Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Under on the experimental conditions of the screening reproductive toxicity study (OECD 422) performed with the registered substance, the No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 1000 mg/kg/day, the No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 April 2008 - 22 june 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
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 -6 to 9, and except for the absence of chemical analyses of dosage forms
Limit test:
no
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=433 g, F=276 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: 29 April 2008 / end: up to 21 June 2008
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 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, A0247283 and 1223873
- Purity: not indicated
Details on mating procedure:
- M/F ratio per cage: 1
- Length of cohabitation: until mating occurred
- Proof of pregnancy: vaginal plug, or sperm in vaginal smear - referred to as day 0 post-coitum
- In case of unsuccessful pairing: not detailed (pairing always succeeded)
- After successful mating each pregnant female was caged individually
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 44-55 days)
Frequency of treatment:
once daily
Details on study schedule:
- no F1 parents (only one generation mated).
- Age at mating of the mated animals in the study: 13-16 weeks
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: no serious effects at up to 1000 mg/kg/day in a 14-day range-finding study, see 7.5.1
- Rationale for animal assignment: computerized stratification procedure (average body weight of each group is similar)
Positive control:
none
Parental animals: Observations and examinations:
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
Oestrous cyclicity (parental animals):
Yes : from a fresh vaginal lavage, each morning during the mating period, until the females were mated
Sperm parameters (parental animals):
No seminology examinations.
Testis and epididymis : weight (all males), microscopic exmaination (some rats: see table 1).
Litter observations:
STANDARDISATION OF LITTERS: No

PARAMETERS EXAMINED:
The following parameters were examined in offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight on days 1 and 5, clinical signs
Postmortem examinations (parental animals):
SACRIFICE
- All male survivors: after the end of the mating period
- All female survivors: on day 6 post-partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- Sacrifice on non-selected breeders/progeny: not applicable (only 1 generation of parents and of offspring)
- All pups sacrificed on day 5 post-partum

GROSS NECROPSY: Yes, on pups sacrificed and found dead
- external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS: Not performed
Reproductive 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
Mating index = 100 * Number of mated animals / Number of paired animals
Fertility index = 100 * Number of pregnant female partners / Number of mated pairs
Gestation index = 100 * Number of females with live born pups / Number of pregnant females
Live birth index = 100 * Number of live born pups / Number of delivered pups
Offspring viability indices:
Viability index = 100 * Number of surviving pups on day 5 post-partum / Number of live born pups
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Hypersalivation was observed in 11/20, 11/20, 16/20 and 13/20 animals treated at 0, 100, 300 or 1000 mg/kg/day, respectively (females counted during the pre-mating phase). Hypersalivation was observed mostly in or from the second week of dosing in the controls and low-dose group but was more often observed in week 1 in animals treated at 1000 mg/kg/day. During gestation slightly more females showed hypersalivation but it was observed in less females during lactation.
Reflux at dosing was observed in 0/20, 5/20, 3/20 and 7/20 animals treated at 0, 100, 300 or 1000 mg/kg/day, respectively. It was observed on one to five occasions in each affected animal and tended to occur towards the end of the dosing period.
Hypersalivation and reflux at dosing are considered to be related to treatment either with the vehicle and/or the test item but are non-adverse.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The male groups treated at 100 or 1000 mg/kg/day gained minimally less weight than the controls during treatment period as a whole (-11% and -8%, respectively), however the scale of the difference and the absence of a dose-relationship renders the effect not toxicologically significant.
No effects were observed on body weight evolution in males treated at 300 mg/kg/day.
There were no effects on mean female body weight or body weight gains during the pre-mating, gestation or lactation phase; all values were comparable with the controls.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Mean male food consumption at 1000 mg/kg/day was slightly lower than that of the controls
during the first week of treatment. This was in part due to male R21433 which consumed
markedly less than the other males in the group. During the second week of dosing the mean food
consumption was identical to the controls so it was considered that the slightly decrease in week 1
was not related to treatment with the test item. There were no effects on mean male food
consumption at 100 or 300 mg/kg/day.
Mean food consumption of all female groups treated with LCE07104 was apparently slightly lower than that of the controls during the second week of treatment, however one control female had a particularly high consumption which skewed the group mean. It was considered that there were no effects of treatment with the test item. There were no differences between the controls and the test item-treated groups during gestation and lactation.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Bile acid concentrations are highly variable and the differences in males and females were inconsistent.
Inorganic phosphorus concentration was unaffected in males and slightly increased in females treated at 1000 mg/kg/day.
It was considered that neither of these parameters had been affected by treatment with the test item.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
The only clinical signs observed were hypersalivation and reflux at dosing, which were considered to be related to treatment with the test item but were non-adverse.
Key result
Dose descriptor:
NOAEL
Remarks:
parental toxicity
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
other: NOAEL = highest tested dose, without relevant effects.
Key result
Dose descriptor:
NOEL
Remarks:
reproduction (mating and fertility)
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive performance
other: NOEL = highest tested dose, without relevant effects.
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
Not applicable only 1 generation study
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Isolated clinical signs were observed in a few animals per group, except the group treated at 1000 mg/kg/day whose pups showed no clinical signs, but no one sign was observed consistently.
It was considered that there were no effects of treatment with the test item.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Pup survival was not markedly different between the control group and the groups treated with LCE07104
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean body weight gain of the pups from the group treated at 100 or 1000 mg/kg/day was
slightly lower than that of the controls from day 1 to day 5 post-partum, however individual litter
values were within the control range. It was therefore considered that the apparent effect was not
related to treatment with the test item.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Not required (no effects)
Key result
Dose descriptor:
NOEL
Remarks:
offspring toxicity
Generation:
F1
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: NOEL = highest tested dose, without relevant effects.
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Not applicable
Reproductive effects observed:
not specified

Not required (no effects)

Conclusions:
Under 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, the No Observed Effect Level (NOEL) for reproductive performance (mating and fertility) was considered to be 1000 mg/kg/day and the NOEL for toxic effects on progeny was 1000 mg/kg/day.
Considering REACH Annex IX 8.7.2 and 8.7.3 criteria alone, a developmental toxicity study and a two-generation study in one species should be proposed as the substance is not genotoxic or toxic to reproduction according to available data, and there are no data on plasmatic exposure after dosing. However, although no exemption can be derived from these criteria, it should be underlined that it seems irrelevant to propose and perform this test, both from scientific and regulatory standpoints:
- the substance is clearly non-toxic based on the available tests including evaluations of fertility and development (as detailed above),
- it is expected to be metabolised into endogenous compounds (as discussed under 5.1),
- the expected metabolism and excretion do not suggest any bioaccumulation potential (as discussed under 5.1),
- exposure of workers is negligible when taking into account the high particle size limiting dermal and respiratory absorption (as discussed under 5.1), and the various risk management measures which are applied by SEPPIC (summarized under part A.1),
- the risk assessment for consumers of the final cosmetic product is exempted under REACH, Directive 2003/15/EC forbids in vivo testing on cosmetic ingredients for the dossier of the final cosmetic product from March 2009, and cosmetic regulations are stated to prevail over REACH requirements.
Executive summary:

The test item, LCE07104, 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 unscheduled 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 were non-adverse. There were no treatment-related effects on body weight, body weight gain or food consumption at any dose-level. There were no differences from controls for pairing, mating and fertility parameters. Pups showed no effects of treatment on survival or body weight performance.

There were no treatment-related effects on organ weights and no treatment-related macroscopic or microscopic findings were observed.

Considering REACH Annex IX 8.7.2 and 8.7.3 criteria alone, a developmental toxicity study and a two-generation study in one species should be proposed as the substance is not genotoxic or toxic to reproduction according to available data, and there are no data on plasmatic exposure after dosing. However, although no exemption can be derived from these criteria, it should be underlined that it seems irrelevant to propose and perform this test, both from scientific and regulatory standpoints:

-     the substance is clearly non-toxic based on the available tests including evaluations of fertility and development (as detailed above),

-     it is expected to be metabolised into endogenous compounds (as discussed under 5.1),

-     the expected metabolism and excretion do not suggest any bioaccumulation potential (as discussed under 5.1),

-     exposure of workers is negligible when taking into account the high particle size limiting dermal and respiratory absorption (as discussed under 5.1), and the various risk management measures which are applied by SEPPIC (summarized under part A.1),

the risk assessment for consumers of the final cosmetic product is exempted under REACH, Directive 2003/15/EC forbids in vivo testing on cosmetic ingredients for the dossier of the final cosmetic product from March 2009, and cosmetic regulations are stated to prevail over REACH requirements.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
K1
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

A developmental study on rats (OECD test n°414) was performed with a read-across substance (acetalization product between glucose and C16/18(even numbered)-alcohol) and gave a developmental NOAEL of 1000 mg/kg .

Link to relevant study records
Reference
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.
Reason / purpose:
reference to other study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Except for absence of chemical analysis of the dosage forms
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals 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
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
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)
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
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
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)
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
gross pathology
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 000 mg/kg bw/day (nominal)
Basis for effect level:
number of abortions
pre and post implantation loss
total litter losses by resorption
effects on pregnancy duration
early or late resorptions
dead fetuses
changes in pregnancy duration
changes in number of pregnant
other: developmental toxicity
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)
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
Abnormalities:
not specified
Developmental effects observed:
not specified

Not required (no effects)

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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
K2 (read-across GLP study)
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

For Annex IX, the available pre-natal developmental study OECD 414 with Acetalization product between glucose and C16/18(even numbered)-alcohol can be used as representative for the category.

Based on the similarity of chemical structure and physico-chemical properties of the category members, there is no reason to expect any differences in toxicokinetic behaviour among the category members. Absorption via the dermal and inhalation route will be limited due to the low water solubility (<1 mg/L), the high logKow (>5.7) and the low vapour pressure (<2E-03 Pa). By oral route, the APG in the UVCBs are hypothesised to undergo hydrolytic deglycosylation, leading to formation of glucose and fatty alcohol. The fatty alcohol part may turn into fatty acids, and then possibly undergo the same metabolism as endogenous fatty acids. The limited toxicity of the substances that were tested in the screening tests, as well as the lack of toxicity seen in the OECD 414 test with Acetalization products between glucose and C16/18(even numbered)-alcohol confirms these expectations. The pre-natal developmental study (OECD 414) with Acetalization products between glucose and C16/18(even numbered)-alcohol is therefore considered a suitable representative for the substances in the category. The results of this study can be read-across towards other category members.

Justification for classification or non-classification

The substance is not classified as reprotoxic according to GHS