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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 April 2008 - 11 June 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: compliant to GLP and testing guideline; adequate coherence between data, comments and conclusions.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
except during study days -1 to 16, and except for the absence of chemical analyses of dosage forms
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): LCE07103 = Alkylpolyphosphate
- Substance type: UVCB
- Physical state: white powder or white flakes
- Purity: not indicated
- Impurities (identity and concentrations): not indicated
- Percentage of components: not indicated
- Purity test date: not indicated
- Lot/batch No.: T72851
- Expiration date of the lot/batch: 15 July 2008
- Stability under test conditions: not indicated
- Storage condition of test material: at room temperature, protected from sunlight

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: breeder
- Age at first treatment: approx. 10 weeks
- Weight at first treatment (mean): M=408 g, F=269 g
- Housing: individually, except during pairing
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Relative humidity: 50 ± 20%
- Light/dark cycle: 12h/12h
- Ventilation: 12 cycles/hour of filtered, non-recycled air.

IN-LIFE DATES: beginning: 22 April 2008 / end: up to 11 June 2008

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
test item was ground, heated to 80°C, mixed with vehicle heated to 80°C, forming a suspension.
The test item dosage forms were prepared daily

VEHICLE
- Justification for use and choice of vehicle (if other than water): lipophilicity of the substance
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg/day
- Lot/batch no. (if required): 057K6093
- Purity: not indicated
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Absence of a practical method of analysis
Duration of treatment / exposure:
from 2 weeks before mating until the end of mating (males: total of 39 days) or day 5 pp (females: total of 43-51 days)
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg/day (m/f)
Basis:
other: Nominal per gavage
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in a previous 14-day toxicity study in the rat (see 7.5.1) no relevant adverse effects occured at the dose-levels of 100, 300 or 1000 mg/kg/day.

- Rationale for animal assignment: computerized stratification procedure (average body weight of each group is similar)

- Satellite and post-exposure recovery period: not performed.
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule: day 1 and then weekly; and in F also days 0, 7, 14 and 20 post-coitum and days 1 and 5 post-partum

FOOD CONSUMPTION for each animal: Yes
- Time schedule: weekly (last 7-day consumption period)

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5M+5F

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5M+5F

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule: at the end of the treatment period for M, on day 5 post-partum for F
- Dose groups that were examined: all
- Battery of functions tested: behavior / reflexes / sensory activity / grip strength / motor activity / rectal temperature
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, adults and pups of all groups
ORGAN WEIGHTS: Yes, adults of all groups
HISTOPATHOLOGY: Yes, adults in control and high-dose

all : see Table 1

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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 examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no treatment-related deaths or sacrifices (deaths were due to gavage errors, cranial hematoma or non-pregnancy).
Hypersalivation and reflux at dosing were observed in all groups and may be related to the vehicle and/or the test item but are non-adverse

BODY WEIGHT GAIN:
All female dose-groups gained less body weight than controls during the premating period, but this did not continue during gestation and lactation and was therefore considered to be non-adverse.

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: NOAEL = highest tested dose. All female dose-groups gained less body weight than controls during the premating period, but this did not continue during gestation and lactation and was therefore considered to be non-adverse.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Not necessary

Applicant's summary and conclusion

Conclusions:
Based on the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 1000 mg/kg/day.
Executive summary:

The test item, LCE07103, was administered daily by oral gavage to male and female Sprague-Dawley rats, for 2 weeks before mating, during mating, gestation and until day 5 post-partum, at dose-levels of 100, 300 or 1000 mg/kg/day.

There were no treatment-related deaths during the study and the only clinical signs observed were hypersalivation and reflux at dosing, which were considered to be related to treatment with the test item but are non-adverse. All female groups treated with LCE07103 gained less body weight during the premating period but this did not continue during gestation and lactation and was therefore considered to be non-adverse. There were no effects at any dose-level on food consumption. The Functional Observation Battery, motor activity assessment, hematology and blood biochemistry revealed no treatment-related effects. No treatment-related macroscopic or microscopic findings were noted and there were no treatment-related organ weight changes.