Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted study to OECD Guidelines with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: colourless liquid
Details on test material:
Name of test material (as cited in study report): Hydrogenated oligomerisation product, including dimers and trimers, of tetradec-1-ene and alkene
- Molecular formula (if other than submission substance): C10 polyalphaolefin (trimer to hexamer oligomer mixture; C30-60.H62-122)
- Molecular weight (if other than submission substance): 552 (weight average), 528 (number average)
- Smiles notation (if other than submission substance): (CCCCCCCCCC) x 3.8 average
- Substance type: hydrogenated polyalphaolefin oligomer
- Trade name: Durasyn (R) 164 X
- Lot/batch No.: 1000172-11-1
- Physical state: clear colourless liquid
- Storage condition of test material: room temperature in a metal container with lid. Room temperature in the dark under nitrogen

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, Kent
- Age at study initiation: Approximately 10-12 weeks old - timed-mated day 3 gestation.
- Weight at study initiation: At the start of treatment females weighed 186 to 291g.
- Fasting period before study: None
- Housing: The animals were housed in a single air-conditioned room. Environmental conditions were continuously monitored.
- Diet ad libitum
- Water ad libitum
- Acclimation period: None
ENVIRONMENTAL CONDITIONS
- Temperature (°C): Target values of 21±2ºC.
- Humidity (%): Target values 55 ±15% respectively.
- Air changes (per hr): The rate of air exchange was at least fifteen air changes per hour.
- Photoperiod (hrs dark / hrs light): 12:12 Low intensity fluorescent light.

IN-LIFE DATES: From: 29 January 2012 To: 16 February 2012

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Vehicle dissolved test substance completely, was inert and formed stable solutions.
- Amount of vehicle (if gavage): 4 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of test article in the formulations was determined by gas chromatography (GC) using an external standard technique. Doses tested weekly were within the range 95 to 105% of nominal value throughout treatment.

The stability and homogeneity of the test item formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK Analytical
Services (Harlan Laboratories Ltd., Project No. 41101033); See 7.8.1.

Results show the formulations to be stable for at least twenty one days.

Formulations were therefore prepared once and stored at approximately +4°C in the dark. Samples were taken of each test item formulation and were analysed for concentration of Hydrogenated oligomerisation product, including dimers and trimers,of tetradec-1-ene and alkene at Harlan Analytical Laboratory, Shardlow. The results indicate that the prepared formulations were within ± 3% of the nominal concentration.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant.
Duration of treatment / exposure:
Between GD 5 and GD 19.
Frequency of treatment:
Daily.
Duration of test:
Test terminated on GD20.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 100, 1000mg/kgbw/day
Basis:
actual ingested
measured dose by gavage
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: historical toxicology data. The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man.

Examinations

Maternal examinations:
CLINICAL OBSERVATIONS
Once daily during the gestation period. Additionally, during the dosing period observations were recorded immediately before and soon after dosing and one hour post dosing. An additional observation was also performed five hours after dosing during the normal working week. All observations were recorded.
BODYWEIGHT
Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for surviving animals at terminal kill (Day 20).
FOOD CONSUMPTION
Food consumption was recorded for each surviving individual animal at Days 3, 5, 8, 11, 14, 17 and 20 of gestation.
POST MORTEM
All surviving animals were killed by carbon dioxide asphyxiation followed by cervical dislocation on Day 20 of gestation. All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded.
Ovaries and uterine content:
The ovaries and uteri of pregnant females were removed, examined and the following data recorded:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Foetal sex
iv) External foetal appearance
v) Foetal weight
vi) Placental weight
vii) Gravid uterus weight

Implantation types were divided into:
Early Death: No visible distinction between placental/decidual tissue and embryonic tissue
Late Death: Separate embryonic/foetal and placental tissue visible
Dead Foetus: A foetus that had died shortly before necropsy. These were included as late deaths for reporting purposes
All implantations and viable foetuses were numbered according to their intrauterine position
Fetal examinations:
Foetuses from each litter were divided into two groups and examined for skeletal alterations and soft tissue alterations. Alternate foetuses were identified using an indelible marker and placed in Bouin’s fixative. Foetuses were transferred to 90% industrial methylated spirits (IMS) in distilled water and examined for visceral anomalies under a low power binocular microscope. The remaining foetuses were identified using colour coded wires and placed in 70% IMS in distilled water. The foetuses were eviscerated, processed and the skeletons stained with alizarin red. The foetuses were
examined for skeletal development and anomalies. Following examination foetuses that were examined for skeletal development were placed in 100% glycerol.
Statistics:
The following parameters were analysed statistically, where appropriate, using the test methods outlined below:
Female body weight change, food consumption and gravid uterus weight: Bartlett’s test for homogeneity of variance and one way analysis of variance, followed by Dunnett’s multiple comparison test or, if unequal variances were observed, an alternative multiple comparison test.

All caesarean necropsy parameters and foetal parameters: Kruskal-Wallis nonparametric analysis of variance; and a subsequent pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test, where significance was seen.

Foetal evaluation parameters, including skeletal or visceral findings: Kruskal-Wallis nonparametric analysis of variance and Mann-Whitney ‘U’ test.
Indices:
Pre- and post-implantation losses and sex ratio calculated by standard formulae.
Historical control data:
Not required - no observed effects to refer to.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
CLINICAL OBSERVATIONS AND MORTALITY
There were no toxicologically significant clinical observations detected in any treated females. There were no unscheduled deaths.

BODY WEIGHT
No treatment-related effects in body weight development were detected.

FOOD CONSUMPTION
No adverse effects were detected in food consumption.

POST MORTEM
No toxicologically significant macroscopic abnormalities were detected in treated females.
One female treated with 1000 mg/kg bw/day had generalised fur loss at necropsy. This was an isolated incident and is considered not to be of toxicological significance. One female treated with 300 mg/kg bw/day had a mass in the left mammary gland. As similar observations were not apparent in animals treated with 1000 mg/kg bw/day, this was considered to be an isolated finding and is considered not to be of toxicological significance.

No treatment-related effects were detected in the uterine parameters examined, in foetal viability or in growth and development.

Effect levels (maternal animals)

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

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
There was no adverse effect on in-utero offspring survival, as assessed by the mean numbers of early or late resorptions, live litter size and pre and post-implantation losses.
Animals treated with 300 mg/kg bw/day showed a statistically significant (p<0.01) increase in total corpora lutea when compared to control animals. In the absence of a true dose related response or any associated effects in the uterine parameters examined the intergroup difference is considered not to be of toxicological significance.
For all dose groups, there were no significant treatment-related trends in the proportion of foetuses (or litters) with evidence of visceral or skeletal anomalies. The type of visceral and skeletal anomalies were those commonly observed for this type of study.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOEL is considered to be 1000 mg/kg bw/day as no toxicologically significant changes were detected in the offspring parameters measured.
Executive summary:

In a guideline (OECD414) GLP study, oral administration of "Hydrogenated oligomerisation product, including dimers and trimers, of tetradec-1-ene and alkene" to pregnant rats by oral gavage during organogenesis at dose levels of 100, 300 and 1000 mg/kg bw/day did not result in any toxicologically significant effects at any dose level. The `No Observed Adverse Effect Level' (NOAEL) was therefore, considered to be 1000 mg/kg bw/day. No toxicologically significant changes were detected in the offspring parameters measured. The `No Observed Adverse Effect Level' (NOAEL) for reproductive and developmental toxicity was therefore considered to be 1000 mg/kg bw/day.