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Diss Factsheets

Administrative data

Description of key information

[1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide is not irritating to skin and is very slightly irritating to eyes.

 

Skin irritation

The acute dermal irritation of powder formulation containing 40% of [1,3(or 1,4) -phenylenebis(1-methylethylidene) ]bis[tert-butyl] peroxide was evaluated in rabbits according to OECD 404 guideline (Prinsen and van Beek, 1986a). The substance was applied undiluted (purity 40%) and not pre-moistened to the abraded and intact skin of 6 New-Zealand White albino rabbits and held in contact for 4 hours by means of an occlusive dressing. No irritation was observed on the intact skin. Under the experimental conditions, [1,3(or 1,4) -phenylenebis(1-methylethylidene) ]bis[tert-butyl] peroxide was considered as non irritant when applied topically in rabbits.

 

In an acute dermal toxicity study (Manciaux, 1999) where no dermal signs were observed at high doses (2000 mg/kg) strengthen that the pure substance is not irritant.

 

In addition, an in vitro skin irritation test (performed according to the OECD 439 guideline) on the pure meta isomer (CAS 2212-81-9) is also available (Warren, 2012). In this test, the relative mean viability of the test item was 99.5 % of the negative control item. Therefore there was no skin irritation potential for the pure meta isomer. It can be anticipated there is no skin irritation potential for the mixture of meta+para isomers.

 

Eye irritation

The potential of a powder containing 40% of [1,3(or 1,4) -phenylenebis(1-methylethylidene) ]bis[tert-butyl] peroxide to induce ocular irritation was evaluated in rabbits according to OECD 405 guideline (Prinsen and Van Beek, 1986b). The substance was administered to three male New Zealand White rabbits. A single dose of 0.1 g of the substance was instilled into the left/right conjunctival sac. The right/left eye was not treated and served as control. The eyes were not rinsed after administration of the test item. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration of the test substance. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. After one hour, the eyes effects observed in all rabbits consisted of slight or moderate redness and slight or moderate swelling of the conjunctivae. All these clinical signs were fully reversible within 72 hours. Mean scores calculated for each animal over 24, 48 and 72 hours were (0) (0.6) and (0) for chemosis, (0.3) (1) and (0.6) for redness of the conjunctiva, (0) (0) and (0) for iris lesions and (0) (0) and (0) for corneal opacity. Under these experimental conditions, [1,3(or 1,4)-phenylenebis(1-methylethylidene) ]bis[tert-butyl] peroxide was considered as slight irritant when administered by ocular route to rabbits.

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:
weight of evidence
Study period:
january 13, 1986 to january 16, 1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was conducted in accordance with a recognized scientific procedure for analyzing the primary dermal irritation of a test material in experimental animals. However, the test material was a solid and was not pre-moistened. The test was performed on a 40% formulation. Study details were sufficient to support the conclusions in the report regarding the dermal irritation toxicity of the formulated test material. However, they are not sufficient to identify the dermal irritation potential of the more pure form of Bis (t-butyl peroxyisopropyl) benzene.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
other: EEC Directive 79-831, Annex V, part B: Methods for the determination of toxicity, B.4. Acute toxicity, skin irritation, date December 1983
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: ENKI-Konijnenfarm, Someren, the Netherlands
- Weight at study initiation: 2500-3500 g
- Housing: individually in galvanised cages
- Diet : ad libitum
- Acclimation period: six days

ENVIRONMENTAL CONDITIONS
- Temperature : 15-21 °C
- Humidity: 40-70 %
- Air changes : 10 per hour
- Photoperiod : 12 hrs dark /12 hrs light):
Type of coverage:
occlusive
Preparation of test site:
other: shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
Amount applied: 0.5 g
Duration of treatment / exposure:
4 hours
Observation period:
76 hours
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 1 inch diameter
- Type of wrap if used: impervious material

SCORING SYSTEM:
- The skin reaction were evaluated by the method of Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
The undiluted test substance is not a primary skin irritant
Interpretation of results:
GHS criteria not met
Conclusions:
Test material is not considered as a primary dermal irritant.
Executive summary:

The acute dermal irritation of the peroxide was evaluated in rabbits according to OECD 404 guideline. The substance was applied undiluted and not pre-moistened to the skin of 6 New-Zealand White albino rabbits and held in contact for 4 hours by means of an occlusive dressing. No irritation was observed. Under the experimental conditions, the substance was considered as non irritant when applied topically in rabits.

Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2012-03-06 to 2012-03-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-conducted and documented study performed under GLP according to current guideline.
Qualifier:
according to guideline
Guideline:
OECD Guideline 439 (In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
human
Details on test animals or test system and environmental conditions:
The EPISKIN(TM) model is a three-dimensional reconstructed human epidermis model consisting of adult human-derived epidermal keratinocytes seeded on a dermal substitute consisting of a collagen type I matrix coated with type IV collagen. A highly differentiated and stratified epidermis model is obtained after a 13-day culture period comprising of the main basal, supra basal, spinous and granular layers and a functional stratum corneum.
Type of coverage:
other:
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
Approximately 10 mg of the test item was applied to the epidermis surface. The epidermis surface had previously been moistened wtih 5 µl of sterile distilled water to improve contact between the solid test item and the epidermis.
Duration of treatment / exposure:
Triplicate tissues were treated wtih the test item for an exposure period of 15 minutes. Culbecco's Phosphate Buffered Saline (DPBS) with Ca++ and Mg++ was used as the negative control. Sodium Dodecyl Sulphate (SDS) 5% w/v was used as the positive control.
Observation period:
Rinsed tissues were incubated at 37 °C, 5% CO2 in air for 42 hours.
Number of animals:
not applicable
Details on study design:
Pre-incubation: 2 ml maintenance medium, warmed to approximately 37 °C, was pipetted into the first column of 3 wells of a pre-labeled 12-well plate. Each epidermis unit was transferred into the maintenance medium felled wells (3 units per plate). A different 12-well plate wasused for the test item and each control item. The tissues were incubated at 37 °C, 5% CO2 in air overnight.
Application of test item and rinsing (Day 1): 2 ml maintenance medium, warmed to approximately 37 °C, was pipettted into the second column of 3 wells of the 12-well plate. Triplicate tissues were treated with the test item for an exposure period of 15 minutes. the test item was applied topically to the corresponsding tissues ensuring uniform covering. Approximately 10 mg of the test item ws applied to the epidermis surface. The epidermis surface had previously been moistened with 5 µl of sterile distilled water to improve contact between the solid test item and theepidermis. Triplicate tissues treated with 10 µl of DPBS served as the negative controls and triplicate tisues treated with 10 µl of SDS 5% w/v served as the positive controls. The plates were kept in the biological safety cabinet at romo temperature for 15 minutes.

At the end of the exposure period, each tissue was removed from teh well using forceps and rinsed using a wash bottle containing DPBS with Ca++ and Mg++. Rinsing was achieved uby filling and emptying each tissue insert for approximately 40 seconds using a constant soft stream of DPBS to gently remove any residual test item. The rinsed tissues were transferred to the second column of 3 wells containing 2 ml of maintenance medium in each well. The rinsed tissues were incubated at 37 °C, 5% CO2 in air for 42 hours.

Following the 42-hour post-exposure incubation period, each 12-well plate was placed onto a plate shaker for 15 minutes to homogenize the released mediators in the medium. 1.6 ml of the maintenance medium from beneath each tissue was transferred to pre-labelled micro tubes and stored in a freezer at -14 to -30 °C for possible inflammatory mediator determination.

2 ml of a 0.3 mg/ml MTT solution, freshly prepared in assay medium, was pipetted into the third column of 3 wells of the 12 well plate(s). The tissues were transferred to the MTT filled wells, being careful to remove any excess maintenance medium from the bottom of the tissue insert by blotting on absorbent paper. The tissues were incubated for 3 hours at 37 °C, 5% CO2 in air. At the end of the 3-hour incubation period each tissue was placed onto absorbent paper to dry. A total biopsy of the epidermis was made using the EPISKIN(TM) biopsy punch. The epidermis was carefully separated from the collagen matrix using forceps and both parts (epidermis and collagen matrix) placed into labelled 1.5 ml micro tubes containing 500 µl acidified isopropanol, ensuring that both the epidermis and collagen matrix were fully immersed. Each tube was plugged to prevent evaporation and mixed throughly on a vortex mixer. The tubes we3re refrigerated at 1 to 10 °C until Day 6 of the experiment, allowing the extraction of the formazan crystals out of the MTT-loaded tissues.

At the end of the formazan extration period each tube was mixed throughly on a vortex mixer to produce a homogenous coloured solution.

For each tissue, duplicate 200 µl samples were transferred to the appropriate wells of a pre-labelled 96-well plate. 200 µl of acidified isopropanol alone was added to the two wells designated as "blanks". The optical density was measured (quantitative viability analysis) at 540 nm (without a reference filter) using the Anthos 2001 microplate reader.
Irritation / corrosion parameter:
% tissue viability
Value:
99.5
Negative controls validity:
valid
Remarks:
100%
Positive controls validity:
valid
Remarks:
7.8%
Remarks on result:
no indication of irritation
Other effects / acceptance of results:
The relative mean viability of the test item treated tissues was 99.5% after a 15-Minute exposure period.
The relative mean tissue viability for the positive control treated tissues was 7.8% relative to the negative control treated tissues and the standard deviation value of the percentage viability was 0.7%. The positive control acceptance criterion was tehrefore satisfied.
The mean OD540 for the negative control treated tissues was 0.847 and the standard deviation value of the percentage viability was 5.8%. The negative control acceptance criterion was therefore satisfied.
The standard deviation calculated from individual percentage tissue viabilities of three identically treated tissues was 3.3%. The test item acceptance criterion was therefore satisfied.

The MTT solution containing the test item did not turn blue which indicated that the test item did not directly reduce MTT.

Interpretation of results:
GHS criteria not met
Conclusions:
Tes test item is considered a Non-Irritant (NI).
Executive summary:

The purpose of this test was to evaluate the skin irritation potential of the test item using the EPISKIN(TM) reconstructed human epidermis model after a treatment period of 15 minutes followed by a post-expousre incubation period of 42 hours. The principle of the assay was based on the measurement of cytotoxicity in reconstructed human epidermal cultures folowing topical exposure to thetest imte by means of the colourimetric MTT reduction assay. Cell viability is measured by enzymatic reduction of the yellow MTT tetrazolium salt (3 -[4,5 -dimethylthiazol-2 -yl]-2,5 -diphenyl-tetrazolium bromide) to a blue formazan salt (within the mitochondria of viable cells) in the test item treated tisssues relative to the negative controls. The concentration of the inflammatory mediator IL-1a in the culture medium retained following the 42 -hour post-exposure incubatino period is also determined for test items whicha re found to be borderline non-irritant based upon the MTT reduction endpoint. This complimentary end-point will be used to either confirm a non-irritant result or will be used to override the non-irritant result.

Triplicate tissues were treatd wtih the test item for an exposure period of 15 minutes. At the end of the exposure period each tissue was rinsed before incubating for 42 hours. At the end of the post-exposure incubation period each tissue was taken for MTT-loading. The maintenance medium from beneath each tissue was transferred to pre-labelled micro tubes and stored in a freezer for posssible inflammatory mediator determinatino. After MTTT loading a total biopsy of each epidermis wasmade and placed into micro tubes containing acidified isopropanol for extraction of formazan crystals out of the MTT-loaded tissues. At the end of the formazan extraction period each tube was mixed thoroughly and duplicate 200 µl samples were tranferred to the appropriate wells of a pre-labelled 96 -well plate. The optical density was measured at 540 nm. Data are presented in the form of percentage viability (MTT reduction in the test item treated tissues relative to negative control tissues).

The relative mean viability of the test item treated tissues was 99.5% after the 15 -minute exposure period. The quality criteria requried for acceptance of results in the test were satisfied.

The test item was considered to be Non-Irritant (NI).

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:
January 13 to january 17, 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study. Study was conducted in accordance with a recognized scientific procedure for analyzing the primary eye irritation of a test material in experimental animals. The test was performed on a 40% formulation. Study details were sufficient to support the conclusions in the report regarding the eye irritation of the formulated test material.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
other: EEC Directive 79-831, Annex V, methods for the determination of toxicity, B.5., Acute toxicity, eye irritation, dated December 1983
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: ENKI-Konijnenfarm, Someren, the Netherlands
- Weight at study initiation: 2500-3000 g
- Housing: individually in galvanized cages
- Diet and water : ad libitum
- Acclimation period:


ENVIRONMENTAL CONDITIONS
- Temperature: 15-21 °C
- Humidity: 40-70 %
- Air changes : 10 per hr
- Photoperiod : 12 hrs dark / 12 hrs light


IN-LIFE DATES: From: To:
Vehicle:
unchanged (no vehicle)
Amount / concentration applied:
Concentration: 0.1 g of test material was instilled into the everted lower eye lid of one eye of each rabbit.
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3
Details on study design:
Comment: not rinsed
Irritation parameter:
cornea opacity score
Basis:
animal: #1, 2 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: #1, 2and 3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.6
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal: #1 and 3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
The scores recorded for cornea and iris were zero (0) in all rabbits at all reading times. A maximum score of 2 (slight to moderate) for redness and 2 (slight to moderate swelling) for chemosis were observed in 2/3 rabbits after 1 hour. At 24 hours only 1/3 rabbits still had a score of 2 for redness, all other scores were 1 or 0. 2/3 animals had a score of 1 for redness, and 1/3 had a score of 1 for chemosis at 48 hours. At 72 hours all scores were zero (0).

 

 

Rabbit

Opacity

Iris

Redness

Chemosis

After one hour

1

0

0

2

1

2

0

0

2

2

3

0

0

1

1

After 24 hours

1

0

0

1

0

2

0

0

2

1

3

0

0

1

0

After 48 hours

1

0

0

0

0

2

0

0

1

1

3

0

0

1

0

After 72 hours

1

0

0

0

0

2

0

0

0

0

3

0

0

0

0

 

Interpretation of results:
GHS criteria not met
Conclusions:
The test material was not an eye irritant based upon the CLP/GHS standards for evaluation.
Executive summary:

The potential of a powder containing 40% of 2,2-Bis(t-butylperoxy isopropyl)benzene to induce ocular irritation was evaluated in rabbits according to OECD405 guideline. The substance was administered to three male New Zealand White rabbits.

A single dose of 0.1 g of the substance was instilled into the left/right conjunctival sac. The right/left eye was not treated and served as control. The eyes were not rinsed after administration of the test item. Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration of the test substance. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

After one hour, the eyes effects observed in all rabbits consisted of slight or moderate redness and slight or moderate swelling of the consjunctivae. All these clinical signs were fully reversible within 72 hours.

Mean scores calculated for each animal over 24, 48 and 72 hours were (0) (0.6) and (0) for chemosis, (0.3) (1) and (0.6) for redness of the conjunctiva, (0) (0) and (0) for iris lesions and (0) (0) and (0) for corneal opacity.

Under these experimental conditions, the test item was considered as sligh irritant when administered by ocular route to rabbits.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

According to EU Regulation (EC) N0. 1272/2008 (CLP), [1, 3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide is no classified as an eye irritant or as a skin irritant.