Octadecene, reaction products with hexadecene, hydrogenated

Specific investigations: other studies

Administrative data

Endpoint:

specific investigations: other studies

Remarks:

A 28-day Dietary Study to assess the Palatability of SynNova® Base Oil

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

07 June 2021 to 05 July 2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: OECD Guidelines for Testing of Chemicals, 407 – Repeated Dose 28-day Oral Toxicity Study in Rodents, OECD Guidelines for Testing of Chemicals 443, Extended One-Generation Reproductive Toxicity Study

Version / remarks:

OECD Guidelines for Testing of Chemicals, 407 – Repeated Dose 28-day Oral Toxicity Study in Rodents, OECD Guidelines for Testing of Chemicals 443, Extended One-Generation Reproductive Toxicity Study, adopted 25 June 2018

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: OECD Guidance Document 116 on the Conduct of Chronic Toxicity and Carcinogenicity Studies

Version / remarks:

OECD Guidance Document 116 on the Conduct of Chronic Toxicity and Carcinogenicity Studies, Supporting Test Guidelines 541, 452 and 453, 2nd Edition (13, April, 2012)

Deviations:

no

GLP compliance:

no

Type of method:

in vivo

Endpoint addressed:

repeated dose toxicity: oral

Test material

Test material information

Constituent 1

Reference substance name:

Oligomerisation products of alpha-alkenes C16-18 (even numbered), hydrogenated, hydroisomerised

EC Number:

832-827-5

Cas Number:

2241366-04-9

Molecular formula:

Variable - UVCB

IUPAC Name:

Oligomerisation products of alpha-alkenes C16-18 (even numbered), hydrogenated, hydroisomerised

Test material form:

liquid

Details on test material:

Name: SynNova Base Oil
CAS number: 2241366-04-9
Batch/Lot number: TS20371/TS21270
Description: Liquid - water white colorless oil.
Purity: 100%
Expiry date: 25 February 2021/31 July 2021
Storage conditions: Controlled room temperature (15-25°C, ≤70% relative humidity)
Safety precautions: Routine safety precautions (gloves, goggles, face mask, lab coat) for unknown materials were applied to ensure personnel health and safety.

Specific details on test material used for the study:

No further details specified in the study report.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species and strain: Han:WIST rats
Source: Toxi-Coop Zrt., H-1122 Budapest, Magyar Jakobinusok tere 4B
Hygienic level at supplier: SPF
Hygienic level during the study: Standard housing conditions
Justification of strain: The Wistar rat as a rodent is one of the standard strains for repeated dose toxicity studies
Number of groups: 4 dose groups
Number of animals: 16 male and 16 female rats, 4 animals/group/sex.
Sex: Male and female. The females were nulliparous and nonpregnant
Age of animals at start *: Young adult rats, at least approximately 8-9 weeks old at the beginning of the study.
Acclimatization period: 11 days

Husbandry
Animal health: Only healthy animals were used for the test. The health status was certified by the Veterinarian.
Housing: Group caging (2 animals / cage)
Cage type: T3H polycarbonate
Bedding and nesting: “SAFE 3/4-S-FASERN” certified wooden chips (batch number: 03027201125 / 03027210315, expiry date: 11 November 2023 /15 March 2024) produced by J. Rettenmaier & Söhne GmbH & Co.KG (Holzmühle 1, D-73494 Rosenberg, Germany) and “Sizzle pet” nest material (batch number: 201016/02, expiry date: 01 December 2023) produced by LBS (Serving Biotechnology) Ltd. (Unit 20, Gatwick Business Park, Kennel Lane, Hookwood, Surrey, RH6 0AH, United Kingdom) were available to animals during the study.
Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 19 – 24 °C (target: 22 ± 3 °C)
Relative humidity: 39 – 68 % (target: 30-70%)
Ventilation: 15-20 air exchanges/hour
Enrichment: Rodents were housed with more than one animal per cage to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
The minimum and maximum temperature and relative humidity values were recorded daily during the study.

Food and water Supply
Animals received standard laboratory rat diet, ad libitum. The food is not considered to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. The supplier provided an analytical certificate for the batches used, which is archived with the raw data.
Details of the diets used in the study were as follows:
Name: SM R/M-Z+H + 2% Corn oil 10 mm
Manufacturer: ssniff Spezialdiäten GmbH (D-59494 Soest, Germany)
Batch number: 588 1220
Expiry date: 30 September 2021
Name: SM R/M-Z+H + 1250 mg/kg SynNova® Base Oil with 1.875% Corn oil 10 mm
Manufacturer: ssniff Spezialdiäten GmbH (D-59494 Soest, Germany)
Batch number: 590 1220
Expiry date: 30 September 2021
Name: SM R/M-Z+H + 4000 mg/kg SynNova® Base Oil with 1.6% Corn oil 10 mm
Manufacturer: ssniff Spezialdiäten GmbH (D-59494 Soest, Germany)
Batch number: 591 1220
Expiry date: 30 September 2021
Name: SM R/M-Z+H + 12500 mg/kg SynNova® Base Oil with 0.75% Corn oil 10 mm
Manufacturer: ssniff Spezialdiäten GmbH (D-59494 Soest, Germany)
Batch number: 592 1220
Expiry date: 30 September 2021

Animals received tap water from the municipal supply, as for human consumption, from drinking bottles, ad libitum. Water quality control analysis and microbiological assessment are performed once per year by the laboratory of Veszprém County Government Office, Department of Public Health (Veszprém Megyei Kormányhivatal Népegészségügyi Főosztály, H-8200 Veszprém, József A. u. 36., Hungary). The quality control results are retained in the archives of NEXTREAT Laboratories.

Bedding and nesting
Bedding of certified wood chips and nest building material were provided to animals during the study. Fresh bedding was provided for the animals as frequently as appropriate/practical, but at least twice weekly.

Randomisation
Before start of dosing, the animals were assigned to their respective dose groups by randomisation based on body weights. It was checked that all animals were within 20% of the overall mean at the start of the study. Animals were randomly allocated to the control and dose groups based on the most recent body weight. Males and females were randomised separately.

Animal identification
Animals were individually identified by unique numbers written on the tail with an indelible pen and cross-referenced to the Animal Master File.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

corn oil

Remarks:

To ensure the proper distribution of the test item in the diet, it was added with a carrier oil. For this purpose, corn oil was chosen, as it is planned to be the vehicle in the upcoming reproduction toxicity study.

Details on exposure:

Carrier item
To ensure the proper distribution of the test item in the diet, it was added with a carrier oil.
For this purpose, corn oil was chosen, as it is planned to be the vehicle in the upcoming reproduction toxicity study, and it was considered as proper technically for supporting the test item’s distribution in the diet.
Name: Corn Oil
Batch/Lot number: 8006248001
CAS number: 8001-30-7
Appearance: Faint yellow oil
Purity: Ph.Eur.10, Supplement 10.1
Expiry date: At least until 31 August 2022
Storage conditions: Room temperature (15-25 ºC, below 70 RH%).

Vehicle item
Ssniff® SM R/M-Z+H “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” was used as a vehicle for SynNova® Base oil. A Certificates of Analysis of the actual batches of the diet was provided by the manufacturer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The test item was incorporated into ssniff® SM R/M-Z “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” by ssniff Spezialdiäten GmbH, D-59494 Soest Germany. Ssniff Spezialdiäten GmbH was chosen as manufacturer of the diet because of their extensive experience in the production of experimental diets for regulatory purposes.
In the first step, a premix was prepared from the proper amount of test item and the corn oil.
In the second step, this premix was mixed with the ingredients of the basal diet, and pelleted by a simple compression.
All diets were sampled and analysed in the laboratory of the Test Facility, and subjected to GC-FID analysis following appropriate sample preparation. Also, some portions of the pelleted diets were subjected to storage details of the sampling and the results will be given in the report of the analytical method validation procedure (Study code: N21001-917).

Duration of treatment / exposure:

The test item was administered orally by dietary route for 28 consecutive days.

Frequency of treatment:

Animals were provided with the diet respectively their dose groups ad libitum.

Post exposure period:

No post exposure period specified in the study report.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Targeted test item intake

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Targeted test item intake

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Targeted test item intake

No. of animals per sex per dose:

8 animals (4 male/4 female per test group)

Control animals:

yes, plain diet

Details on study design:

The objective of this study was to obtain information on the palatability characteristics of the test item, when administered incorporated into the diet of young adult Wistar rats, in preparation for an upcoming reproductive toxicity study according to OECD 443.

Justification of the doses and route of administration
The dose levels were selected by the Sponsor in consultation with the Study Director, with the aim to meet the targeted dose levels in the subsequent reproduction toxicity study.
The dietary route was selected since it is one of the routes of administration requested by the regulatory authorities, and it is considered suitable to provide the exposure required for the reproduction toxicology study abovementioned. Concentrations of the test item in the diet were chosen based on the historical control data set of NEXTREAT Laboratories of food consumption of rats in the same age and sex.

Procedure
The test item was administered orally by dietary route for 28 consecutive days. Animals were provided with the diet respectively their dose groups ad libitum.

Examinations

Examinations:

IN-LIFE PROCEDURES
Clinical observation
Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day).
General, cage side clinical observations were made once a day at approximately the same time with minor variations, at the end of the working day.

Body weight
The body weight of all animals was measured daily for 10 days (last 5 days of the acclimation period, and from Day 0 until Day 4), and twice weekly afterwards with a precision of 1 g.

Food consumption
The determination of food consumption was performed together with the body weight measurements daily for ten days (last 5 days of the acclimation period, and from Day 0 until Day 4), and twice weekly afterwards. The remaining, non-consumed food was weighed with a precision of 1 g. Daily food consumption was calculated.

PATHOLOGY
Terminal procedures
Necropsy and macroscopic examination was performed on all animals, at the end of treatment period, on Day 28. The animals were euthanized by exsanguination under pentobarbital anaesthesia.
After exsanguinations, the external appearance was examined, all orifices, and the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed macroscopically. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate.

Positive control:

No required for the study.

Results and discussion

Details on results:

MORTALITY
There was no mortality during the study.

CLINICAL OBSERVATIONS
No clinical signs were observed during the study.

BODY WEIGHT AND BODY WEIGH GAIN MEASUREMENTS
No toxicologically significant adverse effect was noted on the body weight of the SynNova® Base Oil treated animals. The body weight of the animals was as expected in the same strain and age of animals. However whilst there was no statistically significant effect, in male animals, a tendency was noted that the body weight in all treated groups was higher than control under the duration of the study. The mean body weight was higher than control with 9%, 7% and 9% in the low, mid and high dose groups respectively, at the end of the 28 days treatment period. Similar, but not so clear tendency was noted in females as well (1%, 6%, and 4% higher than control group mean body weight on Day 28). Statistically significantly higher than control body weight noted on Day 4 (p˂0.05) and was considered as a minor variation without toxicological relevance.
Administration of SynNova® Base Oil mixed into the diet did not cause any test item related adverse effect in the body weight gain of the animals. No toxicologically relevant, significant changes were noted. At some isolated occasions, statistically significant differences (p˂0.05) could be observed in test item treated groups compared to the controls, but these changes were not toxicologically relevant. No statistically significant difference was noted in the overall mean values. It is presumed, that mainly the male animals preferred the diet added with the test item which led to an increase in food consumption, correlated with somewhat more intensive body weight gain in animals exposed to the test item.

FOOD CONSUMPTION MEASUREMENTS
In males, higher than control mean food consumption was noted in the waste majority of the measuring points (11/11, 11/11 and 10/11 occasions in low, mid and high dose groups respectively). The overall mean was 105%, 106% and 109% of the control in the low, mid and high dose groups respectively. In females, the mean food consumption was somewhat less than control in low and mid dose groups, however the difference was negligible (98% and 98% of the control respectively in the low and mid dose groups). The overall food consumption was higher than control in the high dose group (105% of the control).

DOSE INTAKE
The overall dose intake was 95%, 96% and 89% of the targeted in low, mid and high dose males, while 100%, 101% and 98% in low, mid and high dose females respectively.

PATHOLOGY EVALUATION
Unilateral or bilateral pelvic dilatation was observed in one control, two low dose, and one mid dose male and in one mid dose female, being a common background change in rats, therefore not considered as test item-related effect.
Bilateral dilation of the body and horns of the uterus was observed in two low dose and four high dose female animals. As this is known as a common sign of oestrus, it was not considered as test item-related effect.

Any other information on results incl. tables

ANALITICAL RESULTS

All diets were sampled and analysed in the laboratory of the Test Facility at the reception, and on the last week of the study. Results are detailed below:

 

Measured concentration of the test item in the diet

Dose groups	Nominal Concentration (%)	Measured concentration (%)
		At reception	On the last week of the study
Control	0	0.000	0.000
Low	0.125	0.116	0.108
Mid	0.375	0.341	0.350
High	1.125	1.159	1.134

 

 

BODY WEIGHT AND BODY WEIGH GAIN MEASUREMENTS

 

Body weight and body weight gain group means

Dose groups	Body weight (g)		% of control		Bodu weight gain (g)		% of control
	Males	Females	Males	Females	Males	Females	Male	Females
Control	373.0	236.2	NA	NA	98.2	42.8	NA	NA
Low	406.8	238.5	+9	+1	127.5	40.5	+30	-5.3
Mid	397.8	250.5	+7	+6	120.5	52.8	+23	+23.4
High	408.2	245.2	+9	+4	124.8	45.5	+27	+6.4

NA = Not applicable

 

DOSE INTAKE

Overall mean dose intake

Dose groups	Overall mean does intake (mg/kg bw/day)		Target dose (mg/kg bw/day)	% of target
	Males	Females		Males	Females
Control	0	0	0	NA	NA
Low	95	100	100	95	100
Mid	288	304	300	96	101
High	888	975	1000	89	98

NA = Not applicable

Applicant's summary and conclusion

Conclusions:

The palatability characteristic of the test item incorporated into the diet at the concentrations (or similar) given in this present study were shown to be acceptable by the animals, and will be suitable for an upcoming reproductive toxicity study. Under the conditions of this study, administration of SynNova® Base Oil incorporated into diet did not cause any test item related adverse effect, and did not cause any biologically significant decrease in food consumption in comparison with the control, or with acclimation period values. In male animals higher than control food consumption was noted in all dose groups, showing dose dependency (overall mean 105%, 106% and 109% of the control in low, mid and high dose groups respectively). Body weight and body weight gain was in correlation with food consumption. In female animals, there was no remarkable difference in food consumption in comparison with the control in the low and mid dose groups, while in the high dose group the overall mean was 105% of the control value. Body weight and body weight gain was in correlation with food consumption.
The overall dose intake was 95%, 96% and 89% of the targeted dose in male animals in the low, mid and high dose groups respectively, and 100%, 101% and 98% in female animals in the low, mid and high dose groups respectively.

Executive summary:

The objective of this study was to obtain information on the palatability characteristics of the test item, when administered incorporated into the diet of young adult Wistar rats, in preparation for an upcoming reproductive toxicity study according to OECD 443.

 

The dose levels were selected by the Sponsor in consultation with the Study Director and chosen to meet the targeted dose levels in the subsequent reproductive toxicity study (1000, 300, 100 mg/kg bw/day).

 

Male and female Wistar rats were dosed in the study for 28 consecutive days as follows:

Group Designation	Nominal Concentration of the diet (%)	Targeted test item intake (mg/kg bw)	Number of animals
			Males	Females
Control	0	0	4	4
Low Dose	0.125	100	4	4
Mid Dose	0.375	300	4	4
High Dose	1.125	1000	4	4

 

Mortality checking was performed twice daily. Clinical observation was performed daily. Body weight and food consumption were measured for all animals daily for 10 days from Day -5 until Day 4, and twice weekly afterwards. Gross macroscopic examination was performed at necropsy at the termination.

 

The palatability characteristic of the test item incorporated into the diet at the concentrations (or similar), given in this present study were shown to be acceptable by the animals, and will be suitable for an upcoming reproductive toxicity study. Under the conditions of this study, administration of SynNova® Base Oil incorporated into diet did not cause any test item related adverse effect, and did not cause any biologically significant decrease in food consumption in comparison with the control, or with acclimation period values. In male animals higher than control food consumption was noted in all dose groups, showing dose dependency (overall mean 105%, 106% and 109% of the control in low, mid and high dose groups respectively). Body weight and body weight gain was in correlation with food consumption. In female animals, there was no remarkable difference in food consumption in comparison with the control in the low and mid dose groups, while in the high dose group the overall mean was 105% of the control value. Body weight and body weight gain was in correlation with food consumption.

 

The overall dose intake was 95%, 96% and 89% of the targeted dose in male animals in the low, mid and high dose groups respectively, and 100%, 101% and 98% in female animals in the low, mid and high dose groups respectively (Calculated with nominal concentrations).