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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:
15 August 2005 to 30 December 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
OECD Guidelines for the Testing of Chemicals, Section 4, Health Effects, Number 407, July 27, 1995.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Version / remarks:
Directive 96 / 54 / EC, B. 7. "Repeated dose (28 days) toxicity (oral)", September 30, 1996.
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Guidelines for Screening, Toxicity Testing of Chemicals: Testing Methods for new Substances, enacted July 13, 1974, amended December 5, 1986
Deviations:
no
Principles of method if other than guideline:
Guidelines followed
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
Batch: P2/05 UL
Appearance: light orange crystalline powder
Expiration date: 31.05.2011
Storage: at room temperature
Specific details on test material used for the study:
- Identity: FAT41039/A
- Description: light orange crystalline powder
- Batch number: P2/05 UL
- Purity: content of organic pigments >99%; 97% main components
- Expiry date: 31 May 2011
- Storage conditions at room temperature (15-25°C) in the original container away from direct sunlight
- Safety precautions Routine hygienic procedures (gloves, goggles, face mask)
The test item information was supplied by the sponsor.
- Analytical standard: FAT 41039/A (the test item served as its own analytical standard)

Test animals

Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Details on species / strain selection:
Recognized by the international guidelines as the recommended test system.
Sex:
male/female
Details on test animals or test system and environmental conditions:
- 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 used: 30 males and 30 females
- Total number of animals ordered: 31 males and 31 females
- Age at delivery: 6 weeks
- Body weight range at acclimatization: Males: 138-161 grams (mean 150 grams); Females: 120-132 grams (mean 126 grams)
- Identification: Acclimatization - Cage card and tail mark (later ear tattoo); Treatment - 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 environmental conditions (temperature range: 22 ± 3 °C; relative humidity range: 30-70 %).
Values outside of these ranges occasionally occurred, usually following room cleaning. These transient variations are considered not to have any influence on the study and, therefore, these data are not reported but are retained at RCC. There was 12-hour fluorescent light/12-hour dark cycle with 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. 39/05) rat maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland) was available ad libitum. The feed batch was analyzed for contaminants.

- Water:
Community tap-water from Itingen was available ad libitum in water bottles. Results of bacteriological assay, chemical and contaminant analyses of representative samples were attached to the report.
None of the contaminants analyzed in the water and diet is considered to have been present at a concentration that would have affected the validity of the results.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- The dose formulations were prepared weekly.
- FAT 41039/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 (15-25°C).
- Homogeneity of the test item in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Lot/batch no.: 2257/983
- Expiry date: 06 June 2010
- Storage conditions: At room temperature (15-25°C) in the original container in the dark
- Safety precautions: Routine hygienic procedures (gloves, goggles, face mask)
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:
Daily (7 days/week)
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:
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
Details on study design:
Rationale for dose level selection: Based upon the results of a non-GLP 5-day dose range- finding study (RCC Study Number A21396) in which FAT 41039/A was administered by gavage to 2 rats per group and sex.

Dose volume: 5 ml/kg body weight
Duration of acclimatization period: 7 days
Duration of recovery: 14 days

Examinations

Observations and examinations performed and frequency:
MORTALITY
- Observations for mortality/viability were recorded twice daily.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily. The animals were observed for clinical signs once before commencement of administration; twice daily on days 1-3; as well as once daily on days 4-28, and once daily during days 29-42 (recovery).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly. The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly (weeks 1-3) thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during pretest, treatment and recovery and before necropsy, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.

FOOD CONSUMPTION:
- The food consumption was recorded once during the pretest period and weekly thereafter, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks and after 6 weeks
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks and after 6 weeks
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes

URINALYSIS: Yes
- Time schedule for collection of urine: after 4 weeks and after 6 weeks
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4
- Dose groups that were examined: all dose groups
- Battery of functions tested: sensory activity / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes.
All animals were weighed and necropsied. Descriptions of all macroscopic abnormalities
were recorded.
All animals surviving to scheduled necropsy were anesthetized by intraperitoneal injection of
sodium pentobarbitone and killed by exsanguination.

HISTOPATHOLOGY: Yes.
Samples of the tissues and organs were collected from all animals at necropsy and
fixed in neutral phosphate buffered 4 % formaldehyde solution.

ABSOLUTE AND RELATIVE ORGAN WEIGHTS: Yes.
The following organ weights were recorded on the scheduled dates of necropsy: Brain, Thymus, Spleen, Ovaries, Heart, Kidneys, Testes, Liver, Adrenals, Epididymides.
The organ to terminal body weight ratios as well as organ to brain weight ratios were determined.
The determination of the terminal body weight was performed immediately prior to necropsy.
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:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes of toxicological relevance were noted during daily observations in rats at any dose level.
Orange feces were recorded in males and females treated with 1000 mg/kg bw/day from day 2 of treatment onwards, and persisted for two days of the recovery period. This was considered to be a typical passive effect resulting from large oral doses of a dyestuff.
Diverse alopecia was noted in one control male (days 12-16), one control female (days 27-29), and one female treated with 1000 mg/kg bw/day (days 20-28), accompanied in the latter case with a dermal scab (days 20-25). The low incidence of dermal findings in test item treated rats was considered to be incidental.

DETAILED CLINICAL OBSERVATIONS (WEEKLY)
No test item-related changes of toxicological relevance were noted during weekly observations (weeks 1-3) in rats at any dose level. Diverse alopecia was recorded in one control male at week 2 and in one high dose female (accompanied by a dermal scab) at week 3.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control male (no. 8) was found dead shortly after administration on day 22. Dosing error was considered to be a possible cause of death. All other animals survived until scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weights and the body weight gain of the control and test item-treated rats were similar.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean daily food consumption of the test item-treated rats compared favorably with those of the controls during the treatment and recovery periods.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No test item-related differences in the hematology parameters were noted in any dose level after the treatment and recovery periods.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related differences in the clinical biochemistry parameters were noted in any dose level after the treatment or recovery periods.
Significant reductions of the mean calcium levels in males treated with 50 mg/kg bw/day (p<0.01) and 1000 mg/kg/day (p<0.05), and significant elevations of the mean sodium level in males treated with 1000 mg/kg bw/day (p<0.05) and chloride level in males treated with 50 mg/kg bw/day (p<0.05) were considered to be incidental in the absence of other changes in electrolytes.

After the recovery period in males previously treated with 1000 mg/kg bw/day significantly reduced mean plasma concentrations were noted in creatinine (p<0.05), alanine aminotransferase (p<0.01) and globulin (p<0.01). In females previously treated with 1000 mg/kg bw/day significantly elevated mean plasma concentrations were noted in total bilirubin (p<0.05), triglycerides (p<0.01), calcium (p<0.05), protein (p<0.05) and albumin (p<0.05). These changes were not considered to be late effects of toxicological relevance.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related differences in the urinalysis parameters were noted in any dose level after the treatment or recovery periods.
In males treated with 1000 mg/kg/day leukocyte concentration was significantly elevated (p<0.05) and urine appearance was cloudy to turbid. In females treated with 1000 mg/kg bw/day nitrite was found in the urine. Both findings were considered to be unrelated to the test item and may result from spontaneous bacterial activity in urinary tract.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related changes of toxicological relevance were noted during functional observational battery (week 4) in rats at any dose level. Diverse alopecia was recorded in one high dose female at week 4.

Grip Strength
The mean fore- and hind limb grip strength of the test item-treated rats were similar to those of the controls.

Locomotor Activity
In females treated with 1000 mg/kg bw/day, elevated mean locomotor activity was noted from 0-10 minutes (p<0.01), 10-20 minutes (p<0.01) and 20-30 minutes (p<0.05). These differences resulted in an overall increase (p<0.01, 0-60 minutes) when compared with controls. As similar differences were not seen in males, a relationship with the test item treatment was considered unlikely. All differences noted in females treated with 50 mg/kg bw/day or 200 mg/kg bw/day were considered to be of no toxicological relevance.
In test item-treated males, the mean locomotor activity was not affected by the test item administration. The slightly elevated locomotor activities recorded from 30-40 minutes (p<0.05) in males treated with 50 mg/kg bw/day resulted in significant changes in the overall locomotor activity (p<0.05, 0-60 minutes), as well as from 0-10 minutes (p<0.05) and 30-40 minutes (p<0.05) of males treated with 200 mg/kg/day. In the absence of any dose-response relationship, these changes were considered to be incidental.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
After 4 Weeks
The mean absolute and relative organ weights of the test item-treated rats and the control rats were similar.

After 6 Weeks
No test item-related changes were noted in the mean absolute and relative organ weights of rats previously treated with 1000 mg/kg bw/day. In males previously treated with 1000 mg/kg bw/day, the mean absolute liver weights were reduced (p<0.01) when compared with controls, and the mean brain-to-body weight ratio was increased (p<0.01) when compared with controls. The elevated mean absolute brain weight resulted in reduced organ-to-brain weight ratios for heart (p<0.05), liver (p<0.01), kidneys (p<0.01) and adrenals (p<0.05). These differences were considered to be artifacts and of no toxicological relevance.
Gross pathological findings:
no effects observed
Description (incidence and severity):
After the treatment and recovery periods no test item-related gross lesions were observed. The macroscopic findings recorded were considered to be within the range of normal background lesions, which may seen in rats of this strain and age in this study type and were considered incidental, reflecting the usual individual variability.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
A variety of changes were found in this study. These findings commonly occur in laboratory rats of this strain and age, neither their incidences nor their distribution or morphologic characteristics gave any indication of a treatment-related association.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
The no-observed-adverse-effect-level (NOAEL) was considered to be higher than the highest dose level tested, 1000 mg/kg bw/day.
Executive summary:

FAT 41039/A was evaluated for potential to cause toxicity on repeated exposure in a study conducted according to OECD Guideline 407 and EU Method B.7. Oral administration of FAT 41039/A to Wistar rats at doses of 50, 200 and 1000 mg/kg bw/day, for 28 days resulted in no test item-related deaths (one control male died from a suspected dosing error), no clinical signs during daily or weekly (weeks 1-3) observations, no clinical signs during the functional observation battery (week 4), no effects upon fore- or hindlimb grip strength or mean locomotor activity, mean daily food consumption and mean body weight, no changes or effects upon hematology, clinical biochemistry or urinalysis and no changes in mean absolute or relative organ weights. No macroscopical or microscopical changes of toxicological relevance were seen at any dose level. Therefore, the no-observed-adverse-effect-level (NOAEL) was considered to be higher than the highest dose level tested, 1000 mg/kg bw/day.