Registration Dossier

Administrative data

Description of key information

Irritation:
- skin: not irritant (OECD 404)
- eyes: not irritant (OECD 405)

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain / quality: New Zealand White Al1077 IN RA (SPF)
- Source: Centre Lago S.A., 01540 Vonnas, France
- ldentification: Ear tattoo
- Age at study initiation: about 6 - 7 months
- Weight at study initiation: 3.52 kg - 3.89 kg
- Housing: single housing in stainless steel wire mesh cages with grating, floor area: 3000 cm2
- Diet (e.g. ad libitum): Kliba-Labordiät, Provimni Kliba SA, Kaiseraugst, Switzerland (about 130 g/animal per day); ad libitum
- Water (e.g. ad libitum): tap water; ad libitum
- Acclimation period: at least 5 days before the beginning of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animal
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): 100%
Duration of treatment / exposure:
4 hour(s)
Observation period:
72 h
Number of animals:
3 (2 females, 1 male)
Details on study design:
TEST SITE
- Area of exposure: Flank of animal
- Site preparation: At least 24 hours before the beginning of the study clipping of the dorsolateral part of the trunk of the animal(s).
- Type of wrap if used: test patch (2.5 cm x 2.5 cm) was moistened with a dose of 0.5 ml of the unchanged liquid test substance.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with Lutrole and Lutrole : water (1 : 1)
- Time after start of exposure: 4 h

SCORING SYSTEM:
The evaluation of skin reactions is performed according to the guidelines:

Erythema and eschar formation
0 = No erythema
1 = Very slight erythema (barely perceptible)
2 = Well defined erythema
3 = Moderate to severe erythema
4 = Severe erythema (beet redness) to eschar formation preventing grading of erythema

Edema formation
0 = No edema
1 = Very slight edema (barely perceptible)
2 = Slight edema (edges of area well defined by definite raising)
3 = Moderate edema (raised approx. 1 mm)
4 = Severe edema (raised more than 1 mm and extending beyond area of exposure)

Description of any dermal findings not covered by this scale were recorded.
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Reversibility:
fully reversible within: 48 h
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritant / corrosive response data:
Slight erythema (ER) was observed in all animals during the course of the study. The cutaneous reactions were reversible in all animals within 48 hours after removal of the patch. The average score (24 to 72 hours) for irritation was calculated to be 0.1 for erythema and 0.0 for edema.

Results:

Readings Animal Erythema Edema Additional findings
1 h 1 1 0  
2 1 0  
3 1 0  
24 h 1 0 0  
2 0 0  
3 1 0  
48 h 1 0 0  
2 0 0  
3 0 0  
72 h 1 0 0  
2 0 0  
3 0 0  
mean 24 - 72 h 1 0.0 0.0  
2 0.0 0.0  
3 0.3 0.0  
mean 1 0.1 0.0  
Interpretation of results:
GHS criteria not met
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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Strain / quality: New Zealand White A1077 INRA (SPF)
- Source: Centre Lago S.A., 01540 Vonnas, France
- Identification: Ear tattoo
- Age at study initiation: About 3 - 4 months
- Weight at study initiation: 2.82 kg -2.99 kg
- Housing: Single housing in stainless steel wire mesh cages with grating, floor area: 3000 cm^2
- Diet (e.g. ad libitum): Kliba-Labordiät, Provimi Kliba SA, Kaiseraugst, Switzerland (about 130 g/animal per day); ad libitum
- Water (e.g. ad libitum): Tap water ad libitum; ad libitum
- Acclimation period: At least 5 days before the beginning of the study.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Air changes (per hr): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Vehicle:
physiological saline
Controls:
other: untreated eye of same animal
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): 100%
Duration of treatment / exposure:
24 hour(s)
Observation period (in vivo):
72 h
Number of animals or in vitro replicates:
3 (2 females, 1 male)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, tap water
- Time after start of exposure: 24 h

SCORING SYSTEM:
The evaluation of eye irritation is performed according to the guidelines:

Cornea opacity (op): Degree of density (the most dense area is taken for reading)
0 = No ulceration or opacity
1 = Scattered or diffuse areas of opacity (other than slight dulling of normal luster), details of iris clearly visible
2 = Easily discernible translucent area, details of iris slightly obscured
3 = Nacreous area, no details of iris visible, size of pupil barely discernible
4 = Opaque cornea, iris not discernible through the opacity

Area of cornea involved (the assessment of these ocular reactions is performed independent of the quoted guidelines):
1 = >0<=1/4
2 = >1/4<1/2
3 = >1/2<3/4
4 = >3/4

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

Conjunctivae redness (red): Refers to palpebral and bulbar conjunctivae, cornea and iris
0 = Blood vessels normal
1 = Some blood vessels definitely hyperaemic (injected)
2 = Diffuse, crimson colour, individual vessels not easily discernible
3 = Diffuse beefy red

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

Discharge (the assessment of these ocular reactions is performed independent of the quoted guidelines):
0 = No discharge
1 = Any amount different from normal (does not include small amounts observed in inner
canthus of normal animals)
2 = Discharge with moistening of the lids and hairs just adjacent to lids
3 = Discharge with moistening of the lids and hairs, and considerable area around the eye

Description of any ocular findings not covered by this scale were recorded.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Slight to moderate conjunctival redness (1 and 24 h) and slight discharge (1 h) were observed initially for 24 h at maximum. The ocular reactions were reversible in all animals within 48 hours after application. The average score (24 to 72 hours) for irritation was calculated to be 0.0 for corneal opacity and for iris, 0.3 for conjunctival redness and 0.0 for chemosis.

Animal 1: female, 2.82 kg

Animal 2: male, 2.84 kg

Animal 3: female, 2.99 kg

Results.

Readings Animal Cornea Iris Conjunctival Symptoms
Opacity Area Erythema  Chemosis Discharge
1h 1 0 0 0 1 0 1  
2 0 0 0 2 0 1  
3 0 0 0 1 0 1  
24 h 1 0 0 0 1 0 0  
2 0 0 0 1 0 0  
3 0 0 0 1 0 0  
48 h 1 0 0 0 0 0 0  
2 0 0 0 0 0 0  
3 0 0 0 0 0 0  
72 h 1 0 0 0 0 0 0  
2 0 0 0 0 0 0  
3 0 0 0 0 0 0  
mean 24 - 72 h 1 0.0   0.0 0.3 0.0    
2 0.0   0.0 0.3 0.0    
3 0.0   0.0 0.3 0.0    
mean 1 0.0   0.0 0.3 0.0  
Interpretation of results:
GHS criteria not met
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

Irritation to skin was evaluated in a study performed under GLP according to guidelines OECD 404, EU Method B.4 and EPA OPPTS 870.2500 (BASF, 2002). Thereby, test patches containing 0.5 mL of di-(2-propylheptyl) phthalate (purity: 99,2 % (sum of isomers)) were applied to the flanks of one male and two female White New Zealand rabbits for 4 hours. The skin sites were evaluated for erythema/eschar and edema formation 1, 24, 48 and 72 hours following removal of the patches. At one hour following patch removal, slight erythema was observed in all animals and persisted in one animal up to 24 hours, but within 48 hours after patch removal, these skin reactions were reversed. The resulting mean irritation scores for 24-72 hours were 0.1 for erythema/eschar and 0.0 for edema, respectively. Thus, di-(2-propylheptyl) phthalate was found to be not irritating to the skin.

In another study, the test sites on the backs of six albino rabbits were clipped free of hair and one side was abraded to allow the substance to penetrate the stratum corneum (Biosearch, Inc., 1982). Then, 0.5 g mixture of 91.3% di-(2-propylheptyl) phthalate and 8.7% 2-propylheptyl/4-methyl-2-propylhexyl and di-(4-methyl-2-propylhexyl)phthalate was applied and covered with gauze, which was removed 24 hours later. The treated areas were examined for erythema, eschar and edema formation using the Draize scale where zero corresponded to no irritation. A second examination was conducted 72 hours following the removal. As result, the scores for erythema and edema, as well as the primary skin irritation score were found to be 0. Thus, no irritation to skin was found.

 

Eye irritation

Irritation to eyes was tested in a study, which was performed under GLP according to guidelines OECD 405, EU Method B.5 and EPA OPPTS 870.2400 (BASF, 2002). A single ocular application of 0.1 mL of di-(2-propylheptyl) phthalate (purity: 99,2% sum of isomers) was given to one male and two female White New Zealand rabbits and washed out 24 hours later by rinsing with water. The resulting ocular reactions were scored 1, 24, 48 and 72 hours after application. Slight to moderate conjunctival redness and slight discharge were observed up to 24 hours following instillation, but these reactions were reversible in all animals within 48 hours. The average irritation score was 0.0 for corneal opacity, iris effects and chemosis. The conjunctival redness score was 0.3. Thus, di-(2-propylheptyl) phthalate was found to be not irritating to eyes.

In another study, 0.1 g of 91.3% di-(2-propylheptyl) phthalate and 8.7% 2-propylheptyl/4-methyl-2-propylhexyl/di-(4-methyl-2-propylhexyl)phthalate was instilled into the right eyes of six young adult albino rabbits (Biosearch Inc., 1982). While no removal by rinsing was reported, ocular reactions including irritation of the cornea, iris and conjunctivae were examined 1, 24, 48, 72, 120, and 168 hours following the administration. As result, a primary irritation score of 0.0 for all effects was reported. Thus, the tested phthalate mixture was not irritating to eyes.

Justification for classification or non-classification

Based on the available data for skin and eye irritation the test item is not classified according to Regulation (EC) No 1272/2008.