acetalization product between glucose and C16-18(even numbered)- alcohol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 November 2007 - 25 August 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Except for absence of chemical analysis of the 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): LCE07051 = Acetalization product between glucose and C16/18(even numbered)-alcohol
- Substance type: UVCB
- Physical state: white powder
- Purity: not indicated
- Impurities (identity and concentrations): not indicated
- Percentage of components: not indicated
- Purity test date: not indicated
- Lot/batch No.: T70615
- Expiration date of the lot/batch: 7 February 2009
- Stability under test conditions: not indicated
- Storage condition of test material: at room temperature, protected from sunlight

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Batch No. T70615
- Purity test date: 7 February 2009

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test item was stored at room temperature protected from sunlight.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: breeder
- Age at first treatment: 10-11 weeks
- Weight at first treatment (mean): 280 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 4 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: 3 December 2007 / end: 28 December 2007

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test item was ground, heated to 80°C, mixed with vehicle heated to 80°C, forming a solution.
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

Details on mating procedure:

- Impregnation procedure: purchased time pregnant
- Proof of pregnancy: vaginal plug

Duration of treatment / exposure:

day 6 to day 20 post-coitum

Frequency of treatment:

once daily

Duration of test:

21 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Doses / Concentrations:
0, 100, 300, 1000 mg/kg/day (f)
Basis:
other: nominal per gavage

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

24 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: no effects on dams and development at up to 1000 mg/kg/day in a range-finding study, see 7.8.2
- Rationale for animal assignment: computerized stratification procedure (average body weight of each group is similar)

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule: regularly at 3- to 4-day intervals

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined daily: Yes

WATER CONSUMPTION: No

POST-MORTEM MACROSCOPIC EXAMINATION: Yes
- Sacrifice on gestation day# 21
- Examined: principal thoracic and abdominal organs

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of uterine scars, evaluation of placenta

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Other : number dead and live, body weight, sex

Indices:

% Pre-implantation loss = 100 * (Number of corpora lutea - Number of implantation sites) / Number of corpora lutea
% Post-implantation loss = 100 * (Number of implantation sites - Number of live fetuses) / Number of implantation sites

Historical control data:

Not provided; not required for interpretation of the data obtained

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

There were no treatement-related maternal toxic effects observed.

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Not required (no effects)


There were no treatement-related embryotic ou teratogenic effects observed.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Developmental toxicity

Fetal abnormalities

Key result

Abnormalities:

effects observed, non-treatment-related

Localisation:

visceral/soft tissue: cardiovascular

Description (incidence and severity):

Several fetal variations were observed at soft tissue examination (absent innominate artery) and skeletal examination (ossification point on the 14th thoracic vertebra) but the incidences were low with no clear dose-relationship and there were no cartilage abnormalities. Variations at fetal examination are considered not to represent an adverse effect of development.

Overall developmental toxicity

Key result

Developmental effects observed:

no

Any other information on results incl. tables

Not required (no effects)

Applicant's summary and conclusion

Conclusions:

Under the experimental conditions of this study, the No Observed Adverse Effect Level (NOAEL) was considered to be 1000 mg/kg/day for maternal and developmental toxicity.

Executive summary:

The test item, LCE07051, was administered daily, from day 6 to day 20 post-coitum, by the oral route (gavage), to mated female Sprague-Dawley rats at dose-levels of 100, 300 or 1000 mg/kg/day.

There were no test item-related mortalities nor any effects on maternal body weight gain or food consumption. Clinical signs were limited to salivation and several animals with soiled urogenital areas and were considered as non-adverse.

There were no treatment-related effects on pregnancy parameters (numbers of corpora lutea, implantation and live fetuses) nor on fetal body weight or sex.

There were no treatment-related fetal malformations. Several fetal variations were observed at soft tissue examination (absent innominate artery) and skeletal examination (ossification point on the 14th thoracic vertebra) but the incidences were low with no clear dose-relationship and there were no cartilage abnormalities. Variations at fetal examination are considered not to represent an adverse effect of development.