Registration Dossier

Administrative data

Description of key information

Two guideline studies are available to evaluate the irritant properties of DETU : skin irritation (OECD 404) and eye irritation (OECD 405).
The results showed that DETU is not a skin irritating, but severely irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
minors deviations (see below)
Principles of method if other than guideline:
The minor deviations were :
-the relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the protocol,
-on day 1, one animal had a body weight slightly lower than 2.2 kg,
-the animals were given 110 pelleted diet (instead of 112c pelleted diet).
These minor deviations were not considered to have compromised the validity or integrity of the study.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CEGAV, Saint Mars d'Egrenne, France.
-Sex: male
- Age at study initiation: no data
- Weight at study initiation: 2.3 ± 0.2 kg.
- Housing: individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm)
- Diet (e.g. ad libitum): free access to 110 pelleted diet (UAR, Villemoisson, Epinay-sur-Orge, France).
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
. temperature: 18 ± 3°C
. relative humidity: 30 to 70%
. light/dark cycle: 12 h/12 h
. ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
undiluted
Duration of treatment / exposure:
4 hour(s)
Observation period:
The skin was examined approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.
Number of animals:
3
Details on study design:
The day before treatment, both flanks of each animal were clipped using electric clippers and the skin of each animal was examined. Only animals with healthy intact skin were used.

ADMINISTRATION:
- Area of exposure: left flank (3-minute exposure) and right flank (4-hour exposure)
- Total quantity applied: 500 mg
- Administration frequency: once
- Removal of test substance: residual is wiped with a dry gauze patch
The test substance and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. The untreated skin served as control.

EXAMINATIONS:
- Scoring system: Draize's score
Irritation parameter:
erythema score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Neither erythema nor oedema were observed in the three rabbits at any exposure duration (3 minutes and 4 hours).
Interpretation of results:
GHS criteria not met
Conclusions:
Under these experimental conditions, the test substance DETU (DIETHYL THIOUREE) is non-irritant to skin when applied topically to rabbits.
Executive summary:

The potential of the test substance DETU (DIETHYL THIOUREE) to induce skin irritation was evaluated in rabbits according to OECD (No. 404, 17th July 1992) guideline, and in compliance with the principles of Good Laboratory Practice Regulations.

In the first instance, the test substance was applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test substance was not irritant on this first animal, it was then applied for 4 hours to two other animals.

A single dose of 500 mg of the test substance in its original form was applied to the closely­clipped skin of one flank. The test substance was held in contact with the skin by means of a semi-occlusive dressing.

Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.

No cutaneous reactions were observed during the study.

Mean scores over 24, 48 and 72 hours for each animal were 0.0 for erythema and oedema.

Under these experimental conditions, the test substance DETU (DIETHYL THIOUREE) is non-irritant when applied topically to rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
minors deviations (see below)
Principles of method if other than guideline:
The micor deviations are :
-the relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the protocol,
-the animals of the study came from CEGAV and were given 110 diet (instead of 112).
These minor deviations were not considered to have compromised the validity or integrity of the study.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: CEGAV (Saint Mars d'Egrenne, France)
-Sex: male
- Age at study initiation: no data
- Weight at study initiation: 2.6 ± 0.1 kg.
- Housing: housed individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm)
- Diet (e.g. ad libitum): free access to 110 pelleted diet (UAR, Villemoisson, Epinay¬sur-Orge, France).
- Water (e.g. ad libitum): Drinking water filtered by a FG Millipore membrane (0.22 micron) was provided ad libitum.
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
. temperature: 18 ± 3°C
. relative humidity: 30 to 70%
. light/dark cycle: 12 h/12 h
. ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
Vehicle:
unchanged (no vehicle)
Controls:
other: yes, The right eye, which remained untreated, served as control.
Amount / concentration applied:
A single dose of 100 mg of the test substance in its original form was introduced into the conjunctival sac of the left eye of three animals, after gently pulling the lower lid away from the eyeball.
Duration of treatment / exposure:
a single exposure ; the eyes were not rinsed before examination.
Observation period (in vivo):
The eyes were examined approximately 1 hour, 24, 48 and 72 hours after administration of the test substance.
Following the OECD and EC guidelines, since there was persistent ocular reactions at 72 hours, the observation period was extended. In the absence of complete reversibility of ocular reactions on day 22 in one animal, the study was ended.
Number of animals or in vitro replicates:
3
Details on study design:
The day before treatment, the eyes of each animal were examined in order to use only animals without any signs of ocular lesions. Animals showing signs of ocular irritation, ocular defects or pre-existing corneal injury were not used.

EXAMINATIONS:
- Ophthalmoscopic examination: Yes
- Scoring system: Draize's scale
- Tool used to assess score: fluorescein
Conjunctival reactions, iritis and corneal opacification were evaluated daily for each animal.
For the evaluation of corneal opacification (presence or absence, affected area), the eyes were examined under a UV lamp after instillation of one or two drops of 0.5% sodium fluorescein solution (a clear fluorescence is visible in the areas of opacification). This evaluation was performed on day 2 and repeated thereafter whenever necessary.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
2.53
Max. score:
4
Reversibility:
not fully reversible within: 22 days
Remarks on result:
other: Mean score of each animal are : 2.3, 3.0 and 2.3
Irritation parameter:
conjunctivae score
Remarks:
(redness)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 22 days
Remarks on result:
other: Mean score of each animal are: 3.0, 3.0 and 3.0
Irritation parameter:
conjunctivae score
Remarks:
(discharge)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
other: whitish purulent discharge, fully reversible on 7 days
Irritation parameter:
iris score
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within:
Remarks on result:
other: Mean score of each animal are 1.0
Irritation parameter:
cornea opacity score
Remarks:
(intensity)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 22 days
Remarks on result:
other: Mean score of each animal are 2.0
Irritation parameter:
cornea opacity score
Remarks:
(area)
Basis:
mean
Remarks:
3 rabbits
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 22 days
Remarks on result:
other: Mean score of each animal are 2.0
Irritant / corrosive response data:
Very slight to moderate conjunctival reactions were observed in all animals from day 1:
. a very slight to moderate chemosis (grades 1 to 3),
. a very slight to moderate redness of the conjunctiva (grades 1 to 3) and
. a clear to whitish purulent discharge were noted. Some of these reactions persisted up to day 8 or 9, or up to the end of the observation period (day 22) in one animal.
A slight iritis (grade 1) was noted in all animals on day 1; it persisted up to day 4 (two animaIs) or 6. A very slight or slight comeal opacity (grade 1 or 2) was recorded in all animals from day 2; it persisted up to day 7 or 9, or up to the end of the observation period (day 22) in one animal. A myosis was noted in this last animal between days 14 to 17.
Mean scores calculated for each animal over 24, 48 and 72 hours were 2.3, 3.0 and 2.3 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 1.0, 1.0 and 1.0 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity.

Tables : Eye irritation test

 

Rabbit number

Region of eye

Description of ocular reactions

scores

Mean irritation score (1)

1h (D1)

24h (D2)

48h (D3)

72h (D4)

 

981

conjunctivae

Chemosis

3

3

2

2

2.3

Redness

3

3

3

3

3.0

Discharge

2

S

S

S

(2)

Iris

1

1

1

1

1.0

Corneal opacity

Intensity

0

2

2

2

2.0

Area

0

2

2

2

2.0

Other

*

*

*

*

 

Fluorescein

/

U

U

U

 

 

998

conjunctivae

Chemosis

3

3

3

3

3.0

Redness

3

3

3

3

3.0

Discharge

2

2

2

S

(2)

Iris

1

1

1

1

(1)

Corneal opacity

Intensity

0

2

2

2

2.0

Area

0

2

2

2

2.0

Other

*

*

*

*

 

Fluorescein

/

U

U

U

 

 

999

conjunctivae

Chemosis

3

3

2

2

2.3

Redness

3

3

3

3

3.0

Discharge

2

S

S

S

(2)

Iris

1

1

1

1

1.0

Corneal opacity

Intensity

0

2

2

2

2.0

Area

0

2

2

2

2.0

Other

*

*

*

*

 

Fluorescein

/

U

U

U

 

 

 

Rabbit number

Region of eye

Description of ocular reactions

scores

D5

D6

D7

D8

D9

D10

D11

D12

D13

D14

 

981

conjunctivae

Chemosis

2

2

2

1

1

1

1

1

1

1

Redness

3

2

2

2

1

1

1

1

1

1

Discharge

0

0

0

0

0

0

0

0

0

0

Iris

0

0

0

0

0

1

1

1

0

0

Corneal opacity

Intensity

2

2

2

2

2

2

2

2

2

2

Area

2

2

1

1

1

1

1

1

1

1

Other

*

*

*

*

*

*

*

*

*

my

Fluorescein

U

U

U

U

U

U

U

U

U

U

 

998

conjunctivae

Chemosis

2

2

2

1

1

0

-

-

-

-

Redness

3

2

2

1

1

0

-

-

-

-

Discharge

S

S

0

0

0

0

-

-

-

-

Iris

1

1

0

0

0

0

-

-

-

-

Corneal opacity

Intensity

2

2

1

1

1

0

-

-

-

-

Area

2

2

1

1

1

0

-

-

-

-

Other

*

*

*

*

*

*

-

-

-

-

Fluorescein

U

U

U

U

U

U

-

-

-

-

 

999

conjunctivae

Chemosis

1

1

1

1

0

-

-

-

-

-

Redness

2

1

1

0

0

-

-

-

-

-

Discharge

0

0

0

0

0

-

-

-

-

-

Iris

0

0

0

0

0

-

-

-

-

-

Corneal opacity

Intensity

1

1

1

0

0

-

-

-

-

-

Area

1

1

1

0

0

-

-

-

-

-

Other

*

*

*

*

*

-

-

-

-

-

Fluorescein

U

U

U

U

/

-

-

-

-

-

 

 

 

Rabbit number

Region of eye

Description of ocular reactions

scores

D15

D16

D17

D18

D19

D20

D21

 

981

conjunctivae

Chemosis

1

1

1

1

1

1

1

Redness

1

1

1

1

1

1

1

Discharge

0

0

0

0

0

0

0

Iris

0

0

0

0

0

0

0

Corneal opacity

Intensity

2

2

2

2

2

2

2

Area

1

1

1

1

1

1

1

Other

My

My

My

*

*

*

*

Fluorescein

U

U

U

U

U

U

U

 

998

conjunctivae

Chemosis

-

-

-

-

-

-

-

Redness

-

-

-

-

-

-

-

Discharge

-

-

-

-

-

-

-

Iris

-

-

-

-

-

-

-

Corneal opacity

Intensity

-

-

-

-

-

-

-

Area

-

-

-

-

-

-

-

Other

-

-

-

-

-

-

-

Fluorescein

-

-

-

-

-

-

-

 

999

conjunctivae

Chemosis

-

-

-

-

-

-

-

Redness

-

-

-

-

-

-

-

Discharge

-

-

-

-

-

-

-

Iris

-

-

-

-

-

-

-

Corneal opacity

Intensity

-

-

-

-

-

-

-

Area

-

-

-

-

-

-

-

Other

-

-

-

-

-

-

-

Fluorescein

-

-

-

-

-

-

-

 

(1)  mean of scores on days 2, 3 and 4

(2)  not calculated

* : none

U: fluorescein batch No.D616

/: fluorescein not used

S: Whitish purulent discharge

My = myosis

-         : ocular examination not performed

 

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Under these experimental conditions, the test substance DETU (DIETHYL THIOUREE) is severely irritant when administered by ocular route to rabbits.
Executive summary:

The potential of the test substance DETU (DIETHYL THIOUREE) to induce ocular irritation was evaluated in rabbits according to OECD (No. 405, 24th February 1987) and EC (92/69/EEC, B.5, 31st July 1992) guidelines, and in compliance with the principles of Good Laboratory Practice Regulations.

 

A single dose of 100 mg of the test substance in its original form was introduced into the left conjunctival sac of three male New Zealand White rabbits. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test substance. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until the end of the observation period. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

 

Very slight to moderate conjunctival reactions (very slight to moderate chemosis, very slight to moderate redness of the conjunctiva and clear to whitish purulent discharge) were observed in all animals from day 1: some of these reactions persisted up to day 8 or 9, or up to the end of the observation period (day 22) in one animal.

A slight iritis was noted in all animals on day 1; it persisted up to day 4 (two animals) or 6.

A very slight or slight corneal opacity was recorded in all animals from day 2; it persisted up to day 7 or 9, or up to the end of the observation period (day 22) in one animal. A myosis was noted in this last animal between days 14 to 17.

Mean scores calculated for each animal over 24, 48 and 72 hours were 2.3, 3.0 and 2.3 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 1.0, 1.0 and 1.0 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity.

 

Under these experimental conditions, the test substance DETU (DIETHYL THIOUREE) is severely irritant when administered by ocular route to rabbits.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation study (OECD 404, 2001)

In the first instance, the test substance was applied for periods of 3 minutes and 4 hours to a single male New Zealand White rabbit. Since the test substance was not irritant on this first animal, it was then applied for 4 hours to two other animals.

A single dose of 500 mg of the test substance in its original form was applied to the closely­clipped skin of one flank. The test substance was held in contact with the skin by means of a semi-occlusive dressing.

Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.

No cutaneous reactions were observed during the study in all three animals. Mean scores over 24, 48 and 72 hours for each animal were 0.0 for erythema and oedema. Under these experimental conditions, the test substance DETU (diethylthiouree) is non-irritant when applied topically to rabbits.

Eye irritation study (OECD 405, 2001)

A single dose of 100 mg of the test substance in its original form was introduced into the left conjunctival sac of three male New Zealand White rabbits. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test substance. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration and then daily until the end of the observation period.

Very slight to moderate conjunctival reactions (very slight to moderate chemosis, very slight to moderate redness of the conjunctiva and clear to whitish purulent discharge) were observed in all animals from day 1: some of these reactions persisted up to day 8 or 9, or up to the end of the observation period (day 22) in one animal.

A slight iritis was noted in all animals on day 1; it persisted up to day 4 (two animals) or 6 (one animal).

A very slight or slight corneal opacity was recorded in all animals from day 2; it persisted up to day 7 or 9, or up to the end of the observation period (day 22) in one animal. A myosis was noted in this last animal between days 14 to 17.

Mean scores calculated for each animal over 24, 48 and 72 hours were 2.3, 3.0 and 2.3 for chemosis, 3.0, 3.0 and 3.0 for redness of the conjunctiva, 1.0, 1.0 and 1.0 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity. Under these experimental conditions, the test substance DETU (diethylthiouree) is severely irritant when administered by ocular route to rabbits.


Justification for classification or non-classification

Proposed self-classification (Regulation (EC) No 1272/2008):

Eye Dam. 1 (Causes serious eye damage, H318)