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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Experimental start date 29 August 2017 Experimental completion date 02 October 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
4,6-dimethyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran
EC Number:
948-409-1
Cas Number:
1945993-03-2
Molecular formula:
C15H20O
IUPAC Name:
4,6-dimethyl-2-(1-phenylethyl)-3,6-dihydro-2H-pyran
Test material form:
liquid
Specific details on test material used for the study:
Identification: FRET 12-0492
Physical state / Appearance: very pale yellow liquid
Storage Conditions: approximately 4°C in the dark

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Animal Information
Female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were 8 to 12 weeks of age. The body weight variation did not exceed ± 20% of the mean body weight at the start of treatment.

Animal Care and Husbandry
The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately 3 to 4 hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.
The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
For the purpose of the 2000 mg/kg dose level, the test item was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level. For the purpose of the 300 mg/kg dose level, the test item was freshly prepared, as required, as a solution in arachis oil BP. Arachis oil BP was used because the test item did not dissolve/suspend in distilled water.
The test item was formulated within 2 hours of being applied to the test system. It is assumed that the formulation was stable for this duration.
No analysis was conducted to determine the homogeneity, concentration or stability of the test item formulation.

In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.
A single animal was treated at this dose level. In the absence of toxicity at a dose level of 300 mg/kg, an additional animal was treated at 2000 mg/kg. In the absence of toxicity at a dose level of 2000 mg/kg, an additional group of 4 animals was treated at this dose level. A total of five animals were therefore treated at a dose level of 2000 mg/kg in the study.

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose group to confirm the survival of the previously dosed animals.
Doses:
300 and 2000 mg/kg
No. of animals per sex per dose:
1 female treated at 300 mg/kg. A total of 5 females treated at 2000 mg/kg.
Control animals:
no
Details on study design:
Clinical observations were made 30 minutes, 1, 2, and 4 hours after dosing and then daily for 14 days. Morbidity and mortality checks were made twice daily, early and late during normal working days, and once daily at weekends and public holidays.
Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.
At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Dose level - 300 mg/kg: There was no death,
Dose level - 2000 mg/kg: There were no deaths.
Clinical signs:
Dose level - 300 mg/kg: No signs of systemic toxicity were noted during the observation period.
Dose level - 2000 mg/kg: No signs of systemic toxicity were noted during the observation period.
Body weight:
Dose level - 300 mg/kg: The animal showed an expected gain in body weight over the observation period.
Dose level - 2000 mg/kg: All animals showed expected gains in body weight over the observation period.
Gross pathology:
Dose level - 300 mg/kg: No abnormalities were noted at necropsy
Dose level - 2000 mg/kg: No abnormalities were noted at necropsy

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral toxicity test showed an LD50 of > 2000 mg/kg bw
Executive summary:

The acute oral toxicity of FRET 12 -0492 was assessed according to OECD guideline 420. In this study, 1 female rat was administered the substance at a dose level of 300 mg/kg bw. This dose caused no mortality, clinical signs, normal increased in body weight and no abnormalities at necropsy. One female rat, followed by a group of 4 females was then treated at dose level 2000 mg/kg bw. This dose caused no mortality, clinical signs, normal increased in body weight and no abnormalities at necropsy.

The acute oral LD50 for the substance in female rats was determined to be > 2000 mg/kg bw.

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