kg.


Microscopic examination:

Follicular atrophy and congestion in the spleen of all
animals, hemosiderosis all female groups and in males at 60
and 300 mg/kg. RES cell hyperplasia in females (60 and 300
mg/kg) and males (300 mg/kg).

300 mg/kg: brown-greenish pigment accumulation in the
kidneys (cortex, tubular epithelial cells) and liver.

This accumulation was also seen in the liver of some animals
at 60 mg/kg.


Increased severity of RES cell aggregates in the liver of M
+ F at 300 mg/kg.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

< 15 mg/kg bw/day (nominal)

Basis for effect level:

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

2

Dose descriptor:

NOEL

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: Toxic