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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27-12-2001/21-02-2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FAT 41 '034/A
- Analytical purity: approx. 99 %
- Lot/batch No.: MUB 1365-PP1/01
- Expiration date of the lot/batch: October 22, 2008
- Stability under test conditions: Ensured by sponsor

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Test system Rat, HanBitWIST (SPF)
Rationale Recognized by the international guidelines as the recommended test system.
Source RCC Ltd Biotechnology & Animal Breeding Division CH-4414 Füllinsdorf / Switzerland
Total number of animals per group Groups 1 and 4: 10 males; 10 females
Groups 2 and 3: 5 males; 5 females
Total number of animals 30 males and 30 females
Age at delivery 6 weeks
Body weight range at acclimatization: Males: 125-158 grams (mean 142 grams)
Females: 108-132 grams (mean 124 grams)
Identification: Cage card and individual ear tattoo
Randomization: Computer-generated random algorithm
Acclimatization: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.

HUSBANDRY:
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with a target range for temperature of 22 ± 3 °C and for relative humidity between 30-70 %. 12 hours fluorescent light /12 hours dark, music during the light period.
Accommodation: In groups of five in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
Diet: Pelleted standard Provimi Kliba 3433 (batch no. 77/01 and 119/01) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum. The feed batches were analyzed for contaminants.
Water: Community tap-water from Itingen was available ad libitum in water bottles. None of the contaminants analyzed in the water and diet is considered to have been present at a concentration which would have affected the validity of the results.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Polyethylene glycol PEG300
Details on oral exposure:
The test item formulations were prepared weekly.
FAT 41'034/A was weighed into a glass beaker on a tared Mettler balance and the vehicle added. The mixtures were prepared using a magnetic stirrer and stored at room temperature (17-23 °C). Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment.
The analyses were performed by RCC Ltd (Environmental Chemistry & Pharmanalytics Division) according to a HPLC method supplied by the sponsor.
Duration of treatment / exposure:
28 days
Frequency of treatment:
once a day
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
0 mg/kg bw/day : 5 males and 5 females
0 mg/kg bw/day (recovery): 5 males and 5 females
50 mg/kg bw/day: 5 males and 5 females
200 mg/kg bw/day : 5 males and 5 females
1000 mg/kg bw/day : 5 males and 5 females
1000 mg/kg bw/day (recovery): 5 males and 5 females
Female: 10 animals at 0 mg/kg bw/day
Female: 5 animals at 50 mg/kg bw/day
Female: 5 animals at 200 mg/kg bw/day
Female: 10 animals at 1000 mg/kg bw/day
Control animals:
yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
The findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
liver:
minimal to slight hepatocellular hypertrophy, accompanied by finely-granular to floccular cytoplasmic basophilia was noted after four weeks treatment in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period.
Details on results:
Clinical observations:
MORTALITY / VIABILITY: All animals survived until scheduled necropsy.
CLINICAL SIGNS: No clinical signs were noted during weekly observations (weeks 1-3).
FUNCTIONAL OBSERVATIONAL BATTERY: No clinical signs were observed during the functional observation battery (week 4).
Grip Strength:
Significantly decreased mean fore limb grip strength was noted in males (p<0.05) and in females (p<0.01) treated with 1000 mg/kg/day of the test item compared with controls, and significantly decreased (p<0.05) mean hind limb grip strength was noted also in females of the same dose group. It cannot be excluded that this effect is test item related. No further test item-related differences were observed in mean fore- or hind limb grip strength.

Locomotor Activity: Significantly decreased mean locomotor activity recorded from 30-45 minutes (p<0.01) and recorded from 45-60 minutes (p<0.05) was observed in males treated with 50 mg/kg/day of the test item. This was considered to be incidental because it was not seen in any further dose group and not in females.


FOOD CONSUMPTION : No test item related differences in the mean daily and relative food consumption of the test item treated animals were observed compared with controls.
BODY WEIGHT : No changes in mean body weights and mean body weight gain of test item treated animals were observed compared with control animals.

Laboratory findings:
CLINICAL LABORATORY INVESTIGATIONS:
Hematology: No test item-related differences in parameters of hematology were observed in test item treated females or males after 4 or 6 weeks compared with controls.
Clinical Biochemistry: No test item-related differences in parameters of clinical biochemistry were noted in test item treated females or males after 4 or 6 weeks compared with controls.
Urinalysis: No test item-related differences in parameters of urinalysis were observed in test item treated females or males after 4 or 6 weeks compared with controls.
Effects in organs:
ORGAN WEIGHTS: No test item-related differences in organ weights were noted in test item treated animals after 4 or 6 weeks when compared with the control animals.
MACROSCOPIC / MICROSCOPIC FINDINGS: The findings recorded were considered to be within the range of normal background lesions, which may be seen in rats of this strain and age in oral toxicity studies. The following microscopic findings were considered to be test item-related lesions:
Liver: Minimal to slight hepatocellular hypertrophy, accompanied by finely-granular to floccular cytoplasmic basophilia was noted after four weeks treatment in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, 50 mg/kg body weight/day of FAT 41'034/A was established as the no-observed-effect-level (NOEL) and 1000 mg/kg body weight/day of FAT41'034/A as the no-observed-adverse-effect-level (NOAEL).
Executive summary:

In this subacute toxicity study, FAT 41'034/A was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 50, 200 and 1000 mg/kg body weight/day for a period of 28 days. A control group was treated similarly with the vehicle, PEG 300, only. The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 28 days and then allowed a 16-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pretest, the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 4. At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals. From the animals of the low and middle dose groups, additionally, slides of the liver of the animals treated with 50 or 200 mg/kg bw/day, respectively were evaluated to establish a no effect level. Oral administration of FAT 41'034/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no changes in: mortality, body weights, food consumption and absolute or relative organ weights. No clinical signs, changes of parameters of hematology or clinical biochemistry of toxicological relevance were evident. Significantly decreased mean forelimb grip strength was noted in males (p<0.05) and in females (p<0.01) treated with 1000 mg/kg/day of the test item compared with controls, and significantly decreased (p<0.05) mean hind limb grip strength was noted also in females of the same dose group. It cannot be excluded that this effect is test item related. No further test item-related differences were observed in mean fore- or hind limb grip strength. Significantly decreased mean locomotor activity recorded from 30-45 minutes (p<0.01) and recorded from 45-60 minutes (p<0.05) was observed in males treated with 50 mg/kg/day of the test item. This was considered to be incidental because it was not seen in any further dose group and not in females. Treatment-related findings were generally restricted to minimal to slight hepatocellular hypertrophy along with a fine-granular to floccular cytoplasmic basophilia in two males treated with 200 mg/kg/day and four males treated with 1000 mg/kg/day. This finding was not evident in any animals after the recovery period.

Based on the results of this study, 50 mg/kg body weight/day of FAT 41'034/A was established as the no-observed-effect-level (NOEL) and 1000 mg/kg body weight/day of FAT41'034/A as the no-observed-adverse-effect-level (NOAEL).