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Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 2012-12-12 to 2013-03-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-(5'-((5S)-5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2)benzofuran)-1-yl)-2-(methylsulfonyl)ethanone
Cas Number:
1398609-39-6
Molecular formula:
C23H18Cl2F4N2O5S
IUPAC Name:
1-(5'-((5S)-5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2)benzofuran)-1-yl)-2-(methylsulfonyl)ethanone
Specific details on test material used for the study:
Lot No.: PF-06450567-GLK
Purity: Not provided

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Texas Animal Specialties; Humble, TX
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Ca. 9-10 weeks
- Weight at study initiation: 157-200 g
- Fasting period before study: approximately 16 hours before dosing
- Housing: Suspended stainless steel with wire bottom, 1 per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 28-97
- Air changes (per hr): > 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
The test article was mixed with CMC and Tween 80 in Deionized water to produce a 10% w/v concentration. An individual dose was calculated for each animal based on its fasted body weight and administered by gavage at a volume ranging from 0.55 mL/kg at the 55 mg/kg level to 20.0 mL/kg at the 2000 mg/kg level. Each dose was administered using an appropriately sized syringe and stainless steel ball-tipped intubation needle. Animals were returned to their cages immediately after dosing.
Doses:
55, 175, 550 and 2000 mg/kg
No. of animals per sex per dose:
one for 55 &175 mg/kg; 2 for 550 mg/kg, 4 for 2000 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Observations for mortality and clinical/behavioral signs of toxicity were made at least three times on the day of dosing (day 0) and at least once daily thereafter for 14 days. Individual body weights were recorded just prior to dosing and on days 7 and 14, or at time of discovery after death.
- Necropsy of survivors performed: yes, On day 14 after dosing, each surviving animal was euthanized by an overdose of CO2. All study animals were subjected to gross necropsy and all abnormalities recorded.
Statistics:
The LD50 value with 95% confidence interval was calculated using the AOT425 Stat Program supplied by EPA.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
783 mg/kg bw
Based on:
test mat.
95% CL:
> 550 - < 2 000
Mortality:
Mortality occurred only at the 2000 mg/kg level (4/4).
Clinical signs:
Clinical signs in one survivor included activity decrease, emaciation, decreased/no defecation, small/hard feces, piloerection, sensitivity to touch and staggered gait, on Days 3-9. Animals that died on test exhibited activity decrease, body tremors, crusted face, piloerection and small feces.
Body weight:
Animals surviving to termination exhibited weekly weight gain, except for one that lost weight and one that failed to gain weight between Days 0 and 7.
Gross pathology:
Gross necropsy on animals that died on test revealed stained fur and under tail; crusted muzzle; discolored lungs and liver; gas in stomach; and empty gastrointestinal tract. Gross necropsy on animals surviving to termination revealed no observable abnormalities.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute oral LD50 for test item is estimated to be 783 mg/kg in female rats.
Executive summary:

Test article was evaluated for its acute oral toxicity potential in female albino rats when administered as a gavage dose by OECD 425. A main test was conducted following up-and-down procedure (UDP) at 55, 175, 550 and 2000 mg/kg. The study was terminated following stopping rules of this procedure.


Mortality occurred only at the 2000 mg/kg level. Clinical signs in one survivor included activity decrease, emaciation, decreased/no defecation, small/hard feces, piloerection, sensitivity to touch and staggered gait, on Days 3-9. Animals that died on test exhibited activity decrease, body tremors, crusted face, piloerection and small feces. Animals surviving to termination exhibited weekly weight gain, except for two that lost or failed to gain weight between days 0 and 7. Abnormal necropsy findings that occurred, only in the animals dying on test, pertained to fur, muzzle/tail areas, lungs, liver and contents of the stomach/intestines.


The acute oral LD50 was estimated to be 783 mg/kg.