Registration Dossier

Administrative data

Description of key information

Skin irritation: Not irritating
Eye irritation: Slightly irritating

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:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well conducted study performed in accordance with recognised test methods
Qualifier:
according to guideline
Guideline:
other: FHSA
Principles of method if other than guideline:
Method used was Draize as described in "Appraisal of the safety of chemicals in food, drugs and cosmetics" as published by the Association of Food and Drug Officials of the United States.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not reported
- Age at study initiation:
- Weight at study initiation:
- Housing: Not reported
- Diet (e.g. ad libitum): Not reported
- Water (e.g. ad libitum): Not reported
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

IN-LIFE DATES: From: To: Not reported
Type of coverage:
occlusive
Preparation of test site:
other: Shaved and abraded sites on each rabbit
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
0.5 ml of DEP as supplied was applied to a 2X2 cm area of shaved and intact or abraded skin.
Duration of treatment / exposure:
The exposure period was 24 hours.
Observation period:
The observation period was 72 hours with evaluations of skin reaction performed at the end of the 24h contact period and again 48 hours later (72 h after application).
Number of animals:
3
Details on study design:
Three healthy, normal, albino rabbits were used. On the day before the study began 10% of the total body surface was carefully clipped free of hair. On the posterior of the clipped area several minor abraisions were made so as to penetrate the stratum corneum but not disturb the derma in order to prevent bleeding.
0.5 ml of DEP was applied to the unscarified area and an additional 0.5 ml was applied to the scarified area. Each 2X2 cm application area was covered with Webril patches and the entire experimental area sealed with Blenderm surgical tape.
The animals were imobilised in racks for 24 hours. At the end of this contact period and 48 hours later the treated skin was evaluated using the Draize method, as described in "Appraisal of the safety of chemicals in food, drugs and cosmetics" as published by the Association of Food and Drug Officials of the United States.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 hours
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
other: No response on intact or abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 hours
Score:
0
Max. score:
0
Reversibility:
other: Not applicable
Remarks on result:
other: No response on intact or abraded skin
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 72 hours
Score:
0
Max. score:
0
Reversibility:
other: Not applicable
Remarks on result:
other: No response on intact or abraded skin
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 72 hours
Score:
0
Max. score:
0
Reversibility:
other: Not applicable
Remarks on result:
other: No response on intact or abraded skin
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 - 72 hours
Score:
0
Max. score:
0
Irritant / corrosive response data:
No evidence of irritation or corrosive effects. Score of 0 throughout for all 3 rabbits
Other effects:
None reported
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In this study when DEP was applied as solution to the intact or abraded skin of the rabbit for 24 hours under occlusive conditions. No reaction was observed on either type of skin.
Executive summary:

Primary skin irritation has been investigated according to FHSA test methods with 24 hours exposure to intact and abraded skin. The substance was not irritating to the skin of the albino rabbit.

Exposure was for a 24 hour period in contrast with 4 hours required by current OECD/EU test methods. However, the information obtained clearly demonstrate the substance to be not irritating and classification as a skin irritant would not be required under the EU/GHS classification scheme.

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:
weight of evidence
Study period:
1963
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well conducted study in accordance with recognised test methods
Qualifier:
according to guideline
Guideline:
other: FHSA
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
Each animal had 0.1 ml of DEP instilled into the right eye with no further treatment. The untreated left eye of each animal served as it's own control. The treated and control eyes were examined at 24 hour intervals for 4 days and then again on the 7th day. On each occasion the state of the eyes were scored according to the Draize scale and recorded.
GLP compliance:
no
Species:
rabbit
Strain:
other: albino
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Not reported
- Age at study initiation: Not reported
- Weight at study initiation: Not reported
- Housing: Not reported
- Diet (e.g. ad libitum): Not reported
- Water (e.g. ad libitum): Not reported
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported
Vehicle:
other: 98% ethanol
Controls:
other: untreated left of each rabbit acted as contol
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): 12.5% in 95% ethanol
Duration of treatment / exposure:
Single instillation
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3
Details on study design:
Each animal had 0.1 ml of 12.5% DEP in ethanol instilled into the right eye with no further treatment. The untreated left eye of each animal served as it's own control. The treated and control eyes were examined at 24 hour intervals for 4 days and then again on the 7th day. On each occasion the state of the eyes were assessed according to the Draize scale and recorded.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24 - 72 hours
Score:
2.3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24 - 72 hours
Score:
2
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24 - 72 hours
Score:
2.3
Max. score:
3
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24 - 72 hours
Score:
1.7
Max. score:
2
Reversibility:
not fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24 - 72 hours
Score:
1.3
Max. score:
2
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24 - 72 hours
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 4 days
Irritant / corrosive response data:
A severe conjunctival irritation was seen in all 3 animals. This included chemosis and discharge. On day 7 only a slight hyperaemia was seen in the conjunctivae. There were no corneal opacities or iris congestion seen.
Other effects:
None reported.

 

 

 

Animal Number: 1

 

 

Ocular reaction

Region of eye

Parameter

Hours

Days

 

 

 

24

48

72

4

7

 

 

 

Discharge:

 

 

2

 

1

 

1

 

0

 

0

 

 

Conjunctivae:

Chemosis:

 

2

2

1

1

1

 

 

Redness:

 

3

2

2

2

1

 

 

Iris:

 

Inflammation:

 

 

0

 

0

 

0

 

0

 

0

 

 

 

Cornea:

Opacity:

 

0

0

0

0

0

 

 

Area:

 

0

0

0

0

0

 

 

 

 

 

 

 

Animal Number: 2

 

 

Ocular reaction

Region of eye

Parameter

Hours

Days

 

 

 

24

48

72

4

7

 

 

 

Discharge:

 

 

2

 

1

 

1

 

0

 

0

 

 

Conjunctivae:

Chemosis:

 

2

1

1

0

0

 

 

Redness:

 

2

2

2

1

1

 

 

Iris:

 

Inflammation:

 

 

0

 

0

 

0

 

0

 

0

 

 

 

Cornea:

Opacity:

 

0

0

0

0

0

 

 

Area:

 

0

0

0

0

0

 

 

 

 

 

 

 

Animal Number: 3

 

 

Ocular reaction

Region of eye

Parameter

Hours

Days

 

 

 

24

48

72

4

7

 

 

 

Discharge:

 

 

2

 

1

 

1

 

0

 

0

 

 

Conjunctivae:

Chemosis:

 

2

2

1

0

0

 

 

Redness:

 

3

2

2

2

1

 

 

Iris:

 

Inflammation:

 

 

0

 

0

 

0

 

0

 

0

 

 

 

Cornea:

Opacity:

 

0

0

0

0

0

 

 

Area:

 

0

0

0

0

0

 

 

 

Animal

Number

 

Conjunctival

Redness

 

 

Conjunctival

Chemosis

 

Iris

Inflammation

 

Corneal

Opacity

 

1

2

3

2.3

2.0

2.3

1.7

1.3

1.7

0.0

0.0

0.0

0.0

0.0

0.0

 

The mean score recorded for each animal is the average of the individual scores observed at the 24, 48 and 72 hour examinations.

Interpretation of results:
irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Diethyl phthalate was determined to be irritating to the eye. Historical data for eye irritation of ethanol shows similar reaction to that observed in this study.
Executive summary:

Acute eye irritation has been investigated in the rabbit following adminstration of a single dose and following FHSA test methods, which are similar to current OECD test methods. Diethyl phthalate, as a 12.5% solution in ethanol, was determined to be irritating to the eye.

The severity / persistence of reaction are not sufficient for the substance to require classification under Directive 67/548/EEC. However, classification as irritating to eyes (Category 2) would be required under GHS (Regulation 1272/2008).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Primary skin irritation has been investigated according to FHSA test methods with 24 hours exposure to intact and abraded skin. The substance was not irritating to the skin of the albino rabbit. Exposure was for a 24 hour period in contrast with 4 hours required by current OECD/EU test methods. However, the information obtained clearly demonstrate the substance to be not irritating and classification as a skin irritant would not be required under the EU/GHS classification scheme.

Acute eye irritation has been investigated in the rabbit following adminstration of a single dose and following FHSA test methods, which are similar to current OECD test methods. Diethyl phthalate, as a 12.5% solution in ethanol, was determined to be irritating to the eye. Historical data for eye irritation of ethanol showed similar reaction to that observed in this study. The severity / persistence of reaction are not sufficient for the substance to require classification under Directive 67/548/EEC. However, classification as irritating to eyes (Category 2) would be required under GHS (Regulation 1272/2008). A review of the toxicological profile of diethyl phthalate by A.M. Api (Food and Chemical Toxicology 39: 97-108, 2001) describes minimal irritation of the eye following exposure to undiluted DEP. In this study, undiluted diethyl phthalate was instilled into the conjunctival sac of the rabbit eye and reactions were scored at 1, 24, 48 and 96 hours later. Irritation was observed after 1 hour that decreased significantly by 24 hours (Draize et al. Journal of Pharmacology and Experimental Therapeutics 82: 377-390, 1944). Lawrence et al. (Environmental Research 9: 1-11, 1975) reported no signs of irritation in rabbit eyes using undiluted DEP. Minimal irritation has been observed following instillation of 0.1 mL diethyl phthalate into the eyes of New Zealand rabbits (ATSDR. Toxicological Profile for Diethyl Phthalate. Agency for Toxic Substances and Disease Registry, Division of Toxicology Toxicology Information Branch. 1600 Clifton Road NE, E-29, Atlanta, GA 30333, USA, 1995). The eye irritation of undiluted diethyl phthalate has been tested for rabbit eye irritation with or without washing and slight redness of the conjunctivae that did not persist was observed in the unwashed or the washed eye (RIFM. Primary Eye Irritation Study in the Albino Rabbit. Submission to EPA, Anonymous, 3 December. Document number 12327. 1978). These findings support a weight of evidence that diethyl phthalate itself is not significantly irritating to the eye.


Justification for selection of skin irritation / corrosion endpoint:
Best documented study available

Justification for selection of eye irritation endpoint:
Best documented study available

Effects on eye irritation: slightly irritating

Justification for classification or non-classification

Data from in-vivo skin and eye irritation studies indicate that classification is not required.