Benzamide, N-[[4-[(cyclopropylamino)carbonyl]phenyl]sulfonyl]-2-methoxy-

Toxicity to birds

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

short-term toxicity to birds: acute oral toxicity test

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

03 - 17 Nov 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 71-1 (Avian Acute Oral Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.2100 (Avian Acute Oral Toxicity Test)

GLP compliance:

yes (incl. QA statement)

Dose method:

capsule

Vehicle:

no

Details on preparation and analysis of diet:

DIET PREPARATION
- Description and nutrient analysis of basal diet provided in study report: yes / no
- Preparation of doses:

Test organisms (species):

Colinus virginianus

Details on test organisms:

TEST ORGANISM
- Common name: Northern Bobwhite quail
- Source: Poultry farming H.& E. KQberich, Ruderner Strafle 11, Geesdorf, Germany / (hatched on 2004-02-27),
- Sexes used: male and female
- Acclimation: 15 days under test conditions in the test facility
- Disease free: yes
- Kept according to standard practices: yes

Limit test:

yes

Total exposure duration (if not single dose):

14 d

No. of animals per sex per dose and/or stage:

5 male and 5 female

Control animals:

yes

Details on test conditions:

FOOD
A standard rearing diet for quail (type: Alleinfutter fur Wachteln und Enten G4;
Art.No. 3958.9.25 of the company "Provimi KLIBA SA", CH-4303 Kaiseraugst
(Switzerland)) was supplied ad libitum throughout the acclimation period and the
study, except a 16 hours starving period immediately before application.
WATER
Drinking water (Monheim City municipal water), according to the Federal German
Quality Standard (TVO) was available ad libitum prior to and throughout the study.
The water was changed at least every Monday, Wednesday and Friday.
TEST UNITS
The birds were singly housed in stainless steel wire racks which were placed indoors
and contained four rows, one upon the other. The cages measured 38 cm deep x 50 cm width and a height of 24 cm. Each level of the rack was divided into two
completely separated cages of identical size (38 x 25 x 24 cm) by an internal
partition made of invisible plastic, fixed on ceiling and ground of the cage; each cage
was equipped with a plastic feeder located at the front side ( 1 5 x 7 x 5 cm). The tap
water filled a drinking trough along the back side of each cage. The rack levels to be
used in the study were numbered 1 to 5 (for the treatment group) and 6 to 10 (for the
control group), and each cage number represented two, singly housed birds (a male
and a female) assigned to the same treatment level.

Duration (if not single dose):

14 d

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

Results:

Test substance	AE 0001 789 techn. a.s.
Test object	Northern Bobwhite Quail f / m
LD50 mg a.s. / kg b.w.	>2000
Lowest lethal dose (LLD) mg a.s./kg b.w.	>2000

Further observations: No mortalities. 9 treated birds were observed to have soft excrement and diarrhea on the day of exposure, one female bird with soft excrement for further two days, symptoms ceased completely on the third day after exposure until the end of the study. There were no clinical symptoms of toxicity in the controls. No treatment related influence on body weight. No pathological findings within the treatment group.

Validity criteria fulfilled:

not specified

Reference 2

Endpoint:

short-term toxicity to birds: dietary toxicity test

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

24 Jun - 02 Jul 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 205 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.2200 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

other: FIFRA Guideline 71-2

GLP compliance:

yes (incl. QA statement)

Dose method:

feed

Analytical monitoring:

yes

Vehicle:

no

Details on preparation and analysis of diet:

DIET PREPARATION
- Preparation of doses: A quantity of the feed was weighed into a tared container (approximately 11 kg). The compound was weighed into a
separate tared container. A premix for each treatment level was prepared by adding approximately 1 kg of the feed and the appropriate amount of technical compound into a Kitchen Aid Mixer (model no. KSM90) and mixed for at least five minutes. Approximately half of the remaining weighed feed was placed into a Hobart mixing bowl. The premix was then added to the Hobart mixing bowl and mixed for ten minutes. The remaining quantity of feed was then added to the Hobart mixing bowl and mixed for an additional ten minutes. Control birds received basal diet feed only.


HOMOGENEITY AND STABILITY OF TEST MATERIAL IN DIET
- How often was homogeneity and stability tested: Samples were analyzed to determine diet homogeneity, measured concentration, freezer stability
and one-day brooder stability. The brooder stability samples were collected on June 22, 2004 during the treatment period of the study. The one-day brooder stability measurement was sufficient as treated feed was completely replaced daily with fresh feed from the freezer during the exposure phase of the study. The freezer stability measurement (22 days) was sufficient in duration to verify storage of the treated diet was appropriate for the study.

The compound was stable for at least one day (feed was changed daily) in avian feed under brooder conditions. The one-day stability values were 113 % of initial measured concentrations in the 313 and 5000 mg ai/kg feed levels. The compound was stable in avian feed stored under freezer conditions for at least 22 days
- Mixing procedure adequate and variance between nominal and actual dosage acceptable: yes

Test organisms (species):

Colinus virginianus

Details on test organisms:

TEST ORGANISM
- Common name: Northern bobwhite
- Source: Northern bobwhite eggs were obtained from Strickland Gamebird Farm, Pooler, Georgia on May 19, 2004. They were incubated and hatched in the Ecotoxicology avian facility.
- Age at test initiation: 10 days
- Disease free: yes
- Kept according to standard practices: yes

Limit test:

no

Total exposure duration (if not single dose):

5 d

Post exposure observation period:

After five days of exposure, treatment level birds were given a control diet for a three day recovery period.

Control animals:

yes

Nominal and measured doses / concentrations:

Nominal concentrations: 0, 313, 625, 1250, 2500 and 5000 ppm a.i..
Measured concentrations were 0 (< 30), 311, 655, 1336, 2715 and 4959 mg ai/kg feed

Duration (if not single dose):

5 d

Dose descriptor:

LC50

Effect level:

> 4 959 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

No mortalities or sublethal effects occurred during the study. No symptoms of toxicity were noted in any birds during the study.

There were no treatment related adverse effects noted in this study. The subacute dietary LC50 of technical AE0001789 in Northern Bobwhite quail is reported to be > 4959 mg ai/kg feed. Based on all parameters measured, the NOAEL was 4959 mg ai/kg feed and the LOAEL was > 4959 mg a.i./kg feed.

Table 1: Validity criteria for OECD 205 (1984)

Criterion	Outcome	Validity criterion fulfilled
Mortality in the control < 10% at the end of the test.	Mortality in the control was 0% at the end of the test.	yes
There must be evidence that the concentration of the substance being tested has been satisfactorily maintained in the diet (it should be at least 80% of the nominal concentration) throughout the first five days of the test period.	The measured concentrations being tested were 99 to 109 % of nominal concentrations. The feed was changed daily.	yes
The lowest treatment level should not result in compound-related mortality or other observable toxic effects.	No mortalities or toxic symptoms were observed in the lowest treatment level.	yes

 

Validity criteria fulfilled:

yes

Remarks:

See Table 1 in "Any other information on results incl. tables".

Reference 3

Endpoint:

short-term toxicity to birds: acute oral toxicity test

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

09 - 17 Mar 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 205 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.2200 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPP 71-2 (Avian Dietary Toxicity Test)

GLP compliance:

yes (incl. QA statement)

Dose method:

feed

Analytical monitoring:

yes

Details on preparation and analysis of diet:

HOMOGENEITY AND STABILITY OF TEST MATERIAL IN DIET
- How often was homogeneity and stability tested: Feed samples were analyzed to determine measured concentrations in the diets. Historical data
from study number EBUBX002 indicated the compound was homogeneous when mixed into the diet, the compound was stable in the diet while stored in freezer conditions, and that the compound was stable in the diet under study room conditions (Stoughton, 2006). Therefore, no homogeneity, freezer stability, or brooder stability samples were taken during the course of this study.

Test organisms (species):

Anas platyrhynchos

Details on test organisms:

TEST ORGANISM
- Common name: Mallard
- Source: wild birds were received from Whistling Wings, Hanover, Illinois on March 1, 2006.
- Age at test initiation: 9 days
- Disease free: yes
- Kept according to standard practices: yes

Limit test:

no

Total exposure duration (if not single dose):

5 d

Post exposure observation period:

After five days of exposure, all treatment level birds were returned to a control diet for the three-day recovery period.

Control animals:

yes

Nominal and measured doses / concentrations:

Nominal concentrations: 0 (Control), 313, 625, 1250, 2500, and 5000 mg/kg feed.
Measured concentrations: 289, 612, 1260, 2416, 4542 mg ai/kg feed for the 313, 625, 1250, 2500 and 5000 mg/kg feed nominal levels, respectively. This represents a range of 91 - 101% of nominal concentrations. All subsequent observations will refer to the measured concentrations.

Reference substance (positive control):

no

Duration (if not single dose):

5 d

Dose descriptor:

LC50

Effect level:

> 4 542 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

Duration (if not single dose):

5 d

Dose descriptor:

NOEC

Effect level:

>= 4 542 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

Remarks:

or any sublethal parameters

No mortalities occurred during the study. No symptoms of toxicity were noted in any birds during the study.

The sub-acute dietary LC50 of technical AE0001789 in mallards based on mortality was > 4542 mg ai/kg feed or >1068 mg a.i./kg bw/day.

Based on sub-lethal parameters measured, the NOEC was 4542 mg a.i/kg feed or 1068 mg a.i./kg bw/day and the LOEC was >4542 mg a.i/kg feed or >1068 mg a.i./kg bw/day.

Table 1: Validity criteria for OECD 205 (1984)

Criterion	Outcome	Validity criterion fulfilled
Mortality in the control < 10% at the end of the test.	Mortality in the control was 0% at the end of the test.	yes
There must be evidence that the concentration of the substance being tested has been satisfactorily maintained in the diet (it should be at least 80% of the nominal concentration) throughout the first five days of the test period.	The measured concentrations being tested were 91 to 101 % of nominal concentrations. Historical data from study number EBUBX002 indicated the compound was homogeneous when mixed into the diet, the compound was stable in the diet under study room conditions.	yes
The lowest treatment level should not result in compound-related mortality or other observable toxic effects.	No mortalities or toxic symptoms were observed in the lowest treatment level.	yes

 

Validity criteria fulfilled:

yes

Remarks:

See Table 1 in "Any other information on results incl. tables".

Reference 4

Endpoint:

short-term toxicity to birds: acute oral toxicity test

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

17 - 25 Jun 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 205 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.2200 (Avian Dietary Toxicity Test)

Qualifier:

according to guideline

Guideline:

EPA OPP 71-2 (Avian Dietary Toxicity Test)

GLP compliance:

yes (incl. QA statement)

Dose method:

feed

Analytical monitoring:

yes

Vehicle:

no

Test organisms (species):

Anas platyrhynchos

Details on test organisms:

TEST ORGANISM
- Common name: Mallard
- Source: wild birds were received from Whistling Wings, Hanover, Illinois on June 8, 2004.
- Age at test initiation: 10 days
- Disease free: yes
- Kept according to standard practices: yes

Limit test:

no

Total exposure duration (if not single dose):

5 d

Post exposure observation period:

After five days of exposure, all treatment level birds were returned to a control diet for the three-day recovery period.

Control animals:

yes

Nominal and measured doses / concentrations:

Nominal concentrations: 0 (control), 313, 625, 1250, 2500, and 5000 mg/kg feed
Measured concentrations: 0, 311, 655, 1336, 2715, 4959 mg a.i./kg feed.
All subsequent observations will refer to the measured concentrations.

Reference substance (positive control):

no

Duration (if not single dose):

5 d

Dose descriptor:

LC50

Effect level:

> 4 959 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

Duration (if not single dose):

5 d

Dose descriptor:

LOEC

Effect level:

> 4 959 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

mortality

Duration (if not single dose):

5 d

Dose descriptor:

LOEC

Effect level:

311 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

other: reductions in body weight and growth and treatment related reductions in feed consumption

Remarks on result:

other: at all the treatment levels during the recovery period of the study

Observations: No clinical signs of toxicity or treatment-related mortalities were noted at any treatment level. There were no statistically significant reductions in body weight, growth, or food consumption during the exposure period at any treatment level. There were statistically significant reductions in body weight and growth and treatment related reductions in feed consumption at all the treatment levels during the recovery period of the study as compared to the controls.

The sub-acute dietary LC50 of technical AE0001789 in mallards based on mortality was >4959 mg a.i./kg feed or >1161 mg a.i./kg bw/day.

Based on sub-lethal parameters measured, the NOEC was <311 mg a.i/kg feed or <67 mg a.i./kg bw/day and the LOEC was 311 mg a.i/kg feed or 67 mg a.i./kg bw/day.

Table 1: Validity criteria for OECD 205 (1984)

Criterion	Outcome	Validity criterion fulfilled
Mortality in the control < 10% at the end of the test.	Mortality in the control was 0% at the end of the test.	yes
There must be evidence that the concentration of the substance being tested has been satisfactorily maintained in the diet (it should be at least 80% of the nominal concentration) throughout the first five days of the test period.	The measured concentrations being tested were 99 to 109 % of nominal concentrations. The compound was stable for at least one day (feed was changed daily) in avian feed under brooder conditions.	yes
The lowest treatment level should not result in compound-related mortality or other observable toxic effects.	No mortalities or toxic symptoms were observed in the lowest treatment level.	yes

 

Validity criteria fulfilled:

yes

Remarks:

See Table 1 in "Any other information on results incl. tables".

Reference 5

Endpoint:

long-term toxicity to birds: reproduction test

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

28 Jul - 29 Dec 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 206 (Avian Reproduction Test)

Qualifier:

according to guideline

Guideline:

EPA OPP 71-4 (Avian Reproduction Test)

GLP compliance:

yes (incl. QA statement)

Dose method:

feed

Analytical monitoring:

yes

Vehicle:

no

Details on preparation and analysis of diet:

DIET PREPARATION
- Preparation of doses: The adult diet used for all phases of the study was Teklad Bayer Game Bird ration. The compound was mechanically mixed into the adult feed using a Kitchen Aid mixer (Model No. KSM90) as a premix. Then, the premix was mechanically blended with the appropriate mass of
raw feed in a commercial Hobart Mixer. The feed mixing process was a dry mix; no carriers or solvents were needed.

The feed mixing process consisted of the following steps. Approximately half of the weighed feed ration was placed in the Hobart mixing bowl. Approximately 1 kg of the remaining feed ration and the appropriate amount of AE 0001789 technical were placed into the stainless steel mixing bowl of a Kitchen Aid mixer. This compound/feed ration premix was mixed for at least five minutes. This premix was then added to the Hobart mixing bowl. The premix and approximately half of the total feed ration was well mixed for at least five minutes. The remaining feed ration was then added to the Hobart mixing bowl and mixed again for at least five minutes.

- other: Mixed adult feed was stored in labeled plastic tubs until used at approximately -12°C in the walk-in freezer of the Ecotoxicology building. Feed mixing was performed approximately once per week.
The hatchling feed during the study was Teklad Bayer Starter Ration. There were no solvents, carriers or additives. Therefore, the hatchling feed was not mixed.

Test organisms (species):

Colinus virginianus

Details on test organisms:

TEST ORGANISM
- Common name: Northern bobwhite
- Source: Stevenson Game Bird Farm, Riverside, Texas USA.
- Age at test initiation: 18 weeks
- Sexes used: males and females
- Disease free: yes

Limit test:

no

Total exposure duration (if not single dose):

22 wk

No. of animals per sex per dose and/or stage:

18 pairs (18 male and 18 female) of birds at each treatment level.

Control animals:

yes

Nominal and measured doses / concentrations:

Nominal concentrations: 0, 122, 367 and 1100 mg ai/kg feed.
Measured concentrations: (<30), 118, 396, 1162 mg ai/kg feed.
Daily dietary dose was 0, 11, 38 and 104 mg ai/kg bw/day, respectively.

Details on test conditions:

ACCLIMATION
- Acclimation period: approximately 2 weeks

PEN SIZE AND CONSTRUCTION MATERIALS
- Description: Adult birds were housed indoors in a single room in cages with sloping floors to allow the eggs to roll to the front of the cage. Cages were manufactured by Shore Manufacturing and measured approximately 56L X 28W X 27H cm. Cages were constructed of stainless steel wire grid and stainless steel sheeting. Each cage was equipped with both feed and water pans.

NO. OF BIRDS PER REPLICATE
- For negative control: one male and one female
- For treated: one male and one female

NO. OF REPLICATES PER GROUP
- For negative control: 18 pens (one male and one female per pen)
- For treated: 18 pens (one male and one female per pen)

TEST CONDITIONS
- Room temperature: 70°F (21°C)
- Relative humidity (%): 54%
- Photoperiod: The photoperiod through the acclimation period and short day length phase of the study was 7 hours light/17 hours dark per day. The photoperiod was then increased to 17 hours light/7 hours dark per day for the remainder of the study.
- Ventilation: Average air change in the hatchling room was 17.63 air changes per hour of one pass air.

Details on examinations and observations:

MORTALITY / CLINICAL SIGNS
- Time schedule for examinations: daily

BODY WEIGHT
- Time schedule for examinations: The adult body weight change from initiation of dosing to adult termination. Analyzed on a per cage basis by sex.

FOOD CONSUMPTION (if feeding study)
- Time schedule for examinations: The means were calculated as grams/bird/day. Analyzed on a per cage basis.

Egg Endpoints
Eggs Laid (mean): Analyzed as the total egg production. Eggs laid will be analyzed on a per hen basis.

Eggs Cracked (mean): Cracked eggs are determined by candling prior to incubation. Cracked eggs will be analyzed on a per hen basis.

Eggs Set (mean): Eggs placed under incubation are "set." Analyzed as the total number during the dosing phase. Eggs set will be analyzed on a per hen basis.

Viable Embryos (mean): Viability (fertility) is determined by candling on the 11th day of
incubation. Viability (fertility) analyzed as total viable embryos. Viable embryos were analyzed on a per hen basis.

Live Embryos (mean): Live embryos are determined by candling on the 18th day of incubation. Analyzed as the total number of live embryos on a per hen basis.

Eggs Not Cracked of Laid (%): Eggs laid that were not cracked as a percentage of eggs laid on a per hen basis. Analyzed as the mean percentage during the reproductive phase.

Eggs Set of Laid (%): Eggs set as a percentage of eggs laid on a per hen basis. Analyzed as the mean percentage during the reproductive phase.

Viable Embryos of Eggs Set (%): Viable embryos as a percentage of eggs set on a per hen basis. Analyzed as the mean percentage during the reproductive phase.

Live Embryos of Viable Embryos (%): Live embryos as a percentage of viable embryos on a per hen basis. Analyzed as the mean percentage during the reproductive phase.

Hatchling Endpoints:
Number Hatched (mean): Live hatchlings that had liberated themselves from their eggs by day 25 of incubation. Analyzed as the total number of normal hatchlings on a per hen basis.

14-day-old Survivors (mean): Live chicks at 14-days post hatch. Analyzed as the total number of 14-day survivors on a per hen basis.

Number Hatched of Eggs Laid (%): Hatchlings as a percentage of eggs laid on a per hen basis. Analyzed as the mean during the reproductive phase.

Number Hatched of Eggs Set (%): Hatchlings as a percentage of eggs set on a per hen basis. Analyzed as the mean during the reproductive phase.

Number Hatched of Live Embryos (%): Hatchlings as a percentage of live embryos on a per hen basis. Analyzed as the mean during the reproductive phase.

14-day-old Survivors of Eggs Set (%): Live chicks at 14-days post hatch as a percentage of eggs set on a per hen basis. Analyzed as the mean during the reproductive phase.

14-day-old Survivors of Number Hatched (%): Live chicks at 14-days post hatch as a percentage
of hatchlings on a per hen basis. Analyzed as the mean during the reproductive phase.

Hatchling Body Weight: Individual weights of the live hatchlings taken upon removal from the hatcher, analyzed on a per hen basis. Analyzed as the overall mean during the reproductive phase.

14-day-old Survivor Body Weight: Individual weights of the 14-day-old offspring taken at sacrifice, analyzed on a per hen basis. Analyzed as the overall mean during the reproductive phase.

Details on reproductive parameters:

The following parameters were examined per parental pen
- Eggs laid
- Eggs cracked; eggs broken
- Egg abnormalities
- Eggs set
- Eggshell thickness or eggshell strength
- Eggs fertile
- Embryos viable
- Normal hatchlings
- Abnormal hatchlings
- Clinical signs of toxicity, abnormalities and mortality
- 14-day old surviving chicks
- Chick body weight at hatching and 14 days after hatching

Reference substance (positive control):

no

Duration (if not single dose):

22 wk

Dose descriptor:

NOEC

Effect level:

>= 1 162 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

reproductive parameters

Duration (if not single dose):

22 wk

Dose descriptor:

NOEL

Effect level:

>= 104 mg/kg bw/day

Conc. / dose based on:

act. ingr.

Basis for effect:

reproductive parameters

Observations:

There were no compound related symptoms of toxicity in the adults and offspring. The NOEC was 1162 mg ai/kg feed.

Reproductive parameters:

There were no statistically significant adverse effects on any reproductive endpoint. The NOEC was 1162 mg ai/kg feed.

Gross pathology:

There were no compound related findings. The NOEC was 1162 mg ai/kg feed.

Conclusions:

There were no statistically significant adverse effects on the adults or the offspring. The NOEC was 1162 mg ai/kg feed or 104 mg ai/kg bw/day.

Table 1: Validity criteria for OECD 206 (1984)

Criterion	Outcome	Validity criterion fulfilled
Mortality in the control < 10% at the end of the test.	No control mortality occurred in the 18 pair of adult birds during the study.	yes
The average number of 14-day-old survivors per hen in the controls should be at least 12 (bobwhite quail).	The number of 14-day-old survivors per hen in the controls was ≥19.	yes
The average egg shell thickness for the control should be at least 0.19 mm (bobwhite quail).	The egg shell thickness for the controls was≥ 0.33 mm.	yes
There must be evidence that the concentration of the substance being tested has been satisfactorily maintained in the diet (it should be at least 80% of the nominal concentration) throughout the test period.	≥ 95% recovery of the nominal amounts.	yes

 

 

Validity criteria fulfilled:

yes

Remarks:

See Table 1 in "Any other information on results incl. tables".

Reference 6

Endpoint:

long-term toxicity to birds: reproduction test

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 - 17 Apr 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 206 (Avian Reproduction Test)

Qualifier:

according to guideline

Guideline:

EPA OPP 71-4 (Avian Reproduction Test)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 850.2300 (Avian Reproduction Test)

GLP compliance:

yes (incl. QA statement)

Dose method:

feed

Analytical monitoring:

yes

Vehicle:

no

Details on preparation and analysis of diet:

DIET PREPARATION
- Preparation of doses: Test diets were prepared by mixing AE 0001789 into a premix that was used for weekly preparation of the final diet. Control diet and each of the three treated diets were prepared weekly beginning on April 17, 2006 and presented to the birds on Monday of each week. Dietary concentrations were adjusted for purity of the test substance and are presented as parts per million active ingredient (ppm a.i.).

- other: Concentrations of the test substance in the diet were adjusted to 100% active ingredient, corrected based on the original test material received for this study (Wildlife International, Ltd. test substance number 7564). Dietary concentrations are expressed as parts per million active ingredient (ppm a.i.) in the diet.


HOMOGENEITY AND STABILITY OF TEST MATERIAL IN DIET
- How often was homogeneity and stability tested: weekly
- Mixing procedure adequate and variance between nominal and actual dosage acceptable: yes

Test organisms (species):

Anas platyrhynchos

Details on test organisms:

TEST ORGANISM
- Common name: Mallard
- Source: Whistling Wings, Inc., 113 Washington Street, Hanover, IL 61041-0509, U.S.A.
- Age at test initiation: 26 weeks
- Weight at test initiation: range from 923 to 1381 grams
- Sexes used: male and female
- Disease free: yes
- Kept according to standard practices: yes

Limit test:

no

Total exposure duration (if not single dose):

21 wk

No. of animals per sex per dose and/or stage:

64 males and 64 females

Control animals:

yes

Nominal and measured doses / concentrations:

NOMINAL TEST CONCENTRATIONS: control, 122, 367 or 1100 ppm a.i.
ESTIMATED MEAN DAILY DIETARY DOSES: 0, 17.7, 49.3 and 146.1 mg a.i./kg bw/day

Details on test conditions:

ACCLIMATION
- Acclimation period: Approximately 9 weeks

PEN SIZE AND CONSTRUCTION MATERIALS
- Description: The adult birds were housed indoors in batteries of pens manufactured by Safeguard Products, Inc. (Model No. 5355), measuring approximately 75 X 90 X 45 cm high.

NO. OF BIRDS PER REPLICATE
- For negative control: one male and one female
- For treated: one male and one female

NO. OF REPLICATES PER GROUP
- For negative control: 16 pens (birds per pen, one male and one female)
- For treated: 16 pens (birds per pen, one male and one female)

TEST CONDITIONS
- Room temperature: 22.8 ± 1.0°C
- Relative humidity (%): 75.4 ± 6.0%
- Photoperiod: The photoperiod during acclimation and the first 8 weeks of the test was seven hours or less of light per day. The photoperiod was increased to 17 hours of light per day at the beginning of Week 9 to induce egg laying and was maintained at that length until the adult birds were euthanized.
- Ventilation: The air handling system in the study room was designed to vent up to 15 room air volumes every hour and replace them with fresh air.

Details on examinations and observations:

MORTALITY / CLINICAL SIGNS
- Time schedule for examinations: daily

BODY WEIGHT
- Time schedule for examinations: at test initiation, at the end of weeks 2, 4, 6, 8, and at adult termination
- Remarks: Statistical comparisons were made between the control group and each treatment group at each weighing interval by sex.

FOOD CONSUMPTION
- Time schedule for examinations: weekly
- Remarks: Feed consumption expressed as grams of feed per bird per day was examined by pen weekly during the test. Statistical comparisons were made between the control and each treatment group.

OTHER:
Eggs Laid of Maximum Laid - The number of eggs laid per female divided by the largest number of eggs laid by any one female. This transformation was used to convert the number of eggs laid to a percentile value less than or equal to 100.

Eggs Cracked of Eggs Laid - The number of eggs determined by candling to be cracked divided by the number of eggs laid, per pen.

Viable Embryos of Eggs Set - The number of viable embryos at the Day 13 or 14 candling was
divided by the number of eggs set, per pen.

Live 3-Week Embryos of Viable Embryos - The number of live embryos at the Day 20 or 21
candling was divided by the number of viable embryos, per pen.

Hatchlings of 3-Week Embryos - The number of hatchlings removed from the hatcher was divided by the number of live 3-week embryos, per pen.

14-Day Old Survivors of Hatchlings - The number of 14-day old survivors was divided by the
number of hatchlings, per pen.

Hatchlings of Eggs Set - The number of hatchlings was divided by the number of eggs set, per pen.

14-Day Old Survivors of Eggs Set - The number of 14-day old survivors was divided by the
number of eggs set per pen.

Hatchlings of Maximum Set - The number of hatchlings per female divided by the largest number
of eggs set from any one female. This transformation was used to convert the number of hatchlings to a percentile value equal to or less than 100.

14-Day Old Survivors of Maximum Set - The number of 14-day old survivors per pen divided by
the largest number of eggs set.

Egg Shell Thickness - The average egg shell thickness of indiscriminately selected eggs per pen
was measured.

Offspring's Body Weight - The group body weights of surviving hatchlings and 14-day old
survivors were measured by parental pen group.

Details on reproductive parameters:

The following parameters were examined per parental pen per week:
- Eggs laid
- Eggs cracked; eggs broken
- Egg abnormalities
- Eggs set
- Eggshell thickness or eggshell strength
- Eggs fertile
- Embryos viable
- Normal hatchlings
- Abnormal hatchlings
- Clinical signs of toxicity, abnormalities and mortality
- 14-day old surviving chicks
- Chick body weight at hatching and 14 days after hatching

Reference substance (positive control):

no

Duration (if not single dose):

21 wk

Dose descriptor:

NOEL

Effect level:

>= 1 100 mg/kg diet

Conc. / dose based on:

act. ingr.

Basis for effect:

reproductive parameters

Duration (if not single dose):

21 wk

Dose descriptor:

NOEL

Effect level:

>= 146.1 mg/kg bw/day (actual dose received)

Conc. / dose based on:

act. ingr.

Basis for effect:

reproductive parameters

There were no treatment-related mortalities, overt signs of toxicity or treatment-related effects upon body weight or feed consumption at any of the concentrations tested. Additionally, there were no treatment-related effects upon any of the reproductive parameters measured at the 122, 367 or 1100 ppm a.i.. The no-observed-effect concentration for mallard exposed to AE 0001789 in the diet during the study was 1100 ppm a.i., the highest concentration tested.

Table 1: Validity criteria for OECD 206 (1984)

Criterion	Outcome	Validity criterion fulfilled
Mortality in the control < 10% at the end of the test.	No mortalities occurred in the control group.	yes
The average number of 14-day-old survivors per hen in the controls should be at least 14 (mallard duck).	The average number of 14-day-old survivors per hen in the controls was 35.	yes
The average egg shell thickness for the control should be at least 0.34 mm (mallard duck).	The average egg shell thickness of the control was 0.400±0.021 mm.	yes
There must be evidence that the concentration of the substance being tested has been satisfactorily maintained in the diet (it should be at least 80% of the nominal concentration) throughout the test period.	For the three test concentrations measured concentrations were 129 ± 4.12 ppm a.i., 398 + 9.21 ppm a.i. and 1270 + 55.81 ppm a.i., respectively. These values represented 106, 107 and 110% of nominal concentrations.	yes

 

Validity criteria fulfilled:

yes

Remarks:

See Table 1 in "Any other information on results incl. tables".

Description of key information

LD50 (14 d): >2000 mg/kg bw (Colinus virginianus, US EPA OPP 71-1)

 

LC50 (5 d): >4542 mg/kg diet (Anas platyrhynchos, OECD 205)

 

LC50 (5 d): >4559 mg/kg diet (Colinus virginianus, OECD 205)

 

NOEL (22 w): >1162 mg/kg diet (Colinus virginianus, OECD 206)

 

NOEL (21 w): >1100 mg/kg diet (Anas platyrhynchos, OECD 206)

Key value for chemical safety assessment

Long-term EC10, LC10 or NOEC for birds:

2 000 mg/kg bw

Additional information

A total six GLP studies is available investigating the toxicity of the substance to birds, following the prevailing guidelines OECD 205/206 and/or US EPA OPP 71-1 and 2.

After single oral application LD50 values of >2000 mg/kg bw were obtained in a study with northern bobwhite quails (M-129362-01-2). Neither mortality nor clinical signs of toxicity occurred in the study. Short-term (5-day) feeding resulted in LC50 values of >4542 and >4959 mg/kg (diet, measured data) for mallard duck and northern bobwhite quail (M-278425-01-1, M-278433-01-1 and M-271799-01-1). Neither mortality nor clinical signs of intoxication attributable to the test substance were observed in any study. In two reproduction studies (M-284854-01-1, M-283926-01-1) one conducted with the northern bobwhite quail and the other one with the mallard duck, the NOEL for systemic and reproductive toxicity was considered to be >1100 mg/kg (diet), which is the maximal dose according to the OECD testing guideline.

The substance showed no acute, short- and long-term hazard potential to birds as evidenced by endpoint data being above or equal the limit doses as specified in the corresponding testing guidelines. All studies referred to herein have been conducted according to the prevailing OECD or US EPA testing guidelines and GLP.