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

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Study period:

11-06-1990 to 12-07-1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

High quality study, according to GLP and well documented methods. However, greater than 10% maternal mortality observed in high dose group thus the study is used as supporting data.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:

1990

Materials and methods

Principles of method if other than guideline:

Seventy-two F0 generation female rabbits were assigned randomly to treatment with either a Vehicle Control (tap water) or to one of three graded doses (10, 20, and 40 mg/kg/day) of L-158,086 (18 animals per treatment group). Oral dosing was performed once daily from Day 6 through 18 of gestation. On Day 28 of gestation, all pregnant rabbits underwent C-section. Each fetus was identified and examined for alterations.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

L-158, 086

IUPAC Name:

L-158, 086

Constituent 2

Reference substance name:

losartan potassium

IUPAC Name:

losartan potassium

Details on test material:

- Name of test material (as cited in study report): L-158, 086

- Analytical purity:99.8 %

- Expiration date of the lot/batch:L-158, 086-005H010

- Stability under test conditions: Stable
:

Test animals

Species:

rabbit

Strain:

New Zealand White

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

The high does of L-158, 086 was dissolved in the vehicle daily, just piror to dosing. Aliquots of the high dose were diluted with appropriaet amounts of vehicle to obtain the middle and low dosages of L-158,086.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

daily on gestational days 6-18

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 10,20,40 mg/kg/day
Basis:
nominal conc.

No. of animals per sex per dose:

18

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: range finding test where maternal toxicity was observed at 60 mg/kg/day

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestational Days 0 through 28. Exam for postdosing toxicity conducted 1-5 hrs after dose administration.

BODY WEIGHT: Yes
- Time schedule for examinations: Gestational Days: 0,6,8,10,12,14,16,18,19,22,and 28


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- Organs examined: uterus, thoracic and abdominal viscera. Stomach contents (for hairballs).

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:

- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all
- Soft tissue examinations: Yes: all

- Head examinations: Yes: half per litter

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
40 mg/kg/day: three deaths, one abortion and depressed body weight gain and food consumption. 20 mg/kg/day: one maternal death.

Effect levels (maternal animals)

1

Dose descriptor:

NOEL

Effect level:

10 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
decreased fetal body weight and delays in fetal ossification in the 40 mg/kg/day group

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Maternal toxicity occurred in the form of three deaths and one abortion in the 40 mg/kg/day group, as well as depressions in maternal body weight gain and food consumption. In the 20 mg/kg/day group, there was one maternal death resulting in a no-effect dose for maternal toxicity of 10 mg/kg/day. 
 
Developmental toxicity occurred in the form of decreased fetal body weight and delays in fetal ossification in the 40 mg/kg/day group resulting in a no-effect dose for developmental toxicity of 20 mg/kg/day.

Executive summary:

The results for losartan potassium, which are read-across to losartan free acid, are summarised below. Maternal toxicity occurred in the form of three deaths and one abortion in the 40 mg/kg/day group, as well as depressions in maternal body weight gain and food consumption. In the 20 mg/kg/day group, there was one maternal death resulting in a no-effect dose for maternal toxicity of 10 mg/kg/day. 

 

Developmental toxicity occurred in the form of decreased fetal body weight and delays in fetal ossification in the 40 mg/kg/day group resulting in a no-effect dose for developmental toxicity of 20 mg/kg/day.