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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From January 15 to February 28, 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No GLP, aged study. Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
1000 mg/kg/day of FAT 11'110/N where administrated daily (5 times a week) by gavage over a period of 30 days to male and female rats.
GLP compliance:
no
Limit test:
yes

Test material

Constituent 1
Reference substance name:
refer to section 13 of IUCLID
IUPAC Name:
refer to section 13 of IUCLID
Details on test material:
Please refer to confidential details on test material

Test animals

Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: approx. 4 weeks
- Weight at study initiation: males: 128 - 129 g, females: 113 - 115 g
- Housing: individual housing in Macrolon cages type 3 with standardized granulated soft wood bedding (Societé Parisienne des sciures Pantin)
- Diet (e.g. ad libitum): pelleted standard diet (Nafag No. 890) ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 5
- Air changes (per hr): 15 - 17
- Photoperiod (hrs dark / hrs light): 14 / 10

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
2%
Details on oral exposure:
DOSING SOLUTIONS:
daily prepared suspension of the test compound in CMC 2%; control animals received a similar trweatment with CMC 2% without the compound

VEHICLE
- Concentration in vehicle: 10% compound in CMC 2%
- Amount of vehicle (if gavage): 10 ml/kg
Duration of treatment / exposure:
4 weeks and 2 days of the 5th week (30 days)
Frequency of treatment:
5 times a week (in total 22 doses)
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
20 (10 male and 10 female animals had to undergo a two week recovery period)
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure recovery period in satellite groups: 2 weeks

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality: daily (a.m. and p.m.), symptoms: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Time schedule: weekly

FOOD EFFICIENCY:
- Mean food conversion (g food/kg bw/day) was calculated according to the following formula: MFC = (weekly food consumption (g)) / (midweek body weight (g)) * 1000/7

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: by observation prior to dosing and after the treatment period

HEARING TEST: Yes
- Time schedule for examinations: prior to dosing and after the treatment period (by hand clapping)

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at test day 28
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 20 randomized rats (5 males, 5 females per group)
- Parameters examined: Hb, RBC, WBC (total count and differential count)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at test day 28
- Animals fasted: Yes
- How many animals: 20 randomized rats (5 males, 5 females per group)
- Parameters cexamined: GOT, GPT, AP

URINALYSIS: Yes
- Time schedule for collection of urine: at test day 28
- Animals fasted: Yes
- Parameters examined: pH, protein, glucose, urobilinogen, urine sediment
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Macroscopical Examination: At the end of the 30 day toxicity study or after an additional recovery period of two weeks the treated and control rats were bled under ether anaesthesia and complete autopsy was carried out. The total weight of each animal was determined and following organs were weighed: liver, kidneys and adrenals. The mean organ weights and mean organ to body weight ratios of each of these organs were calculated for all treated and control groups.

HISTOPATHOLOGY: Yes
Tissue portions of trachea, lungs, liver, pancreas, salivary gland, stomach, small and large intestine, heart, spleen, lymph nodes, thymus, kidneys, urinary bladder, testicles or ovaries, prostate or uterus, pituitary, thyroid, adrenals, skeletal muscle, skin, malMlary glands, bone marrow, eyes, brain, spinal cord , sciatic nerve, oesophagus and all other organs and tissues which showed macroscopical changes were fixed in buffered 10 % formalin.
The fixed tissues samples of liver, kidneys and adrenals were embedded in paramat and cut at 3 - 5 µ. The routine stain was haematoxylin and eosin. Sections from liver, kidneys and adrenals were also stained by Perl's method for·iron.
Additional frozen sections from liver were specifically stained for fat with Sudan Ill. Only the liver, kidneys and adrenals were histologically examined.
Statistics:
For each time point and parameter a uni-variate statistical analysis was conducted. Due to the routine manner of the analysis system parameter free methods were applied. The treated group was compared to the control group in respect of dispersion and displacement (Y. Lepage, Biometrika (1971) 58: pp. 213-217).

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
Food efficiency:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No animal died during the treatment and/or the recovery period. No clinical symptoms and no signs of local and/or systemic toxicity were observed.

BODY WEIGHT AND WEIGHT GAIN
The body weight gain of all treated and control rats was comparable during the test and the recovery period.

FOOD CONSUMPTION
The mean food consumption of all treated animals was comparable to the controls during the 30 days of administration and during the recovery period.

FOOD EFFICIENCY
The mean food conversion of the males and females of the treated group was comparable to the controls.

OPHTHALMOSCOPIC EXAMINATION
Eye examinition did not reveal any ocular changes.

AUDITORY PERCEPTION
No loss of hearing ability was registred.

HAEMATOLOGY
The observed haematological findings between treated rats and controls were unremarkable.

CLINICAL CHEMISTRY
In the assessment of blood chemistry values the findings were unremarkable and comparable to those of the controls.

URINALYSIS
The findings in the urine were unremarkable. Individual rats revealed some degree of physiological proteinuria including those of the control group. This is considered normal in laboratory rats.

ORGAN WEIGHTS
Organ weights and organ to bodyweight ratios revealed no statistically significant differences between treated and control animals.

GROSS PATHOLOGY
No compound related gross anatomical changes were noted.

HISTOPATHOLOGY
All minor changes seen in some control and treated rats were only incidental in nature and not related to the treatment withthe test item.

Effect levels

Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
It can be concluded from the observations made during the study that 1000 mg/kg/day of the test item produced no observable effects in male and female rats when administrated daily by gavage over a period of 30 days.
Executive summary:

The toxicity of FAT 11'110/N was investigated during a period over 30 day on females and males rats by oral administration.

No observable effects were observed at a dosage of 1000 mg/kg/day.