acetalization product between glucose and C20-22(even numbered)- alcohol

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:

developmental toxicity

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

27 November 2007 - 25 August 2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

compliant to GLP and testing guideline; adequate coherence between data, comments and conclusions. The subsatnce in the study (Acetalization products between glucose and C16/18 (even numered) alcohol) is a member of the category The following information is at present available:  - A pre-natal developmental study (OECD 414) with acetalization products between glucose and C16/18 (even numbered)-alcohol - A combined repeated dose-reproduction study (OECD 422) with acetalization products between glucose and C14 alcohol - A combined repeated dose-reproduction study (OECD 422) with acetalization products between glucose and C20/22 (even numbered) -alcohol In all studies a NOAEL of 1000 mg/kg bw was derived for reproduction and developmental effects. These data are considered sufficient to support the category approach, as they cover the different carbon chain lengths that are included in the category. For Annex IX a two generation reproduction toxicity study is requested. In view of the consistency across the category and based on the available data from the above mentioned studies on both reproductive performance and developmental effects, the toxicokinetic behaviour and the low exposure (see CSR), the two generation reproduction study is waived. Any effects on the male reproductive organs will be investigated in the 90-day study that is proposed with acetalization products between glucose and C16/18 (even numbered) -alcohol. Therefore the endpoints on fertility and reproduction are covered in a weight of evidence approach.

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

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:
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

Remarks:

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

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

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Salivation was observed in 0, 5, 9 and 20 females treated at 0, 100, 300 and 1000 mg/kg/day, respectively, during the second half of the treatment period and lasting from between 1 and 11 days.
One female from each group treated with LCE07051 showed soiled urogenital area on day 20 and/or 21 post-coitum.
These signs were considered to be related to treatment with the test item but are not adverse.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One female (Q23307) treated at 100 mg/kg/day was prematurely sacrificed on day 7 post-coitum because of clinical signs of loud breathing, dyspnea, chromorhinorrhea and salivation. At necropsy, perforations were found in the trachea and esophagus, there were oily contents in the thoracic cavity and a pouch of yellowish oily contents in the subcutaneous tissue (right axillary area). These necropsy findings and clinical signs were the result of a gavage error.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No abnormalities were observed in the females treated at 1000 mg/kg/day.
One female (Q23329) treated at 300 mg/kg/day had two fused placentae and one associated implantation site. This was considered to be spontaneous in origin.
One female (Q23314) treated at 100 mg/kg/day had a markedly reduced in size left kidney, atresia of the left uterine horn which was also malpositioned and contained serous contents. The right kidney was enlarged with a markedly dilated pelvis. These findings are considered to be congenital abnormalities.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

The mean pre-implantation losses were slightly higher for the groups treated at 100 or 300 mg/kg/day when compared with the controls, although the mean pre-implantation loss of the group treated at 1000 mg/kg/day was similar to the control value. As a result the mean number of fetuses per female was minimally lower in the groups treated at 100 or 300 mg/kg/day but, again, was unaffected at 1000 mg/kg/day. Give the lack of dose-relationship, it was considered that these differences did not represent an effect of treatment with the test item.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

effects observed, non-treatment-related

Description (incidence and severity):

he number of early resorptions was increased in all groups treated with LCE07051 when compared with the controls but the mean post-implantation losses were not significantly increased and were within CIT background data. In addition, for two groups (those treated at 100 or 1000 mg/kg/day) one half to one third of the early resorptions for each group occurred in one litter and it was therefore considered that these differences were not toxicologically relevant.

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed

Changes in number of pregnant:

effects observed, non-treatment-related

Description (incidence and severity):

There were 4, 2, 2 and 1 non-pregnant females in each of the groups treated at 0, 100, 300 or 1000 mg/kg/day.

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Not required (no effects)

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

gross pathology

mortality

other: maternal toxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

changes in number of pregnant

changes in pregnancy duration

dead fetuses

early or late resorptions

effects on pregnancy duration

number of abortions

pre and post implantation loss

total litter losses by resorption

other: developmental toxicity

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

One fetus from the group treated at 1000 mg/kg/day had omphalocele (congenital herniation of viscera into the base of the umbilical cord). Given the fact that only one fetus in the high-dose group had an external abnormality it was considered to be unrelated to treatment with the test item.

Skeletal malformations:

no effects observed

Visceral malformations:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

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

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in postnatal survival

external malformations

skeletal malformations

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

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.