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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February to March 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Alcohols, C18-22, distn. residues
Cas Number:
1160164-88-4
IUPAC Name:
Alcohols, C18-22, distn. residues
Details on test material:
- Name of test material (as cited in study report): Alcohols, C18-22, Distn. Residues
- Substance type: product
- Physical state: waxy solid with yellowish colour
- Stability under test conditions: stable and homogeneous for 8 days at ambient dark in formulation
- Storage condition of test material: at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Limited, Margate, Kent, UK
- Age at study initiation: approx. 9 weeks
- Weight at study initiation: 196-265 g
- Fasting period before study: no
- Housing: one per cage in solid-bottomed polycarbonate cages (ca 48 x 37.5 x 25 cm); sterilised wood shavings as bedding
- Diet (e.g. ad libitum): Rat and Mouse Breeder Diet No. 3 (Expanded) SQC, supplied by Special Diets Services Ltd., Essex, UK ad libitum
- Water (e.g. ad libitum):domestic quality mains water ad libitum
- Acclimation period: from arrival until commencement of treatment on Day 6 of gestation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2 (on one occasion outside the target range: actual 18-22°C)
- Humidity (%): 55 +/- 15
- Air changes (per hr): min 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2010-02-05 To: 2010-03-30

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% Carboxymethylcellulose (medium viscosity) with 0.2% Tween 80
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The formulations were prepared at convenient intervals and were used within the 8 days stability period (established in Charls River Study No. 425902) at ambient temperature in the dark. The test item was formulated by adding the appropriate volume of vehicle to require amounts of test item and mixed manually and magnetically stirred until a visibly homogeneous suspension was obtained. Formulations were magnetically stirred for at least 60 minutes prior to and during both sampling and dosing.


VEHICLE
- Justification for use and choice of vehicle (if other than water): no justification given
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
An analytical method for the determination of Alcohols, C18-22, distn. residues in 1% Carboxymethylcellulose (Medium Viscosity) in WIR (water for irrigation) with 0.2% Tween 80 oral (gavage) dosing formulations was developed and validated by the testing laboratory (Test Facility Study No. 425902, Report No. 30848; Final Report: Development and Validation of Methologies for the Analysis of Alcohols C18-22 Distn. Residues in Oral (Gavage) Dosing Formulations).
In the validated analytical method, samples of the dosing formulation were diluted in Chloroform and analysed by gas chromatography with flame ionisation detection. External stadaristation was employed.
The chromatographic system was shown to give a linear response over the range of ca. 0.0500 mg/mL to ca 1.00 mg/mL. The correlation coefficient obtained was 0.9998. The system precision, determined by the coefficient of variation was 1.1% for 0.0503mg/mL resp. 0.6% for 1.01 mg/mL of the test item. The low level assay accuracy (n=5) was 115.4% and the prescision, expressed as the coefficient of variation, was 1.9%. The high level accuracy (n=5) was 99.5%, expressed as the coefficient of variation, was 2.2%.
The formulation and analytical procedures were found to be satisfactory over the range ca 1.00 mg/mL to ca 100 mg/mL in 1% Carboxymethylcellulose (Medium Viscosity) in WIR with 0.2% Tween 80.
The formulation process was found to be suitable for the preparation of accurate and homogeneous formulations for the test item at concentrations of ca 1 mg/mL and ca 100 mg/mL.
Dose formulations were found to be stable for at least 8 days when stored at ambient laboratory temperatue in the dark.
The analysis of dosing formulations indicated acceptable accuracy of formulation (+/- 13.7% of nominal concentration). The low coefficients of variation (< 5.5%) indicated that the formulations were homogeneous.
Details on mating procedure:
No more than two females were mated by any one male, day of detection of a vaginal plug or sperm in a vaginal smear = Day 0 of gestation. It was ensured that females inseminated by the same male did not appear in the same dosing group. No more details mentioned.
Duration of treatment / exposure:
Animals were dosed over Days 6-19 inclusive of gestation (Day 0 = day of detection of mating).
Frequency of treatment:
once daily
Duration of test:
up to day 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 and 1000 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose level were agreed with the Sponsor after evaluation of existing relevant toxicological data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: early in the morning and again as late as possible in each day
- Cage side observations checked in table: No, due to lack of symptoms

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once prior to the start of dosing and daily from commencement of dosing

BODY WEIGHT: Yes
- Time schedule for examinations: on days 4 and 6-20 of gestation

FOOD CONSUMPTION: Yes, daily, commencing on day 4 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: gross necropsy, in which the thoracic and abdominal contents were examined macroscopically
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
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
Statistical analyis performed on matenal body weight gain over Days 6-20 of gestation (analysis of variance) and on mean foetal weight (Kruskal-Wallis test). Tests were 2-sided and performed at the 5% significant level, pairwise comparison only performed against the control group.
For the other parameters, no formal statistical analyses were considered necessary, interpretation of the data being by inspection of the individual and group values.
Indices:
no indices were calculated
Historical control data:
no historical data were used for comparison with test data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
- Clinical observations and necropsy findings: there were no clinical observations or necropsy findings that were considered to be related to treatment.
- Body weight and food consumption performance: group mean body weight gains and food consumption performance in all groups were similar to control throughout the treatment period.
- Pregnancy performance: pregnancy performance was simililar in all groups. In 1000 mg/kg/day, a slight increase in early embryonic deaths was due to one animale with 6 embryonic deaths. In absence of any similar deaths in this group, this incidence was considered to be incidental.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Foetal weight: there was no obvious effect of treatment at any dose on mean foetal weights compared to control (P>0.05)
- Foetal abnormalities and variants: the types and distribution of the major and minor foetal abnormalities did not indicate any association with treatment. Considering the ossification parameters together, there was no obvious effect on the state of skeletal ossification.

Effect levels (fetuses)

Key result
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
At levels up to 1000 mg/kg/day Alcohols, C18-22, distn. residues, there were no obvious effects of treatment on body weight gain, food consumption performance or clinical signs. The incidence of embryo-foetal deaths and mean foetal weights did not suggest any obvious effect of treatment.
The type and distribution of foetal abnormalities and variants did not suggest any obvious effect of treatment.
It was conluded that, under the conditions of this study, Alcohols, C18-22, distn. residues had no obvious effects on pregnancy when administered to rats during the period of organogenesis; there was no evidence of embryotoxicity of foetal abnormalities. The maternal and foetal no observed effect level (NOEL) were both considered to be 1000 mg/kg/day.
Executive summary:

Alcohols, C18 -22, distn. residues was tested in rats to detect the effects on pregnant animals, when the material was administered during the period of organogenesis. The study design was based on OECD Guideline of Testing of Chemicals No. 414 "Prenatal Developmental Toxicity Study", adopted 22nd January 2001.

Mated female Sprague Dawley rats were randomised into 3 test groups and a control group, each containing 24 animals. The animals were dosed by oral gavage over Days 6 -19 inclusive of gestation, where the day of detection of mating was designated Day 0. Dose levels administered were 0, 100, 300 and 1000 mg/kg/day.

Animals were regularly monitored during gestation for clinical signs of toxicity and for effects on body weight and food consumption performance. Animals were killed on Day 20 of gestation. The status of each implantation was recorded and the foetuses were weighed and examind for visceral and skeletal abnormalities, including the state of skeletal ossification.

At levels up to 1000 mg/kg/day Alcohols, C18-22, distn. residues, there were no obvious effects of treatment on body weight gain, food consumption performance or clinical signs. The incidence of embryo-foetal deaths and mean foetal weights did not suggest any obvious effect of treatment.

The type and distribution of foetal abnormalities and variants did not suggest any obvious effect of treatment.

Under the conditions of this study, the maternal and foetal no obseved effect level (NOEL) were both considered to be 1000 mg/kg/day.