Avermectin A1a, 25-cyclohexyl-5-O-demethyl-25-de(1-methylpropyl)-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 31 May to 15 Jun 1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study run to a method comparable with current guidelines and to GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Report date:

1989

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

according to guideline

Guideline:

other: Standard Procedures of the Centre de Recherche, Amboise

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(1'R,2S,4'S,5S,6R,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S)-6-cyclohexyl-21',24'-dihydroxy-12'-{[(2R,4S,5S,6S)-5-{[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-4-methoxy-6-methyloxan-2-yl]oxy}-5,11',13',22'-tetramethyl-5,6-dihydro-3',7',19'-trioxaspiro[pyran-2,6'-tetracyclo[15.6.1.1⁴,⁸.0²⁰,²⁴]pentacosane]-10',14',16',22'-tetraen-2'-one

EC Number:

601-490-4

Cas Number:

117704-25-3

Molecular formula:

C50H74O14

IUPAC Name:

(1'R,2S,4'S,5S,6R,8'R,10'E,12'S,13'S,14'E,16'E,20'R,21'R,24'S)-6-cyclohexyl-21',24'-dihydroxy-12'-{[(2R,4S,5S,6S)-5-{[(2S,4S,5S,6S)-5-hydroxy-4-methoxy-6-methyloxan-2-yl]oxy}-4-methoxy-6-methyloxan-2-yl]oxy}-5,11',13',22'-tetramethyl-5,6-dihydro-3',7',19'-trioxaspiro[pyran-2,6'-tetracyclo[15.6.1.1⁴,⁸.0²⁰,²⁴]pentacosane]-10',14',16',22'-tetraen-2'-one

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Batch No.: 15497-120-1
Purity: 92.1%

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charies River, St-Aubin-Les-Eibeuf, France
- Age at study initiation: 80 days (mean)
- Weight at study initiation: 240.4±6.1 (mean, grams±SD)
- Fasting period before study:
- Housing: individually on decontaminated (autoclaved) sawdust bedding (Litalabo, Societe Parisienne des Sciures, France) in makrolon cages (425x266x150 mm)
- Diet (e.g. ad libitum): Animals had free access to a pelleted commercial laboratory animal food (diet A04C, from Usine d'Alimentation Rationnelie, Villemolsson-sur-Orge, France)
- Water (e.g. ad libitum): Animals had free access to tap water.
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3
- Humidity (%): 60±20
- Air changes (per hr): 14 times per hour
- Photoperiod (hrs dark / hrs light): From 7:00H to 19:00H.

IN-LIFE DATES: From 31 May To 15 Jun 1988

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0.6 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): A21606, A21395
- Purity:

Duration and frequency of treatment / exposure:

10 days (day 6 to day 15 p.i.)

Doses / concentrations

Remarks:

Doses / Concentrations:
6 mg/kg/day

No. of animals per sex per dose / concentration:

5 females

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

None stated

Details on study design:

None stated

Details on dosing and sampling:

On day 15 p.i. blood was taken, by puncture of the orbital sinus under light ether anaesthesia, at 1, 3, and 5 hours after dosing. The females were sacrificed with their fetuses after the last blood withdrawal. Amniotic fluid was then collected, pooled and about 2 mL kept for test substance estimation. Fetuses were taken for detection of test substance in their tissues.

Statistics:

None stated

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

1. Maternal plasma

Plasma test substance concentrations were sustained for at least 5 hours with maximal individual values between 0.48 and 1.27 μg/mL.

2. Fetal homogenates

Fetal test substance concentrations were comparable to those found in maternal plasma at 5 hours with individual values ranging from 0.27 to 1.10 μg/g wet weight.

3. Amniotic fluid

Drug concentrations were much lower than in fetal homogenates with values between 0.007 and 0.025 μg/mL.

Applicant's summary and conclusion

Conclusions:

Under the conditions of the reproductive study in rats, the dams and their fetuses were exposed to similar concentrations of the unchanged drug. However, very little drug was found in the amniotic fluid.