Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 28 - September 11, 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterize

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
and 21 CFR 28
GLP compliance:
yes
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Hsd: SPRAGUE DAWLEY®SD®
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley Inc, Indianapolis, Indiana
- Age at study initiation: 7 - 9 weeks
- Weight at study initiation: 200 to 224g
- Fasting period before study: overnight.
- Housing: individually in hanging stainless steel cage
- Diet: Certified Rodent Chow ad libitum
- Water: tap water ad libitum
- Acclimation period: 6 days before

ENVIRONMENTAL CONDITIONS
- Temperature: 69 - 72°F
- Humidity : Ambient
- Photoperiod :12hrs light/12rhs dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.2% hydroxypropyl methylcellulose (HPMC)
Details on oral exposure:
dose levels: 0, 125, 250, 500, or 2000 mg/kg. In addition 5 male rats were administered 375 or 437.5 mg/kg
dose volume: 10 ml/kg
Doses:
5 males and 5 females were orally administered Abbott -172245 in 0.2% HPMV one time only in doses of 125, 250, 500 or 2,000 mg/kg. In addition 5 male rats were administered doses of 375 or 437.5 mg/kg.
No. of animals per sex per dose:
5 females/males per dose
Control animals:
no
Details on study design:
All animals were observed frequently on day of dosing and daily thereafter for at least 13 days after treatment for a total of 14 days. Day of treatment = day 0.
Daily observations included signs of toxicity in addition to lethality.
Animals weighed on a weekly basis.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
> 437.5 - < 500 mg/kg bw
Based on:
test mat.
Sex:
female
Dose descriptor:
LD50
Effect level:
ca. 250 mg/kg bw
Based on:
test mat.
Mortality:

Dose (mg/kg).................................................... Males.........................................Females
125 0/5 0/5
250 0/5 2/5
375 0/5 n/a
437.5 1/5 n/a
500 4/5 5/5
2000 5/5 5/5
Clinical signs:
No clinical signs in males or females at 125mg/kg immediately after treatment or during the 2 wk observation period.
Clinical signs in males and females at 250mg/kg or higher included decreased activity, jerks, tremors, ataxia, salivation, hunched posture, rales, blinking, red discharge from nose and mouth rough coat and increased activity.

In addition the following were noted in males:
squinting in a single animal at 250mg/kg.
small amount of stool under the cage of a single animal at 437.5mg/kg
Sneezing, excessive grooming and vocalizaation in a second animal also at 437.5mg/kg.
Red discharge eyes in several animals at 500 or 2000 mg/kg.
Body weight:
No apparent treatment related body weights changes were observed in rats during week one or two of the observation period following treatment.
Gross pathology:
No gross morphological abnormalities observed in rats necropsied following acute death or in animals euthanized and necropsied at the end of the two wk observation period..
Other findings:
The acute oral approximate no-observed-effect-level (ANOEL) of Abbott 172245 in rats was found to be 125 mg/kg.

Applicant's summary and conclusion

Conclusions:
The approx oral LD50 was determined to be 250mg/kg in females and between 437.5 and 500mk/kg in males