Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report Date:
2017

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Test Animals
Animals were received from Charles River, Raleigh NC and Stone Ridge NY, on 13 Jul 2017, 25 Jul 2017, 01 Aug 2017, 17 Aug 2017 and 05 Sep 2017. Following an acclimation period of at least five days, three healthy male and nine healthy, non-pregnant and nulliparous female Sprague Dawley rats were assigned to treatment groups without conscious bias.
The male animals were born on 17 Jul 2017 and the female animals were born on 17 May 2017, 30 May 2017, 05 Jun 2017 and/or 21 Jun 2017. The pretest body weight range was 225 - 253 grams for males and 181 - 228 grams for females. The weight variation of the animals used did not exceed ±20% of the mean body weight of the previously dosed animals within a sex.
The animals were identified by cage notation and indelible body marks, and housed in suspended wire cages; five per sex per cage prior to dosing and three per sex per cage following dosing. Absorbent
paper bedding was placed beneath the cages and changed at least three times per week. Fresh PMI Rat Chow (Diet No. 5012) was freely available except for 16-20 hours prior to dosing. Water was available ad
libitum. The animal room, reserved exclusively for rats on acute tests, was temperature controlled, had a 12-hour light/dark cycle, and was kept clean and vermin free.

Housing
Animals will be housed in suspended wire cages which conform to the size recommendations in Guide for the Care and Use of Laboratory Animals DHEW (NIH). Rats will be housed 5 per sex per cage prior to dosing and 3 per sex per cage following dosing. Absorbent paper bedding, placed beneath the cage, will be changed at least three times per week. The animal room, reserved exclusively for rodents on acute tests, is temperature controlled, has a 12-hour light/dark cycle, and will be kept clean and vermin free.

Acclimation
The test animals will be conditioned to the housing facilities for at least five days prior to testing.

Food
Fresh PMI Rat Chow (Diet #5012) will be available except 16 - 20 hours prior to dosing.

Water
Water will be available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
A single dose was administered orally by syringe and dosing needle.
Control animals:
other: Confirmatory animals for 1000 mg/kg dose level
Details on study design:

Animal ID/Sex Dose Resonse
(mg/kg) (O = Survived, X = Died)

1/F 2000 X
2/F 2000 X
3/F 2000 X
4/F 300 O
5/F 300 O
6/F 300 O
7/F 1000 X
8/F 1000 O
9/F 1000 O
*10/M 1000 O
*11/M 1000 X
*12/M 1000 O

* = Confirmatory animals for 1000 mg/kg dose level

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 1 000 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
300 mg/kg: All three female rats survived following a single 300 mg/kg oral dose.

1000 mg/kg: Two female and two male rats survived following a single 1000 mg/kg oral dose. One female and one male rat died by Day 3.

2000 mg/kg: Three female rats died by Day 2 following a single 2000 mg/kg oral dose.
Body weight:
300 mg/kg: All three animals gained body weight by study termination.

1000 mg/kg: Terminal body weight loss was observed among the animals that died. The surviving four animals gained body weight by study termination.

2000 mg/kg: Terminal body weight loss was observed among all three animals.
Gross pathology:
300 mg/kg: The gross necropsy revealed no observable abnormalities.

1000 mg/kg: The gross necropsy of the animals that died revealed red staining of the nose/mouth area, soiling, wetness and brown staining of the anogenital area, red areas on the lungs, dark areas on the liver and abnormalities of the gastrointestinal tract. No observable abnormalities were discovered during the gross necropsy of the animals that survived.

2000 mg/kg: The gross necropsy revealed wetness and yellow staining of the nose/mouth area, soiling and wetness of the anogenital area, red areas on the lungs, dark areas on the spleen, darker than normal liver and lungs, and abnormalities of the gastrointestinal tract.
Other findings:
300 mg/kg: Abnormal physical signs including piloerection, wetness and brown staining of the nose/mouth area, wetness of the anogenital area, and unkempt appearance were observed.

1000 mg/kg: Prior to death, abnormal physical signs including wetness and brown staining of the nose/mouth area, wetness and soiling of the anogenital area, piloerection, unkempt appearance, diarrhea, chromorhinorrhea, dyspnea, and sagging eyelids were observed. Among the surviving animals, wetness and brown staining of the nose/mouth area, wetness and soiling of the anogenital area, unkempt appearance, hunched posture, diarrhea, piloerection and chromorhinorrhea were observed.

2000 mg/kg: Prior to death, abnormal physical signs including piloerection, diarrhea, soiled anogenital area, dyspnea, lethargy, wetness of the nose/mouth area, and sagging eyelids were observed.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 of 1H-imidazole-1-ethanol, 4,5-dihydro-2-norcoc alkyl dervis. Batch # FPAC1717924 is greater than 1000 mg/kg but less than 2000 mg/kg of body weight in rats and considered to be in GHS Category 4.
Executive summary:

The oral LD50 of 1H-imidazole-1-ethanol, 4,5-dihydro-2-norcoc alkyl dervis. Batch # FPAC1717924 is greater than 1000 mg/kg but less than 2000 mg/kg of body weight in rats and considered to be in GHS Category 4.

Objective: To determine the potential for oral toxicity using the Acute Toxic Class Determination. This study was designed to comply with the standards set forth in the current OECD Guidelines for the Testing of Chemicals, Guideline 423. Guideline 423 is referred to in OPPTS 870.1000 as an acceptable method to assess lethality within a dose range. The test article was assigned to a toxic category based on the mortality results and significant clinical signs of toxicity up to the Category 4 value tested according to the currentGlobally Harmonized System of Classification and Labeling of Chemicals (GHS).

 

Method Synopsis: Initially, three healthy female Sprague Dawley rats were dosed orally with

1H-imidazole-1-ethanol, 4,5-dihydro-2-norcoco alkyl derivs. Batch # FPAC1717924at2000mg/kg. Since all three animals died at this level, additional animals were dosed as per the chart listed below. The rats were observed at 15 minutes, 1, 2 and 4 hours postdose and once daily for 14 days for toxicity and pharmacological effects, and twice daily for mortality. Body weights were recorded immediately pretest, weekly, at death and at termination in the survivors. All animals were examined for gross pathology. The test article was assigned to a toxic category based on the mortality response noted.