Registration Dossier

Administrative data

Description of key information

In vivo studies for skin and eye irritation are available, performed according to OECD and GLP guidelines.

The tests showed that Ditetrahydrofurylpropane is irritating to the eyes (Cat. 2), and mildly irritating to the skin (not sufficient for classification).

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:
8 November - 7 December, 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan, Horst, The Netherlands (animals 607 and 611); Harlan, Gannat, France (animal 596)
- Age at study initiation: at least 6 weeks old
- Weight at study initiation: at least 1.0 kg
- Housing: Individually in labelled cages with perforated floors
- Diet (e.g. ad libitum): ad libitum 100 grams per day
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2 – 22.4°C
- Humidity (%): 42 - 61%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL


Duration of treatment / exposure:
4 hours
Observation period:
The skin reactions were assessed at approximately 1, 24, 48 and 72 hours and 7 and 14 days after the removal of the dressings and test substance.

Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2x3 cm
- % coverage: not indicated
- Type of wrap if used: A metalline patch was mounted on Micropore tape#, which was wrapped around the abdomen and secured with Coban elastic bandage#.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin was cleaned of residual test substance using tap water.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) * 4
*. Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the
maximum grade for erythema (= 4) is given.

Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimeter) 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Four hours exposure to 0.5 mL of Ditetrahydrofurylpropane resulted in well-defined erythema and slight oedema in the treated skin-areas of the three rabbits. Scaliness was seen 24 hours, 48 hours, 72 hours and/or 7 days after exposure. The skin irritation had completely resolved within 14 days after exposure in all animals. There was no evidence of a corrosive effect on the skin.
Other effects:
No staining of the treated skin by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Table 1: Individual skin irritation scores

Animal

5961

607

611

Time after exposure

Erythema

Oedema

comments

Erythema

Oedema

comments

Erythema

Oedema

comments

1 hour

1

1

-

2

2

-

2

2

-

24 hours

2

2

l

2

1

-

2

1

-

48 hours

2

2

l

2

2

-

2

2

-

72 hours

1

2

l

2

2

l

2

2

l

7 days

0

0

l

0

0

l

1

0

l

14 days

0

0

-

0

0

-

0

0

-

1Sentinel.

Comments:l.Scaliness.

Interpretation of results:
GHS criteria not met
Conclusions:
An in vivo skin irritation tudy was performed according to OECD/EC guidelines and GLP prinicples. The average score at 24, 48 and 72 hours is for erythema and edema a 2 and 1.7, respectively, in two out of three animals and a 1.7 and 2, respectively in one animal. According to the CLP Regulation (EC) 1272/2008, no classification for skin irritation is required.
Executive summary:

In a study performed according to OECD 404 test guideline, three rabbits were exposed to the substance by application onto clipped skin using semi-occlusive dressing. Skin reactions were assessed at approximately 1, 24, 48 and 72 hours and 7 and 14 days after the removal of the dressings and test substance. Four hours exposure to 0.5 mL of Ditetrahydrofurylpropane resulted in well-defined erythema and slight oedema in the treated skin-areas of the three rabbits. Scaliness was seen 24 hours, 48 hours, 72 hours and/or 7 days after exposure. The skin irritation had completely resolved within 14 days after exposure in all animals. There was no evidence of a corrosive effect on the skin. No staining of the treated skin by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.  Based on these results it is concluded that the test substance is not corrosive and not irritant to the skin.

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:
19 May - 10 June, 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan France SARL, Gannat, France.
- Age at study initiation: at least 6 weeks old
- Weight at study initiation: at least 1.0 kg.
- Housing: Individually in labeled cages with perforated floors
- Diet (e.g. ad libitum): ad libitum 100 grams per day
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2 – 22.8°C
- Humidity (%): 32 - 74%; Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: The other eye remained untreated and served as the reference control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL


Duration of treatment / exposure:
14 days as the eyes of the test animals have not been washed.

Observation period (in vivo):
The eyes of each animal were examined approximately 1, 24, 48 and 72 hours and 7 and 14 days after instillation of the test substance.
Number of animals or in vitro replicates:
3 males
Details on study design:
SCORING SYSTEM:
CORNEAL IRRITATION
Opacity: degree of density (area most dense taken for reading)
No ulceration or opacity (may include slight dulling of normal luster) 0
Scattered or diffuse areas of opacity, details of iris clearly visible 1
Easily discernible translucent area, details of iris slightly obscured 2
Nacreous area, no details of iris visible, size of pupil barely discernible 3
Opaque cornea, iris not discernible through the opacity 4

Area of cornea involved:
No ulceration or opacity 0
One quarter or less but not zero 1
Greater than one quarter, but less than half 2
Greater than half, but less than three quarters 3
Greater than three quarters, up to whole area 4

IRIS
Normal 0
Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia,
or injection, any of these or combination thereof, iris still reacting to light
(sluggish reaction is positive) 1
No reaction to light, hemorrhage, gross destruction (any or all of these) 2

CONJUNCTIVAL IRRITATION
Redness (refers to palpebrae and sclera, excluding cornea and iris):
Blood vessels normal 0
Some blood vessels definitely hyperaemic (injected) 1
Diffuse, crimson color, individual vessels not easily discernible 2
Diffuse beefy red 3

Chemosis (refers to lids and/or nictitating membranes):
No swelling ………………………………………… 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2
Swelling with lids about half closed 3
Swelling with lids more than half closed 4

Discharge:
No discharge (may include small amounts observed in inner canthus of normal animals) 0
Any amount different from normal and/or lacrimation 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs (considerable area around the eye) 3


TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 24 h
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.7
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritant / corrosive response data:
Instillation of 0.1 mL of Ditetrahydrofurylpropane into one eye of each of three rabbits resulted in effects on the cornea, iris and conjunctivae.
The corneal injury consisted of opacity (maximum grade 1 or 2) and epithelial damage (maximum 65, 50 or 25% of the corneal area). The corneal injury had resolved within 72 hours in one animal and within 7 days in the other two animals.
Iridial irritation grade 1 was observed and had resolved within 24 or 72 hours or within 7 days. The irritation of the conjunctivae consisted of redness, chemosis and discharge and had completely resolved within 14 days in all animals.
There was no evidence of ocular corrosion.
Other effects:
No staining of (peri) ocular tissues by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Table 1: Individual eye irritation scores.

Cornea

Iris

Conjunctivae

Comments

Animal

Time after dosing

Opacity

(0-4)

Area

(0-4)

Fluor area (%)2

(0-2)

Redness

(0-3)

Chemosis

(0-4)

Discharge

(0-3)

8501

1 hour

1

2

-

1

2

4

3

-

24 hours

2

1

65

1

3

2

2

-

48 hours

1

1

-

0

3

1

1

-

72 hours

1

1

25

1

3

1

0

-

7 days

0

0

0

0

1

0

0

-

14 days

0

0

-

0

0

0

0

-

853

1 hour

1

1

-

1

2

3

2

-

24 hours

1

1

25

0

3

1

1

-

48 hours

0

1

-

0

3

1

1

g

72 hours

0

0

0

0

2

0

0

-

7 days

0

0

-

0

1

0

0

-

14 days

0

0

-

0

0

0

0

-

855

1 hour

1

1

-

1

2

2

2

-

24 hours

1

2

50

0

3

3

1

-

48 hours

1

2

-

1

3

3

1

-

72 hours

1

1

25

0

3

3

1

-

7 days

0

0

0

0

1

1

0

-

14 days

0

0

-

0

0

0

0

-

1Sentinel,2Green staining after fluorescein treatment (percentage of total corneal area)

Comments:gSlight dulling of the normal luster of the cornea.

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
An in vivo eye irritation study was conducted according to OECD/EC guidelines and GLP principles. Calculated as the mean scores following grading at 24, 48 and 72 hours, the substance produced at least in 2 of 3 tested animals: corneal opacity ≥1, iritis ≥1 and conjuctival redness ≥2. Conjuctival oedema ≥2 was seen in only 1 animal. Effects were fully reversible within 21 days. According to the CLP Regulation (EC) 1272/2008 the substance is classified as eye irritation Category 2.
Executive summary:

In a study performed according to OECD 405 test guidelines, instillation of 0.1 mL of Ditetrahydrofurylpropane into one eye of each of three rabbits resulted in effects on the cornea, iris and conjunctivae. The corneal injury consisted of opacity (maximum grade 1 or 2) and epithelial damage (maximum 65, 50 or 25% of the corneal area). The corneal injury had resolved within 72 hours in one animal and within 7 days in the other two animals. Iridial irritation grade 1 was observed and had resolved within 24 or 72 hours or within 7 days. The irritation of the conjunctivae consisted of redness, chemosis and discharge and had completely resolved within 14 days in all animals. There was no evidence of ocular corrosion. No staining of (peri) ocular tissues by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred. Based on these effects the test substance is classified for eye irritation Category 2 according to CLP Regulation (EC) 1272/2008.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In a study performed according to OECD 404 test guideline, three rabbits were exposed to the substance by application onto clipped skin using semi-occlusive dressing. Skin reactions were assessed at approximately 1, 24, 48 and 72 hours and 7 and 14 days after the removal of the dressings and test substance. Four hours exposure to 0.5 mL of Ditetrahydrofurylpropane resulted in well-defined erythema and slight oedema in the treated skin-areas of the three rabbits. Scaliness was seen 24 hours, 48 hours, 72 hours and/or 7 days after exposure. The skin irritation had completely resolved within 14 days after exposure in all animals. There was no evidence of a corrosive effect on the skin. No staining of the treated skin by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.  

Eye irritation:

In a study performed according to OECD 405 test guidelines, instillation of 0.1 mL of Ditetrahydrofurylpropane into one eye of each of three rabbits resulted in effects on the cornea, iris and conjunctivae. The corneal injury consisted of opacity (maximum grade 1 or 2) and epithelial damage (maximum 65, 50 or 25% of the corneal area). The corneal injury had resolved within 72 hours in one animal and within 7 days in the other two animals. Iridial irritation grade 1 was observed and had resolved within 24 or 72 hours or within 7 days. The irritation of the conjunctivae consisted of redness, chemosis and discharge and had completely resolved within 14 days in all animals. There was no evidence of ocular corrosion. No staining of (peri) ocular tissues by the test substance was observed and no test substance remnants were seen. No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Justification for classification or non-classification

After application to the skin, the average score at 24, 48 and 72 hours is 2 and 1.7 for erythema and oedema, respectively, in two out of three animals and a 1.7 and 2, respectively in one animal. This is below the threshold of 2.3 as defined in CLP Regulation (EC) 1272/2008 and therefore the substance does not need to be classified for skin irritation.

After application to the eye, calculated as the mean scores following grading at 24, 48 and 72 hours, the substance produced at least in 2 of 3 tested animals: corneal opacity ≥1, iritis ≥1 and conjuctival redness ≥2. Conjuctival oedema ≥2 was seen in 1 of 3 animals. Effects were fully reversible within 21 days. According to the CLP Regulation (EC) 1272/2008 the substance shall be classified as eye irritation Category 2.