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Diss Factsheets

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:
June 19 to August 12, 2003
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report date:
2003

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
GLP compliance:
yes (incl. QA statement)
Limit test:
yes

Test material

Constituent 1
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
Identity FAT40'815/A
Description dark shining solid powder
Batch number WP 8/03
Purity approx. 75%
Composition Confidential information, available in Sponsor's file.
Stability of test item Stable under storage conditions
Expiry date 01 May 2010
Storage conditions at room temperature (17-23°C) in the original container
away from direct sunlight

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Test system : Rat, HanBrhWIST (SPF)
Rationale : Recognized by the international guidelines as the recommended test system.
Source : RCC Ltd, Laboratory Animal Services, 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: 133.2 -156.6 grams (mean 146.6 grams)
Females: 116.4 -130.5 grams (mean 123.7 grams)
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. 17/03 and 40/03) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum
Water : Community tap-water from Itingen was available ad libitum in water bottles.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: bidistilled water
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
Dosing regime: 7 days/week
No. of animals per sex per dose:
Male: 10 animals at 0 mg/kg bw/day
Male: 5 animals at 50 mg/kg bw/day
Male: 5 animals at 200 mg/kg bw/day
Male: 10 animals at 1000 mg/kg bw/day
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

Examinations

Observations and examinations performed and frequency:
Mortality/viability were recorded twice daily.
GENERAL CAGESIDE OBSERVATIONS : twice daily on days 1-3; as well as once daily on days 4-28, and once daily during days 29-42
DETAILED CLINICAL OBSERVATIONS :once weekly (weeks 1 -3)
FOOD CONSUMPTION : once during the pretest period and weekly thereafter
BODY WEIGHTS : weekly
FUNCTIONAL OBSERVATIONAL BATTERY : during week 4
GRIP STRENGTH
LOCOMOTOR ACTIVITY : during the fourth treatment week for a 60-minute period and the total activity of this time period was recorded.
Statistics:
The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, organ weights and ratios, as well as:
• The Dunnett-test (many to one t-test) based on a pooled variance estimate were applied if the variables could be assumed to follow a normal distribution
for the comparison of the treated groups and the control groups for each sex.
• The Steel-test (many-one rank test) were applied instead of the Dunnett-test when the data can not be assumed to follow a normal distribution.
• Fisher's exact-test were applied to the macroscopic findings.

The following statistical methods were used for statistical analysis of clinical laboratory data:
• Quantitative data were analyzed by a one-way analysis of variance (ANOVA) when the variances are considered homogeneous according to Bartlett.
Alternatively, if the variances are considered to be heterogenous (p<0.05), a non-parametric Kruskal-Wallis test was used. Treated groups were compared
to the control groups using Dunnett's test if the ANOVA was significant at the 5% level and by Dunn's test in the case of a significant Kruskal-Wallis test
(p<0.05).

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
Description (incidence and severity):
All differences remained within the range of the historical control data and were therefore considered incidental.
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Description (incidence and severity):
dose-related yellow/brown to brown discoloration in males and females treated with 200 mg/kg/day and 1000 mg/kg/day. Considered to be a passive effect of a test item excreted via the renal system, was reversible after the recovery period.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The mean absolute epididymide weights of males previously treated with 1000 mg/kg/day were significantly higher (p<0.01) when compared with the controls. In the absence of microscopical changes, these findings were considered to be incidental.
Details on results:
FUNCTIONAL OBSERVATIONAL BATTERY
No test item-related signs.

Grip Strength :
No changes of toxicological significance were noted in the fore- and hindlimb grip strength at any dose level.

MACROSCOPIC / MICROSCOPIC FINDINGS
The treatment of the males and females with 1000 mg/kg/day was induced the following occasional gross lesions :
bluish discoloration of the mucous membrane of the stomach, of the jejunum, of the ilenum, the cecum and the rectum, the kidneys, the urinary bladder, the testes and epididymides , the uterus and the mammary gland, salivary glands, lacrymal glands, thyroid gland, the mesenteric and mandibular lymph node.
At 200 mg/kg/day, one femal had a bluish discoloration of the kidney and another one had foci in the lungs.
Following the recovery period, all males and/or females treated with 1000 mg/kg/day had black discoloration of the kidney and bluish discoloration of testes and mesenteric lymph node. Ans several animals of one or the other sex gender had a bluish discoloration of the mucous membrane of thestomach.

The microscopical observations revealed that under this experimental conditions, the substance FAT40 815/A induced morphological modifications within the kidneys and lungs. In general, these microscopic modifications were less frequent and less acute than the macroscopic observations noted during the necropsy. At the end of the treatment period, a minimal to slight deposition of pigment was observed in the renal tubular epithelia in all males and females treated with 1000 mg/kg/day. The
The occasional finding of pigment-containing phagocytic cells in the lungs at 200 mg/kg/day was attributed to accidental penetration of the test item into the airways, representing no systemic effect.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: original NCD unit is mg/kg/day.
Dose descriptor:
NOEL
Effect level:
ca. 50 mg/kg bw/day (nominal)
Sex:
male/female
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
Based on the results of pathology, the no-observed-effect-level (NOEL) of the test item FAT 40'815/A is 50 mg/kg/day. Although the pigment deposition in the renal tubular epithelia at the highest dose did not evoke a local tissue reaction, it was not reversible within the 2-week recovery period. Therefore the no-observed-adverse effect level (NOAEL) of FAT 40'815/A is considered to be 200 mg/kg/day.
Executive summary:

Oral administration of FAT 40'815/A to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days resulted in no deaths, no clinical signs of toxicity (during daily or weekly observations), no effects on the parameters of the functional observational battery (performed durnig week 4), no changes in grip strength or locomotor activity, no effects on food consumption or body weight development, no changes in hematology, clinical biochemistry or urinalysis parameters which could be considered to be of toxicological relevance, and no differences in absolute or relative organ weights. There were no late effects after the recovery period.

Test item-related findings were generally restricted to macroscopical effects (passive discoloration of various organs) at 200 mg/kg/day and 1000 mg/kg/day, whereas microscopically, minimal to slight pigment deposition in the renal tubular epithelia of all males and females treated at 1000 mg/kg/day was seen after the treatment and recovery periods.