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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06 Nov 1985 - 10 Jan 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): H-16035
- Physical state: light brown granular solid
- Analytical purity: 99.0%
- Lot/batch No.: not given
- Stability under test conditions: stable for the course of the study

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Animals, Denver, USA
- Age at study initiation: young adults
- Weight at study initiation: 3.7 kg (mean)
- Housing: female rabbits were housed in units of eight individual stainless steel cages (approx. 0.5 m2)
- Diet: approx. 180 g of "certified rabbit chow" per day
- Water: ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 - 21.7
- Humidity (%): 34 - 64
- Air changes (per hr): minimum 12 changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: aqueous hydroxypropyl methylcellulose (0.5%)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
-Dosage suspensions were prepared daily

VEHICLE
- Concentration in vehicle: 0.4, 2, 10 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Most determined values of Diuron from methyl cellulose dosing solutions were between 91 and 103% of the nominal concentrations. Absolute recoveries of Diuron added to control dosing solutions (0.4 mg/mL, 10.0 mg/mL) were 100% and 99%.
The dosing solution concentration was determined by triplicate injection with a Perkin-Elmer series 4 liquid chromatograph.
Details on mating procedure:
- Impregnation procedure: artificial insemination
Duration of treatment / exposure:
on days 7 to 19 post-mating
Frequency of treatment:
once per day
Duration of test:
Terminal sacrifice was performed on day 29 after insemination
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose selection was based on results of a previous pilot study

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily inspections for clinical signs of toxicity, abortion or mortality

BODY WEIGHT: Yes
- Time schedule for examinations: 5 times during acclimatisation, on day 0 of presumed gestation and daily during gestation (days 7-19)

FOOD CONSUMPTION: Yes
- measured for days 0-29

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- General examinations: Litter size, individual weight, sex, number of live, dead and resorbed foetuses, survival rate after 24 hours of incubation
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
Statistics:
Data were analysed using the Cochran-Armatage test for linear trend in proportions, the Fisher`s exact test, Bartlett`s test of homogeneity of variances, the Mann-Whitney U-test, Dunnett`s test amongst others.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
- No adult animal died during the study.
- There were no adverse clinical signs or gross lesions observed upon autopsy.
- One dam of the top dose group aborted on day 26 of gestation and showed weight loss and reduced food consumption.
- Overall, a statistically significant decreasing average daily food consumption was observed for the top dose animals as compared to
controls on days 13 to 20.
- Body weight gain was decreased for animals dosed with 50 mg/kg bw/d during dosing, resulting in significant weight loss to day 20.
- After completion of dosage, animals consumed significantly more food.
- No effect on liver weight was noted.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
There were no statistically significant differences between the groups for corpora lutea, pregnancies, number of live, dead and resorbed foetuses,
foetal body weights or survival.
No foetal external, soft tissue or skeletal alterations were observed at statistically significant differences to control group.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Summary of maternal data

Dosage Group

0 mg/kg/d

2.0 mg/kg/d

10.0 mg/kg/d

50.0 mg/kg/d

General data

No pregnant/inseminated

21/23

22/24

23/25

23/25

Mortality

0

0

0

0

No. aborted

0

0

0

1

No. of litters

21

22

23

22

Maternal data (excluding rabbits that aborted or were not pregnant)

Mean no.Corporea Lutea

11.0±2.1

10.7±2.3

10.0±2.5

10.4±2.5

Mean no. implantations

7.2±2.6

7.1±2.9

7.6±2.3

7.7±2.1

Mean weight changes

 

 

 

 

Days 0 – 7

0.14 ± 0.07

0.16 ± 0.06

0.15 ± 0.05

0.15 ± 0.06

Days 7 – 20

0.14 ± 0.14

0.13 ± 0.14

0.14 ± 0.20

- 0.04 ± 0.21**

Days 20 – 29

0.04 ± 0.18

0.05 ± 0.14

0.08 ± 0.16

0.22 ± 0.15**

Days 7 – 29

0.17 ± 0.22

0.18 ± 0.24

0.22 ± 0.24

0.18 ± 0.22

Days 0 – 29

0.32 ± 0.23

0.34 ± 0.25

0.37 ± 0.26

0.34 ± 0.23

Liver mean weight (g)

96.9

102.1

101.6

100.6

Mean liver/body weight ratio

2.4

2.4

2.4

2.5

** p < 0.01

Table 2: Summary of foetal data

Dosage Group

0 mg/kg/d

2.0 mg/kg/d

10.0 mg/kg/d

50.0 mg/kg/d

Foetal Death:

Mean No. Resorptionsa)

0.5±0.9

0.4±0.7

0.6±1.0

0.2±0.5

Mean Percentage Resorptionsa)

6.5±12.8

4.3±8.9

7.0±10.3

2.2±5.9

No. Litters with total Resorption

0

0

0

0

Foetuses:

No. Litters

21

22

23

22

Total No. Fetuses (Live and Dead)

142

149

161

166

No. Live Fetuses

141

149

161

166

Mean No. Live

6.7±2.6

6.8±2.8

7.0±2.1

7.5±2.0

Mean weight (g)

46.11±7.42

45.89±8.04

46.13±8.37

45.17±7.16

No. Dead Fetuses

1

0

0

0

Applicant's summary and conclusion

Executive summary:

In a reliable study conducted in compliance with guideline OECD 414 female rabbits obtained p.o. (by gavage) doses of 0, 2, 10, and 50 mg Diuron /kg bw/d on days 7 through 19 of presumed gestation. Overall, a statistically significant decreasing average daily food consumption and body weight gain was observed for the top dose on days 13 to 20, resulting in significant weight loss to day 20, so that the NOAEL of maternal toxic effects is set 10 mg/kg bw/d. In contrast, Diuron did not adversely affect the development of the offspring at the top dose. Therefore, the NOAEL of embryotoxic / teratogenic effects is assessed to 50 mg/kg bw/d. (Dearlove,1986b)