FAME

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: 96/54/EG, B.7; OECD 407 (1995)

GLP compliance:

yes

Limit test:

no

Test animals

Species:

other: rat, Hsd:Sprague Dawley (SD)

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: sesame 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: 5 animals at 0 mg/kg bw/day
Male: 5 animals at 62.5 mg/kg bw/day
Male: 5 animals at 250 mg/kg bw/day
Male: 5 animals at 1000 mg/kg bw/day
Female: 5 animals at 0 mg/kg bw/day
Female: 5 animals at 62.5 mg/kg bw/day
Female: 5 animals at 250 mg/kg bw/day
Female: 5 animals at 1000 mg/kg bw/day

Results and discussion

Results of examinations

Details on results:

Clinical observations:
One female receiving 1000 mg/kg bw/d was found dead on day
27 of the study.

At 1000 mg/kg bw/d several animals (1/5 males, 4/5 females)
showed clinical symptoms, such as stupor, prone position,
hypoactivity, silted gait, squatting posture, irregular
respiration, bristled coat, drawn in flanks as well as
straddled hind limbs, staring between day 14 and 26. These
clinical sighs were also seen in the one female which died
on day 27. Body weight gains and food consumption remained
unaffected in all treatment groups.

Neurotoxicological measurements were not influenced by the
administration of the test substance in all groups.

Laboratory findings:
Hematology revealed statistically significant reduced red
blood cell counts in correlation with an increase in
reticulocytes in females given 1000 mg/kg bw/d. Furthermore,
a slight increase in monocytes was observed in these
females.

Clinical biochemistry revealed statistically significant
increased values of total cholesterin in males of all
treatment groups and in females at 1000 mg/kg bw/d, of
triglyceride in females at the 1000 mg/kg bw/d, and of
calcium (slight dose-dependent) in males and females at 250
and 1000 mg/kg bw/d. An increase in total bilirubin was only
observed in males at 1000 mg/kg bw/d.

Urine in the 1000 mg/kg bw/d dosed females showed red
discoloration as well as urine of two males at 250 mg/kg
bw/d, and of four males at 1000 mg/kg bw/d. No blood was
detected in urine. Bilirubin was detected in urine of all
animals at 1000 mg/kg bw/d. Small amounts of bilirubin in
urine were also detected at 62.5 and 250 mg/kg bw/d, but
only in individual animals.

Urinalysis revealed decreased pH values in animals of both
sexes at 1000 mg/kg bw/d as well as increased urine volume.
An increased urine volume was also noted in females dosed
with 62.5 and 250 mg/kg bw/d, and a decreased pH value in
males dosed with 250 mg/kg bw/d. These alterations were
slight compared with controls in individual sexes, and are
therefore not considered as toxicologically relevant
effects.

Effects in organs:
At macroscopic and microscopic examination of the one female
receiving 1000 mg/kg bw/d, which died on day 27, a small
spleen and atrophy/ hypoplasia/ hypocellularity in the
spleen (in combination with a hemorrhage), the thymus, iliac
and mandibular lymph nodes (partly with hemorrhage) and the
bone marrow were observed.

Organ weight assessment revealed increased absolute liver
and spleen weights in females at 1000 mg/kg bw/d. Male
animals showed also significantly increased relative liver
weights, which exceeded the normal range only slightly.
Microscopy showed no correlate in the liver.

Macroscopic examination of the animals killed at the end of
treatment period showed no macroscopic findings, only in one
male receiving 1000 mg/kg bw/d revealed stomach, ileum and
cecum filled with black mass.

Microscopy revealed erythroid hyperplasia in the spleens for
nearly all 1000 mg/kg bw/d females. Additionally, atrophy/
hypoplasia/ hypocellularity in the spleen, the thymus, iliac
and mandibular lymph nodes and the bone marrow were observed
in the one female receiving 1000 mg/kg bw/d which died on
day 27 and one male showing clinical signs at 1000 mg/kg
bw/d.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Basis for effect level:

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

2

Dose descriptor:

NOEL

Effect level:

62.5 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: Not classified