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

Acute Toxicity: other routes

Administrative data

Endpoint:

acute toxicity: other routes

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 28 Oct to 11 Nov 1987

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:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Acute toxicology Standard Procedure

Deviations:

no

GLP compliance:

yes

Limit test:

no

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.: 15497-87-3
Purity: 95.3%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Wilmington MA
- Age at study initiation: Six-week old
- Weight at study initiation: 164.3 to 176.0 grams
- Fasting period before study:
- Housing: Polycarbonate shoe box-type cages, males or females given the same dose were housed together (three per cage). The cage floor was covered with hardwood chip bedding (Ab-sob-dri, Lab products). All test animals were transferred into a clean cage each day.
- Diet (e.g. ad libitum): Prolab RMH-3000 pelleted rodent diet (Agway) ad libitum
- Water (e.g. ad libitum): Drinking water was obtained from a municipal water source subject to regulation by the U.S. Environmental Protection Agency. Water was suplied ad libitum from bottles that were changed two times a week.
ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70±2
- Humidity (%): 50±5
- Air changes (per hr): approximately 18 times per hour with air filtered through 80-90% efficiency filters and finally through HEPA filters.
- Photoperiod (hrs dark / hrs light): illuminated by fluorescent lighting 12 hours a day (7:00 am-7:00pm).
IN-LIFE DATES: From 28 Oct to 11 Nov 1987

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

other: 0.1% (w/v) aqueous methylcellulose solution

Details on exposure:

Concentration in vehicle: 2%

Doses:

50, 150, and 300 mg/kg

No. of animals per sex per dose:

3 males

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: All rats were observed for clinical signs and mortality for 14 days after dosing. The individual body weights of the animals was obtained at least six times during the study, i.e. on the day of dosing (day 0) and on the day 1, 4, 7, 10, and prior to the sacrifice on day 14.
- Necropsy of survivors performed: Animals that died during the study and those that survived to sacrifice were necropsied for gross pathological changes.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Statistics:

None stated

Results and discussion

Effect levels

Sex:

male

Dose descriptor:

LD50

Effect level:

> 300 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was produced by an intraperitoneal dose of 50 or 150 mg/kg, but one of three rats given high dose of 300 mg/kg died.

Clinical signs:

Clinical signs were observed at all doses tested (50, 150 and 300 mg/kg). Within 15 minutes of dosing, all rats were pulling in the sides of their abdomen. By 1 to 2 hours post dose, the activity and respiration of the animals was decreased, and most tended to remian in a stationary position. In addition, those given 150 or 300 mg/kg walked hunched and with slow placement of the feet.
All rats given the low dose of 50 mg/kg appeared essentially normal on the day after dosing (day 1) and throughout the remainder of the 14-day observation period. The activity and respiration of the rats given 150 or 300 mg/kg were still decreased on day 1. In addition, one high dose animal appeared thin, was shaky and weak, and walked in a crawling fashion. This animal was nearly prostrate on day 2 and was found dead on the morning of day 3. Rats given a dose of 150 mg/kg recovered within 2 or 3 days of dosing. One of the two survivors given the high dose of 300 mg/kg recovered completely by day 4. However, the condition of the other high dose rat began to deteriorate on day 2, and by day 3, it was also weak, appear thin, and by day 5, the rat appeared essentiallty normal.

Body weight:

On day 3, all rats given the low dose of 50 mg/kg weighed several grams less than they did on day 2, but their weight on day 4 was above that recorded on day 2. The overall weight gain of these loe dose animals was normal. Most of the rats given 150 or 300 mg/kg weighted less than they did prior to dosing on day 1. Rats given a dose of 150 mg/kg exhibited a slight loss of weight on day 3, but showed progressive weight gain from day 4 on, and their overal weight gain at the end of the study was essentially normal. One of the two survivors given the high dose of 300 mg/kg was gaining weight by day 3. However, the other high dose rat continued to lose weight by day 3. By day 4, the animal was gaining weight, but at sacrifice on day 14 , this animal weighed considerably less than all other surviving rats.

Gross pathology:

White material (presumably test article) was evident in the abdominal cavity of the high dose animal found dead on day 3. The liver was dark and mottled, a whitish haze was apparent over its surface, and portions of the small intestine were reddened. In all survivors sacrificed on day 14, white material was evident within the peritoneal cavity and was often adhered to the pancreas and liver. In rats given 150 or 300 mg/kg, there was a whitish haze over the surface of the kidneys and/or spleen. In addition, the pancreas, liver, and/or testicular fat bodies were often adhered via the white material.

Applicant's summary and conclusion

Conclusions:

The approximate acute intraperitoneal median lethal dose (LD50) of the test item in the Sprague-Dawley male rat was estimated to be greater than 300 mg/kg body weight.