1H-Imidazole-5-methanol, 2-butyl-4-chloro-1-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

May 31, 1989 through September 1, 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Although the study was conducted according to GLP and well documented methods, " Practical guide 10: How to avoid unnecessary testing on animals", Section 3.3.2 states it is important that the reliability indicator (Klimisch score) reflects the assumptions of similarity. Thus, a score of 1 (reliable without restrictions) should normally not be used for results derived from read-across.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: Guideline not specified but method well documented

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

DuP 753

IUPAC Name:

DuP 753

Constituent 2

Reference substance name:

losartan potassium

IUPAC Name:

losartan potassium

Details on test material:

- Name of test material (as cited in study report): DuP 753
- Substance type: bulk powder
- Physical state: solid
- Analytical purity: 97.9 %
- Lot/batch No.: INE 3340-19M
- Stability under test conditions: confirmed through analysis of one gram sample of bulk powder, collected at pre-test and termination.
- Storage condition of test material: tightly sealed container at ambient room temperature, protected from excessive light exposure.

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: capsule

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

90 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 25, 125
Basis:
actual ingested

No. of animals per sex per dose:

5 female, 5 male

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

125 mg/kg/day= no mortality. gastrointestinal effects. Fecal occult blood.

Mortality:

mortality observed, treatment-related

Description (incidence):

125 mg/kg/day= no mortality. gastrointestinal effects. Fecal occult blood.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

a trend toward decreased mean absolute heart weight in the 125 mg/kg day dogs, but was not statistically significant

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

125 mg/kg/day= 1 female, moderate lymphocyctic infiltration in gastric mucosa. The relationship of this finding in the gastric mucosa to treatment with DuP 753 was considered to be equivocal based upon the low incidence rate.

Histopathological findings: neoplastic:

no effects observed

Details on results:

1- dose-related increase in the incidence of clinical signs suggesting treatment-related gastrointestinal disturbance. These signs included a dose-related increase in the incidence of salivation, vomition and fecal abnormalities. The emetic response following dosing occurred with greatest frequency in the 125 mg/kg/day female group, with animals from this group vomiting on 24-32 days of this study.

Fecal abnormalities were generally limited to the 125 mg/kg-day groups and included abnormal consistency and/or colour of the stool and positive fecal occult blood. All 125 mg/kg day dogs tested positive for fecal occult blood (at least 3 consecutive days) during the study period. Several high dose dogs tested positive for fecal occult blood over several periods of at least three consecutive days.

2- a trend toward decreased mean absolute heart weight in the 125 mg/kg day dogs

3- moderate lymphocytic infiltration in the gastric mucosa of one high dose female dog, which was compatible with gastric irritation.

There were clinical signs suggestive of gastrointestinal irritation, increased salivation and emesis in the 25 mg/kg group at slightly higher frequency than the control group. There were no other effects in this group.

Effect levels

1

Dose descriptor:

NOEL

Effect level:

5 mg/kg bw/day (actual dose received)

Based on:

test mat.

2

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based upon the results of this study, the maxium-tolerated-dosage (MTD) for losartan potassium, and losartan free acid by read-across, was >=125 mg/kg/day, the NOAEL 25 mg/kg/day and the NOEL was 5 mg/kg/day.

Executive summary:

The objective of the study was to characterise the potential toxicity of DuP 753, resulting from daily oral administration.

DuP 753 was administered via liquid-filled gelatin capsules to groups of 5 male and 5 female beagle dogs at daily dosages of 0, 5, 25, or 125 mg/kg for approximately 3 months. Evaluations were made of clinical signs, body weight, food consumption, fecal occult blood, ophthalmoscopic examinations, hematology, serum chemistry, urinalysis, electrocardiography, physical examinations, organ weights, and gross and microscopic post-mortem examinations. Additionally, blood samples were obtained at designated times during the study to determine the plasma levels of DuP 753. 

 

DuP 753 administered in this study was well tolerated in the dog. There were no toxicologically significant effects of treatment on body weight, food consumption, clinical pathology, electrocardiography, physical examinations, ophthalmoscopic examinations, or gross microscopic post-mortem findings. A treatment-related increase in the incidence of vomiting and fecal abnormalities was apparent in the 125 mg/kg/day dogs. These antemortem findings and microscopic evidence of lymphocytic infiltration in the gastric mucosa suggested a dose-related gastrointestinal irritation. There were clinical signs suggestive of gastrointestinal irritation, increased salivation and emesis in the 25 mg/kg group at slightly higher frequency than the control group. There were no other effects in this group. Based upon the results of this study, the maxium-tolerated-dosage (MTD) for losartan potassium, and losartan free acid by read-across was >=125 mg/kg/day, the NOAEL 25 mg/kg/day and the NOEL was 5 mg/kg/day.