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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 based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1999-03-16 to 1999-04-26
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study is classified as reliable without restrictions because it closely followed OECD 407 guidelines and was GLP compliant.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): AmoDrill 1000
- Substance type: Alkenes C16-C18
- Physical state: Liquid
- Analytical purity: 100%
- Lot/batch No.: 300-140
- Expiration date of the lot/batch: A nominal expiration date of 2000-01-06 was assigned to the material on receipt.
- Stability under test conditions: Not reported
- Storage condition of test material: In the dark at ambient temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent, United Kingdom
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: Males:75 to 84 grams at arrival; females: 55 to 62 grams on arrival
- Housing: Individually in polycarbonate cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Approximately 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 22
- Humidity (%): 35% to 65%
- Air changes (per hr): Minimum of 15
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From: 1999-03-29 To: 1999-04-26

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amount of test compound was added to corn oil and mixed by manual inversion.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
- Concentration in vehicle: Varied
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): Not reported
- Purity: Not reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Triplicate samples were taken from a preparation in week 1 and week 4. Because the low dose measured 26% higher than nominal, a formulation was analyzed in week 2. With the exception of the first low-dose measurement, all dose formulations were found to be within 10% of the nominal concentration. During the first week the dose formulation for the 25 mg/kg group was 26% of the nominal concentration. The study authors state that this reflected a system error rather than an incorrect formulation; therefore it is not considered a limitation as all three samples were in agreement.
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 150, or 1000 mg/kg/day
Basis:
other: nominal in corn oil
No. of animals per sex per dose:
Five
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on current data and data on similar compounds.
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice a day
- Cage side observations were not specified.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION: Yes
- Time schedule for examinations: Weekly via visual inspection

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During week 4
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All animal
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During week 4
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 2 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: During week 4
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes
- Parameters checked in table 3 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Pretreatment, then weekly
- Dose groups that were examined: All groups
- Battery of functions tested: sensory activity, grip strength, motor activity, landing foot splay (table 4)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 5)
Other examinations:
The following organs were weighed: adrenals, brain, epididymides, heart, kidney, liver, lungs, ovary, pituitary, prostate, spleen, testes, thymus, thyroid with parathyroid, and uterus.
Statistics:
The majority of the continuous data were subjected to analysis of variance or Kruskal-Wallis non-parametric analysis. The organ weight data were subjected to analysis of variance and of covariance with terminal body weight as the single covariant. Fisher’s Exact Probability test was used on the histological incidence data.

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:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no clinical signs or mortality related to treatment. One animal died due to dosing error and one was put down due to eye damage maintained during blood collection.


BODY WEIGHT AND WEIGHT GAIN: There was a slight, but not significant, increase in the body weight of high-dose males. Marginal changes were also noted at the lower doses in males and females, but were considered within normal variation. Therefore, the slight changes in the high-dose males cannot definitively be attributed to treatment.


FOOD CONSUMPTION: There were no treatment-related changes in food consumption.


HAEMATOLOGY: There were no treatment-related changes in haematology.


CLINICAL CHEMISTRY: There were no treatment-related changes in clinical chemistry.


URINALYSIS: High-dose males and females had slight, significant only in females, increase in urine volume. In females, the increase was dose-related with only the high-dose reaching statistical significance.


NEUROBEHAVIOUR: There were no treatment-related changes in neurobehaviour.


ORGAN WEIGHTS: There was a marginal, but not significant, decrease in relative kidney weights in high-dose males and females.


HISTOPATHOLOGY: There were no treatment-related effects.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Due to the lack of any definitive adverse effects, the reported NOAEL for Amodrill 1000 was 1000 mg/kg/day.
Executive summary:
Short-term toxicity effects were assessed in rats exposed to AmoDrill 1000 via gavage at doses of 25, 150, or 1000 mg/kg/day in corn oil for 28 days.  The test conditions complied with OECD 407 guidelines and the statistical methods used were appropriate. There were no treatment related findings for mortality, clinical signs, functional observation battery tests (FOB), haematology, clinical chemistry, or gross pathology. However, there were sporadic significant findings in the FOB and clinical chemistry data. There was a slight, but not significant, increase in body weight and body weight gain in high-dose males. Body weight gain was also slightly increased in the other two groups, but was not dose dependent. Although the study authors did not indicate any change in food consumption, slight increases noted in the food consumption may be responsible for the slight increases in body weight. However, the significance in relation to treatment is not known and the effect is slight. Urine volume was increased (not significantly) in high-dose males. In females, the urine volume increased in a dose-dependent manner with a statistically significant increase in the high-dose group. There was a marginal decrease in kidney-to-body weight in the high-dose group in both sexes. Although tubular regeneration was observed during histopathology exams, it also occurred in controls and cannot be definitively linked to treatment. Due to the lack of any definitive adverse effects, the reported NOAEL for Amodrill 1000 was 1000 mg/kg/day. This study received a Klimisch score of 1 and is classified as reliable without restrictions because it closely followed OECD 407 guidelines and was GLP compliant.