Registration Dossier

Administrative data

Description of key information

Non Skin irritant

Non eye irritant

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8 days
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Remarks:
Reliable without restriction; study was conducted according to acceptable scientific methodology and according to Good Clinical Practices (GCPs). The investigation was reviewed by an Institutional Review Board in accordance with Title 21 of the U.S. Code of Federal Regulations (CFR).
Principles of method if other than guideline:
The test substance was evaluated in 18 test subjects. Subjects were patched dermally on the back under semi-occlusive patches with 0.2 mL of five dilutions of the test substance in acetone. Subjects were patched three times over a period of five days (Days 1, 3, and 5). The subjects removed the patches after 24 hours, and scoring of patch sites for irritation was made prior to applications on Days 3 and 5 and on Day 8. Dermal reactions, if any, were assessed to determine the primary irritation potential of the test substance. The clinical investigation was reviewed by an Institutional Review Board in accordance with CFR, Title 21, Parts 50 and 56.
GLP compliance:
yes
Remarks:
As this was a human clinical study, it was conducted in compliance with Good Clinical Practice Regulations.
Species:
human
Details on test animals or test system and environmental conditions:
-A total of 38 persons were screened for the study; eighteen subjects (9 males and 9 females) were enrolled and completed all phases of the study.

Study Dates:
-Study Initiation: March 12, 2001
-Study Completion: March 19, 2001
Type of coverage:
semiocclusive
Preparation of test site:
not specified
Vehicle:
other: acetone
Controls:
other: Skin adjacent to the application site was used as a control.
Amount / concentration applied:
0.2 mL of 0.01, 0.05, 0.1, 0.2, and 0.5% of the test substance in acetone
Duration of treatment / exposure:
Each subject received three 24 hour dermal applications of each of the five dilution preparations used in the study.
Observation period:
All sites were scored for irritation approximately 48 hours after patch application.
Number of animals:
9 males and 9 females
Details on study design:
A series of skin sites on the back were used for the application of 0.2 mL of a preparation containing 0.01, 0.05, 0.1, 0.2, and 0.5% of the test substance in acetone. The application sites were semi-occluded using a non-woven cotton pad (Webril) held in place on all sides by a strip of hypoallergenic tape (Micropore) for approximately 24 hours. Applications were made on Days 1, 3, and 5; subjects removed the patches 24 ± 1 hr after applications, and scoring took place on Days 3, 5, and 8. The assignment of the five test substance preparations to individual skin sites were varied in order to eliminate any position or order bias.
Irritation parameter:
overall irritation score
Remarks:
Irritation score
Basis:
other: Human
Remarks:
Human
Time point:
24/48/72 h
Score:
0 - 1
Reversibility:
not specified
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Remarks:
Not performed
Basis:
other:
Time point:
24/48/72 h
Score:
0 - 0
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Remarks:
Not performed
Basis:
other:
Time point:
24/48/72 h
Score:
0 - 0
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
At 48 or 72 hours after patch application, individual overall irritation scores ranged from 0 to 1 (mild erythema (pink)). Reversibility was not addressed. Average scores for the evaluations made on Days 3, 5, and 8 and the overall average score for the different concentrations of the test substance were as follows:

0.01%: 0.00, 0.03, 0.00, and 0.06
0.05%: 0.03, 0.03, 0.06, and 0.11
0.1%: 0.00, 0.03, 0.03, and 0.06
0.2%: 0.00, 0.00, 0.00, and 0.00
0.5%: 0.00, 0.03, 0.03, and 0.06

Since the irritation that was noted was minimal and did not occur in a concentration-dependent manner, it was not considered to be related to test substance exposure.

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
Based on minimal irritation which did not occur in a concentration-dependent manner following three 24-hour applications to intact human skin under semi-occlusive contact, di (2-ethylhexyl) terephthalate is not classified as a primary skin irritant. Therefore, the concentration selected for use in a subsequent HRIPT study was the top concentration, 0.5%.

Under the conditions of the study, di (2-ethylhexyl) terephthalate is not classified under GHS.
Executive summary:

In a primary dermal irritation study, 18 panelists (9 male and 9 female) were exposed to di (2-ethylhexyl) terephthalate at concentrations of 0.01, 0.05, 0.1, 0.2, and 0.5% under semi-occlusion for three 24 hour periods over a period of six days. After 24 hours of exposure, the patches were removed, and 48-72 hours after patch application, the sites were graded for irritation. The maximum irritation score noted was 1 on a scale of 1-3. Irritation was seen irregularly and only at a small proportion of the application sites, was not observed in a concentration-dependent manner, and was therefore not considered to be related to test substance exposure.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 days
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Reliable without restriction: the study was conducted according to GLPs and OECD Guideline 404.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Remarks:
The study met all requirements of GLPs, with the exception that information about the test material characterization was retained by the Study Sponsor.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
Test animals:
-Source: Robinson Services, Inc. Clemmons, NC
-Sex: 2 males and 1 female
-Age at study initiation: young adult
-Acclimation period: 23 days
-Housing: singly housed in suspended stainless-steel cages with mesh floor
-Diet: pelleted Purina Rabbit Chow #5326
-Water: filtered tap water ad libitum
-Method of animal identification: uniquely numbered stainless steel ear tag

Environmental Conditions:
-Temperature: 20 - 24 °C
-Photoperiod: 12 hours light/12 hours dark

In-Life Study Dates:
-Study Initiation Date: 8 March 2006
-Experimental Start Date: 10 March 2006
-Experimental Completion Date: 13 March 2006
Type of coverage:
semiocclusive
Preparation of test site:
other: Fur was clipped from the dorsal and trunk areas the day before application.
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.5 mL undiluted test material
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
Three; two males and one female
Details on study design:
Fur was clipped form the dorsal and trunk areas the day before application. The test material (0.5 mL) was applied to one dose site (6 square cm) on each animal and covered with a 1 x 1 square inch, 4-ply gauze pad. The pad and trunk of each animal were then wrapped with semi-occlusive, 3-inch Micropore tape. Elizabethan collars were placed on each animal. The collars and pads were removed after four hours of exposure and residual material was gently removed. The animals were observed at least once daily during the test period for signs of gross toxicity and behavioral changes. Particular attention was directed toward observation of tremors, convulsions, salivation, diarrhea and coma. Test sites were scored according to the Draize scale 30-60 minutes and 24, 48 and 72 hours after patch removal.
Irritation parameter:
erythema score
Basis:
animal: all animals
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
other: No erythema was observed at any time at any of the treated sites.
Irritation parameter:
edema score
Basis:
other: all animals
Time point:
24/48/72 h
Score:
0
Max. score:
0
Remarks on result:
other: No edema was observed at any time at any of the treated sites.
Irritation parameter:
overall irritation score
Time point:
24/48/72 h
Score:
0 - 0
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No erythema or edema was observed at any time at any of the treated sites. All animals appeared active and healthy during the study. There were no signs of gross toxicity or abnormal behavior.
Interpretation of results:
other: not classified
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
Di (2-ethylhexyl) terephthalate was not acutely toxic, irritating, or corrosive to New Zealand White rabbits after a 4 hour dermal exposure under the semi-occlusive conditions used in this study.

Based on the absence of irritation in any rabbit, di (2-ethylhexyl) terephthalate is not classifiable for Skin Irritation/Corrosion according to GHS.
Executive summary:

In a skin irritation/corrosion study, three New Zealand White rabbits were exposed to 0.5 mL of the neat test substance, di (2-ethylhexyl) terephthalate, under semi-occlusion for 4 hours. The sites of application were examined at 30 - 60 minutes and 24, 48 and 72 hours after patch removal. No signs of irritation were observed for any animal at any time point. Based on the results of this study, di (2-ethylhexyl) terephthalate presents a low toxicity hazard and is not considered an irritant or corrosive.

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:
72 hours
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Reliable without restriction; the study was conducted according to GLPs and OECD Guideline 405 .
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
Due to a technician error, the animals did not receive local anesthetic prior to instillation of the test material. This deviation did not impact the quality or integrity of the study.
GLP compliance:
yes
Remarks:
Compliant with two exceptions; information about the test material characterization retained by the Study Sponsor, and Study Director did not fill in proposed Experimental Start and Termination dates before signing the protocol or prior to study start.
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Test animals:
-Source: Robinson Services, Inc. Clemmons, NC
-Sex: 1 male,and 2 females
-Age at study initiation: young adult
-Acclimation period: 23 days
-Housing: singly housed in suspended stainless-steel cages with mesh floor
-Diet: pelleted Purina Rabbit Chow #5326
-Water: filtered tap water ad libitum
-Method of animal identification: Uniquely numbered stainless steel ear tag

Environmental Conditions:
-Temperature: 20 - 24 °C
-Photoperiod: 12 hours light/12 hours dark

Study Dates:
-Study Initiation Date: 8 March 2006
-Experimental Start Date: 10 March 2006
-Experimental Completion Date: 13 March 2006
Vehicle:
unchanged (no vehicle)
Controls:
other: The other eye of each rabbit was not treated and served as a control.
Amount / concentration applied:
0.1 mL undiluted
Duration of treatment / exposure:
The test substance (0.1 mL) was instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for approximately 1 second. Eyes were not washed.
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3
Details on study design:
Prior to the test, both eyes of a group of animals were examined for pre-existing ocular irritation. One drop of 2% ophthalmic fluorescein sodium was instilled into both eyes of each rabbit. The eyes were rinsed with physiological saline (0.9% NaCl) approximately 30 seconds later and subsequently evaluated for corneal damage using an ultraviolet light source. Three healthy animals without evidence of preexisting ocular irritation were selected for use in the study based on this screening procedure. The test substance (0.1 mL) was instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for approximately 1 second. The other eye of each rabbit was not treated and served as a control. Ocular irritation, including effects on the cornea, iris, and conjunctiva were evaluated according to the method of Draize et al. (1944), using a high intensity white light (Mag Lite) 1, 24, 48 and 72 hours after instillation. In addition, flourescein dye was used as described above to evaluate corneal damage 24 hours after treatment. Individual scores were recorded for each animal. The average score for all rabbits was determined for each evaluation time. The time interval with the highest mean score for all rabbits was used to classify the test material according to the method of Kay and Calandra (1962). The animals were observed at least once daily for signs of gross toxicity and behavioral changes during the test period. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea and coma.

References Cited:
Kay, JH and Calandra, JC, 1962. Interpretation of eye irritation tests. J. Soc. Cos. Chem. 13:281-289.

Draize et al., 1944. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther., 82:377-390.
Irritation parameter:
maximum mean total score (MMTS)
Basis:
mean
Time point:
other: 1 hour
Score:
0
Max. score:
10.7
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
other: all animals
Time point:
other: 1 hour only
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: all other chemosis scores at 24 and 48 hours were 0
Irritation parameter:
other: redness score
Basis:
other: all animals
Time point:
other: 1 hour
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Diffuse, deep crimson red, individuals not easily discernable
Irritation parameter:
other: redness score
Basis:
other: all animals
Time point:
other: 24 hours
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Injected above normal
Irritation parameter:
other: redness score
Basis:
other: all animals
Time point:
other: 48 hours
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
other: discharge score
Basis:
animal #1
Time point:
other: 1 hour
Score:
0
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Discharge with moistening of the lids and hair of a considerable area around the eye.
Irritation parameter:
other: discharge score
Basis:
other: animals #2 and #3
Time point:
other: 1 hour
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Discharge with moistening of the lids and hair adjacent to the lids.
Irritation parameter:
other: discharge score
Basis:
other: all animals
Time point:
other: 24 hours
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: The assigned score of 1 was based on the presence of any amount of discharge different from that normally seen in the untreated rabbit eye.
Irritation parameter:
cornea opacity score
Basis:
other: all animals
Time point:
other: all time points
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
other: no corneal opacity was observed at any time during the study
Irritation parameter:
iris score
Basis:
other: all animals
Time point:
other: all time points
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Remarks on result:
other: no iritis was observed at any time during the study
Irritation parameter:
cornea opacity score
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No corneal opacity or iritis was observed in any treated eye at any time during the study. All three treated eyes exhibited conjunctivitis 1, 24 and 48 hours after instillation but were normal at 72 hours. Redness scores in the 3 rabbits were 2 (diffuse, deep crimson red, individual vessels not easily discernable), 1 (injected above normal), and 1 at 1, 24 and 48 hours, respectively. Chemosis scores of 1 (any swelling above normal) were recorded at 1 hour for all 3 animals (all other chemosis scores were 0). Discharge scores of 3 (discharge with moistening of the lids and hairs; considerable area around the eye), 2 (discharge with moistening of the lids and hairs just adjacent to the lids), and 2 were recorded in the three animals one hour after instillation. Discharge scores of 1 were observed in all 3 animals at 24 hours. The mean irritation scores at 1, 24 and 48 hours were 10.7 (12 + 10 + 10/3), 4.0 (4 + 4 + 4/3) and 2.0 (2 + 2 + 2/3) (respectively). All animals were free of ocular irritation by 72 hours. The maximum mean total score was 10.7, which corresponded to a classification of minimally irritating using the Kay and Calandra (1962) classification system. According to their guidance, since all scores were not 0 at 48 hours, the classification was increased one level (to mildly irritating from minimally irritating).
Other effects:
Other than minimal eye irritation, there were no other signs of toxicity or abnormal behavior.

  Rabbit 1 Rabbit 2 Rabbit 3
  Hours Hours Hours
  1 24 48 72 1 24 48 72 1 24 48 72
I. Cornea  
  A. Opacity 0 0 0 0 0 0 0 0 0 0 0 0
  B. Area 4 4 4 4 4 4 4 4 4 4 4 4
  (AxB)x5 0 0 0 0 0 0 0 0 0 0 0 0
II. Iris  
  A. Values 0 0 0 0 0 0 0 0 0 0 0 0
  Ax5 0 0 0 0 0 0 0 0 0 0 0 0
III. Conjunctivae  
  A. Redness 2 1 1 0 2 1 1 0 2 1 1 0
  B. Chemosis 1 0 0 0 1 0 0 0 1 0 0 0
  C. Discharge 3 1 0 0 2 1 0 0 2 1 0 0
  (A+B+C)x2 12 4 2 0 10 4 2 0 10 4 2 0
Total 12 4 2 0 10 4 2 0 10 4 2 0
Interpretation of results:
other: minimally irritating
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
The maximum mean total score in a primary eye irritation study in rabbits was 10.7, which corresponded to a classification of minimally irritating according to the test scheme of Kay and Calandra (1962). According to their guidance, since all scores were not 0's at 48 hours, the classification was increased one level (to mildly irritating). There was no evidence of corneal opacity or iritis at any time during the study. Conjunctival redness was observed in all animals at 1, 24 and 48 hours but all animals were normal at the 72 hour observation period and the calculated mean score following grading at 24, 48 and 72 hours after installation of the test material was <2. Conjunctival chemosis (grade 1) was also observed in all animals at the 1 hour observation period but all animals were normal

at the 24 hour observation period. Based on these results, di (2-ethylhexyl) terephthalate is not classified as an ocular corrosive or irritant according to GHS.

Executive summary:

In an acute ocular irritation study, 0.1 mL of di (2-ethylhexyl) terephthalate was administered into the conjunctival sac of one eye of three New Zealand White Rabbits. The untreated eye of each rabbit served as a control. The eyes were examined at 1, 24, 48, and 72 hours post-instillation and graded according to the method of Draize. There was no evidence of corneal opacity or iritis at any time during the study. Signs of irritation were limited to conjunctivitis. Chemosis (grade 1) which was observed at the 1 hour observation period was absent at all later observation periods. Conjunctival redness (grade 2 at 1 hour and grade 1 at 24 and 48 hours) had cleared by 72 hours. The pattern of irritation which was observed led to a classification of the test substance as mildly irritating using the method of Kay and Calandra. However, the mean test scores did not meet the criteria for classification as corrosive or irritating to the eye under GHS. Based on the results of this study, di (2-ethylhexyl) terephthalate may cause slight transient ocular irritation and presents a low toxicity hazard.

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

Respiratory irritation

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

Additional information

Skin irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause skin corrosion/irritation is well understood. Two key dermal irritation studies and a supporting dermal toxicity study were available for review. In a primary dermal irritation/corrosion study conducted according to OECD Guideline 404, no erythema or edema was observed in three New Zealand White Rabbits (2 males, 1 female) at any time during the study when 0.5 mL of the undiluted test material was applied to intact clipped skin under semi-occlusive patch for 4 hours. There were also no signs of gross toxicity or abnormal behavior during the study. In a dermal irritation study conducted according to acceptable scientific methodology and according to Good Clinical Practices, irritation was minimal when 0.2 mL of 0.01, 0.05, 0.1, 0.2 and 0.5% di (2-ethylhexyl) terephthalate in acetone was repeatedly applied to a series of skin sites on the backs of 18 human subjects (9/sex). Application sites were semi-occluded and each application of test material was held in place for approximately 24 hours. Applications were made on Days 1, 3 and 5 and scoring was done on Days 3, 5 and 8. The maximum irritation score noted was 1 on a scale of 1-3. Because irritation was seen irregularly and only at a small proportion of the application sites and was not observed in a concentration-dependent manner, it was not considered to be related to test substance exposure. These effects are consistent with those observed in the rabbit study. In a non-guideline dermal toxicity study in which guinea pigs were exposed to 4920, 9840 or 19,680 mg/kg bw of undiluted di (2-ethylehxyl) terephthalate under occlusive wrap for 24-hours, no erythema was observed. However, the three test animals did exhibit reversible moderate to severe edema. In this study, exposure was for 24 hours under occlusive contact, conditions much more stringent than those used in current skin irritation testing protocols. In addition, the dose volumes used, i.e., ~ 5-20 g/kg bw were significantly greater than the 0.5 g/site currently used. Based on the observations made in two guideline skin irritation studies conducted in humans and rabbits, di (2-ethylhexyl) terephthalate is not classified as a primary skin irritant. Based on edema observed in guinea pigs exposed to extremely high dose volumes for prolonged periods of time under occlusive contact, exposure to di (2-ethylhexyl) terephthalate may cause slight reversible irritation.

  

Eye irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause eye burns/irritation is well understood. In an eye irritation study conducted according to OECD Guideline 405, there was no evidence of corneal opacity or iritis in three test rabbits at any time during the study following installation of 0.1 mL of test material into the conjunctival sac. Conjunctival redness was observed in all animals at 1, 24 and 48 hours after test substance administration but all animals were normal at the 72-hour observation period and the calculated mean score following grading at 24, 48 and 72 hours after installation of the test material was <2. Conjunctival chemosis (grade 1) was also observed in all animals at the 1-hour observation period but all animals were normal at the 24-hour observation period. There was no staining in the eyes when tested with fluorescein dye 24 hours after test substance administration and there were no abnormal systemic signs noted during the 72-hour observation period. In a pre-GLP supporting study conducted by a method similar to OECD Guideline 405, adverse effects were limited to slight erythema on the palpebral conjunctiva and nictitating membranes of all animals at the 1-hour post-dose examination. All animals appeared clinically normal from 24 hours onward.  

  

Respiratory irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause respiratory tract irritation is well understood. In a sub-acute non-guideline inhalation study conducted by a credible testing laboratory according to acceptable scientific methods of the time, groups of 5 male rats were exposed to 0.0718 mg/L of di (2-ethylhexyl) terephthalate by whole body inhalation 5 days/week, 6 hours/day for 10 days over a 14-day period. There were no clinical signs to suggest an adverse effect on respiration and there where no treatment-related gross or microscopic effects observed at necropsy. The exposure concentration used in the study could only be generated by passing an airflow of 6.0 L/min through a gas washing bottle containing undiluted di (2-ethylhexyl) terephthalate that was heated on a water bath at 95°C. 

  

Justification for classification or non-classification

No erythema or edema was observed in a primary dermal irritation/corrosion study conducted in rabbits according to OECD Guideline 404. In a dermal irritation study conducted according to acceptable scientific methodology and Good Clinical Practices, irritation was minimal when 0.2 mL of test material at concentrations ranging from 0.01 to 0.5% di (2-ethylhexyl) terephthalate in acetone was repeatedly applied to a series of skin sites on the backs of 18 human subjects. Because irritation was seen irregularly and only at a small proportion of the application sites and was not observed in a concentration-dependent manner, it was not considered to be related to test substance exposure. Although moderate to severe edema but no erythema was observed in a dermal toxicity study conducted in guinea pigs, the doses, i.e., ~5000 – 20,000 mg/kg and the exposure conditions, i.e., 24-hour occluded contact were much more severe than those currently used in skin irritation testing protocols. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for skin irritation. Based on a weight-of-the-evidence assessment, exposure to large volumes of di (2-ethylhexyl) terephthalate under occluded contact for prolonged periods of time may cause transient skin irritation but di (2-ethylhexyl) terephthalate would not be classified for skin irritation according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008. 

  

In the key guideline study, there was no evidence of corneal opacity or iritis in rabbit eyes following instillation of 0.1 mL of di (2-ethylhexyl) terephthalate into the conjunctival sac of the eye. Conjunctival chemosis (grade 1) was observed in all treated eyes but only at the 1-hour examination. Conjunctival redness was observed in all treated eyes at 1, 24 and 48 hours after test substance administration but all animals were normal at the 72-hr examination and the calculated mean score following grading at 24, 48 and 72 hours was <2. A pre-GLP non-guideline study reported similar results. In addition, undiluted di-(2-ethylhexyl) terephthalate was not classified under GHS for either skin corrosivity or irritation following 4-hour semi-occluded contact with intact rabbit skin.  Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for eye irritation. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for eye irritation according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008. 

  

There were no clinical signs indicative of respiratory tract irritation in rats following repeated exposures to the highest airborne concentrations of di (2-ethylhexyl) terephthalate that could be generated by heating the test material to 95°C. Following exposure for 5 days/week, 6 hours/day for 10 days over a 14-day period, there was no gross or microscopic evidence of irritation in the lungs or trachea. In addition, di (2-ethylhexyl) terephthalate is not classified as an eye or skin irritant according to GHS. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for respiratory tract irritation. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for respiratory tract irritation according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008.