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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 December 2014 - 30 November 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according the OECD 408 guideline and GLP compliance. Fully adequate for assessment.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in Section 13.
Cross-reference
Reason / purpose:
read-across: supporting information

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008, laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: Clear colourless liquid
Details on test material:
- Test Material : Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product
- CAS 68911-05-7
- Physical State/Appearance : Clear colourless liquid
- Purity: 100%
- Batch Number : DT1719380A
- Date Received : 09 April 2014
- Storage Conditions : Ambient temperature, in the dark and under nitrogen
- Expiry Date : December 2018
Specific details on test material used for the study:
Identification: Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product CAS 68911-05-7
Alternative Identification:ENORDET 0341
Physical State/Appearance:Clear colorless liquid
Purity:100%
Batch Number:DT1719380A
Date Received: 09 April 2014
Storage Conditions: Ambient temperature, in the dark under Nitrogen.
Expiry Date: December 2018

Test animals

Species:
rat
Strain:
other: Wistar Han™:RccHan™:WIST
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories U.K. Ltd., Oxon, UK
- Age at study initiation: six to eight weeks old
- Weight at study initiation: Males: 195 to 233g, Females: 159 to 192g
- Housing: The animals were housed in groups of three or four by sex in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding
- Diet (e.g. ad libitum): A pelleted diet (Rodent 2014C Teklad Global Certified Diet, Harlan Laboratories U.K. Ltd., Oxon, UK - free access
- Water (e.g. ad libitum): free access
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 50 ± 20%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hr light/12 hr dark

Experimental Starting Date: 10 December 2014
Experimental Completion Date: 30 November 2015

Justification for specie selection: The rat was selected for this study as it is a readily available rodent species historically used in safety evaluation studies and is acceptable to appropriate regulatory authorities.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: arachis oil BP
Details on oral exposure:
The test item was administered daily, for ninety consecutive days, by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 mL/kg of Arachis oil BP.

The volume of test and control item administered to each animal was based on the most recent
scheduled body weight and was adjusted at weekly intervals.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test item was prepared in Arachis oil BP solution. The stability and homogeneity of the test item formulations were determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The results of the analytical determination showed that the formulations were stable for at least 26 days. Formulations were prepared and stored at approximately 4 °C in the dark.
The results indicate that the prepared formulations were within 96% to 108% of the nominal concentration confirming the suitability and accuracy of the formulation procedure.
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on a fourteen day dose range finding study in the rat (Harlan Study Number: 41403659. In this study, a high dosage of 1000 mg/kg bw/day was well tolerated, therefore, the dose 0 (Control), 100, 300 and 1000 mg/kg bw/day have been selected for the OECD 408 study.

Examinations

Observations and examinations performed and frequency:
Clinical Observations:
- Signs of toxicity
- Ill-health or behavioural change immediately before dosing

Functional Observations:
- Prior to the start of treatment and at weekly intervals thereafter

Behavioural Assessment
- Functional Performance Tests: Motor Activity, Forelimb/Hindlimb Grip Strength
- Sensory Reactivity

Body Weight
- Individual body weights were recorded on Day 1 (prior to dosing), at weekly intervals thereafter and at terminal kill

Food Consumption
- Weekly intervals throughout the study

Water Consumption
- Daily by visual inspection of the water bottles

Ophthalmoscopic Examination
- Pre-treatment and before termination of treatment (during Week 12)

Laboratory Investigations
- End of the study
- Hematology
- Blood Chemistry

Sacrifice and pathology:
Sacrifice: All animals were terminated by intravenous overdose of a suitable barbiturate agent followed by exsanguination.

Pathology:
- Necropsy: all animals were subjected to a full external and internal examination.
- Organ Weights (Adrenals, Ovaries, Brain Spleen, Epididymides, Testes, Heart, Thymus, Kidneys, Uterus, Liver)
- Histopathology: Samples of selected tissues were removed from all animals and preserved. All tissues from control and 1000 mg/kg/day groups were examined microscopically.
Statistics:
Bartlett’s test
ANOVA
ANCOVA
Williams Test
Student t-test (parametric)
MannWhitney U test
Shirley Test
Dunnett’s

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Mortality
- No unscheduled death

Clinical Observations
Increased salivation post-dosing on (Days 55 and 56) was observed in 2 females treated with 1000 mg/kg bw/day. This effects was considered related to the oral gavage route and reflect distaste or slight irritancy of the dosing formulations rather than any systemic effect of treatment.
Red/brown staining around the snout was observed in only one animal. This finding was considered to be incidental.

Functional Observations
-No treatment-related effects

Body Weight
- No treatment-related effects

Food Consumption
- No treatment-related effects

Water Consumption
- No treatment-related effects

Ophthalmoscopic Examination
- No treatment-related effects

Laboratory Investigations
- No treatment-related effects

Blood Chemistry
- No treatment-related effects

Pathology
Necropsy and Histopathology
- No treatment-related effects

Organ Weights
- No treatment-related effects


Effect levels

Dose descriptor:
NOEL
Remarks:
systemic toxicity
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects seen at 1000 mg/kg/day

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the No Observed Effect Level (NOEL) for systemic toxicity was considered to be 1000 mg/kg bw/day.
Executive summary:

The test material Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product CAS 68911 -05 -7 was administrated orally to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day for 90 consecutive days. The result of the treatment did not show any adverse effects. Increased post dosing salivation was observed in two animals. These findings were considered to reflect distase or slight irritancy of the dosing formulations and therefore were not treatment-related. No effects were observed in body weight, food and water consumptions parameters. The pathology and histopathology examinations did not detect any treatment- related effects. .

Based on the results of this study, the No Observed Effect Level (NOEL) for systemic toxicity of Hydrocarbons, C12-30, olefin-rich, ethylene polymn by product CAS 68911-05-7 was considered to be 1000 mg/kg bw/day.