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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Jun 1983 - Jul 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions: only 21 d exposure

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
, only two doses were tested
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Analytical purity: 98.8%
- Lot/batch No.: 232114080
- Stability under test conditions: stable for the course of the study at room temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hacking & Churchill, Huntingdon, UK
- Age at study initiation: not stated
- Weight at study initiation: 2.4 - 3.0 kg
- Housing: conventionally rabbit cages, one animal per cage
- Diet: "Ssniff k Alleindiät für Kaninchen"
- Water ad libitum
- Acclimation period: 5 days

During the 6 h-exposure period the animals were kept in harness, so that they can`t take up food or water during that time

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22- 25 °C
- Humidity (%): 50%
- Air changes (per hr): 12- 15 times
- Photoperiod (hrs dark / hrs light): artificial light (12 h dark/ 12 h light)

Administration / exposure

Type of coverage:
open
Vehicle:
other: 2% v/v Cremophor EL in deionized water
Details on exposure:
TEST SITE
- Area of exposure: 6x 9 cm2 on the dorsal and flank skin
- Time intervals for shavings or clipplings: 48 h before exposure and then again twice weekly

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water and soap at the end of each exposure

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL solution/kg bw
- Concentration (if solution): 100 and 500 mg/mL



Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before starting the study the stability of the formulation was tested over 6 hours at room temperature. The concentration of the active ingredient in the prepared formulations was tested once during the study. No further details were described
Duration of treatment / exposure:
6 h
Frequency of treatment:
5 days per week for three weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250 mg/kg bw
Basis:
nominal per unit body weight
No. of animals per sex per dose:
3
Control animals:
yes, concurrent vehicle
Details on study design:
Diuron was formulated with Cremophor/water at concentrations of 100 and 500 mg/mL and administered dermally at dosage levels of
0 (vehicle control), 50 and 250 mg/kg bw daily, five days per week for three weeks.
The mixture was applied to the shaved or abraded skin of 3 male and 3 female rabbits each per dose level group.
Observations were conducted to assess mortality, morbidity and signs of overt toxicity. Haematology, urinalysis and clinical biochemistry, gross pathology and histopathology were performed

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- mortality, morbidity and signs of overt toxicity
- Time schedule: once a day

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: before initiation of the study and 24 h following dosing

BODY WEIGHT: Yes
- Time schedule for examinations: initially, then weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before start of the study and at termination
- Anaesthetic used for blood collection: No, blood was collected from the ear veins
- Parameters were examined: leukocyte and erythrocyte count, haemoglobin, haematocrit, MCV, MHC, MCHC, platelets and differential blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: conducted before start of the study and at termination
- Parameters were examined: alkaline phosphatase, aspartate and alanine aminotransfrease, urea, creatinine and glucose

URINALYSIS: Yes
- Time schedule for collection of urine: start of the study and at termination over a period of 16 h (16 pm to 8 am)
- Parameters were examined: pH, urobilinogen, proteins, glucose, blood, sediment, bacteria, salts, triphosphates
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All animals were euthanized 24 to 48 h after the last dosing by intravenous sodium hexobarbital followed by desanguinations.
They were dissected immediately and subjected to gross pathological examinations. At necropsy, the adrenals, brain, heart, kidneys, liver, lungs, gonads, spleen and thyroids were weighed

HISTOPATHOLOGY: Yes
Samples of the following tissues were preserved in Bouins fixative: liver, lungs, spleen, kidneys, heart, adrenals, thyroids, testes, epidymis, ovaries, uterus, untreated and treated skin and subjected to histopathology (controls and high dose only).

Samples were compared to reference values from pre-test samples

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY:
The animals of all dose groups did not show any alterations in behaviour or appearance. All animals survived until termination of the study.

BODY WEIGHT AND WEIGHT GAIN:
There were no remarkable changes or differences observed in body weights during the study period. However, slight weight loss occurred
intermittently due to withdrawal of food during exposure.

HAEMATOLOGY:
Haematological examination revealed no toxicologically relevant differences between all groups. No abnormalities were observed in the
differential blood count.

CLINICAL CHEMISTRY:
No effects related to treatment with Diuron were observed. Differences in alkaline phosphatase and urea analysis applied
to all groups to the same extent.

URINALYSIS:
Analysis of urine and sediment did not reveal abnormal findings between the groups

ORGAN WEIGHTS:
There were no significant differences in absolute and relative organ weights for either sex among the treatment groups

GROSS PATHOLOGY
No gross changes were noted at autopsy of the test animals.Findings were evenly distributed over all test groups (vesicles o kidneys due to infection, lobular pattern of liver or swollen spleen)

HISTOPATHOLOGY: Histopathological examinations of the control and the top dose group revealed no prominent differences. Only one male of the high dose group showed signs of spleen congestion.

HISTORICAL CONTROL DATA (if applicable)

OTHER FINDINGS

Effect levels

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse and treatment-related effects were observed up to and including the highest tested dose level.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Following repeated dermal administration of Diuron at dose levels up to 250 mg/kg bw/d, no mortalities or toxic effects occurred.No behavioural changes were noted. Examination of the skin according to Draize or skin fold thickness determination did not show any alterations.

Haematology, urinalysis and blood chemistry exhibited no differences between the groups.

Neither relative nor absolute organ weights were affected. Histopathology revealed congestion of the spleen in only one male rabbit. No other toxicologically relevant histopathological findings were noted.

Applicant's summary and conclusion

Executive summary:

This repeated dose dermal toxicity study is partially according to OECD Guideline 410. Rabbits were exposed to 50 and 250 mg/kg bw/d of Diuron for five days per week over three weeks. The repeated dermal exposure to Diuron revealed no toxicologically relevant effects on rabbits. That`s why the the NOAEL is set to 250 mg/kg bw, the highest dose tested. (Mihail and Schilde, 1984)