Registration Dossier

Administrative data

Description of key information

GPMT assay

The delayed contact hypersensivity of Proximon 801 (96.8% tert-buty-cumyl peroxide) was evaluated in Guinea pigs according to OECD N°406 guideline (Magnusson and Kligman test). The induction phase has been realized both by intradermal route on day 1 (10 % in vehicle) and by cutaneous route on day 8 (undiluted) in 2 groups of guinea pigs: 5 males and 5 females for control group and 10 males and 10 females for treated group. The challenge phase was realized on day 22 by cutaneous application of the undiluted test material on one flank (vehicle on the other flank); the cutaneous reactions were scored 24 and 48 hours after the challenge phase.

No cutaneous reactions were observed in the animals of the control group. In the treated group, at the 24-hour reading, a very slight or well-defined erythema (grade 1 or 2) was noted in 6/20 and 1/20 animals, respectively. At the 48-hour reading, a very slight erythema (grade 1) persisted in 5/20 animals and dryness of the skin was recorded in 3/20 animals. The slight cutaneous reactions observed at the 24-hour reading and which persisted at the 48-hour reading are most probably attributable to a weak sensitizing potential of the test substance. Peroximon 801 induced delayed contact hyper sensitivity in 5/20 (25%) guinea-pigs. Nevertheless, a classification is not warranted since only 25 % of animals were supposed sensitized and since topical application was done with the undiluted substance. In conclusion, the test item is not considered as sensitizing in guinea pigs.

 

QSAR models

This conclusion was supported by the negative results for allergic contact dermatitis in 3 QSAR models.

 

The allergic contact dermatitis potential of tert-butyl 1-methyl-1-phenylethyl peroxide in guinea pig and human was evaluated via the Danish QSAR database using MultiCASE Ultra, Leadscope Enterprise and SciMatics SciQSAR versions of commercial CASE Ultra model A33. No indication of skin sensitisation was reported, tert-butyl 1-methyl-1-phenylethyl peroxide being inside the applicability domain of 2/3 models.

The presence of structural alert in the molecular structure of tert-butyl 1-methyl-1-phenylethyl peroxide was evaluated with Toxtree (Version 2.5.0). The alerts for skin sensitization capture electrophilic mechanistic information and include “Michael-type addition reaction”, “Schiff base formation”,“acylation”, “nucleophilic aromatic substitution” (SNAr) and “second order nucleophilic aliphatic substitution” (SN2). The final alert “Reactivity domain alert” is true if any other alert is true. No skin sensitisation reactivity domains alerts were identified.

The Pred-Skin app allows to make predictions using externally validated QSAR models for skin sensitization based on murine (LLNA) and human data. Tert-butyl 1-methyl-1-phenylethyl peroxide was predicted to be non-sensitizer in the LLNA with a high probability (70 or 90%).

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes (incl. certificate)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed before the implementation of the REACH regulation.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
Environmental conditions
. temperature: 21 ± 2°C
. relative humidity: 30 to 70%
. light/dark cycle: 12 h/12 h
. ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
The temperature and relative humidity were under continuous control and recording. The records were checked daily and filed. In addition to these daily checks, the housing conditions and corresponding instrumentation and equipment are verified and calibrated at regular intervals.
During the acclimatization period and throughout the study, the animals were housed individually in polycarbonate cages (48 cm x 27 cm x 20 cm) equipped with a polypropylene bottle. Dust-free sawdust was provided as litter (SICSA, 92142 Alfortville, France).
Bacteriological and chemical analyses of the sawdust, including the detection of possible contaminants (pesticides, heavy metals), are perfonned regularly by external laboratories. The results of these analyses are archived at CIT.
-Food and water ad libitum

Animals:

Route:
intradermal
Vehicle:
corn oil
Concentration / amount:
10%
Day(s)/duration:
Day 1
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
100%
Day(s)/duration:
Day 8
Adequacy of induction:
non-irritant substance, but skin pre-treated with 10% SDS
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
Concentration / amount:
100%
Day(s)/duration:
Day 22
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
treated group: 10 males and 10 female
control group: 5 males and 5 females
Details on study design:
RANGE FINDING TESTS:
Intradermal test: In the two animals (both sexes), concentration of the substance at 75 %, 50 % and 25 % (with or without FCA) caused necrosis and severe oedema at 24 and 48 hours, no effects after 6 days.
At 10 %, 5 % and 1 % with FCA caused irritation at 24, 48 hours and 6 days (both sexes)
At 10 %, 5 % and 1 % without FCA caused irritation at 24, 48 hours and slight irritation at 6 days (both sexes)


Cutaneous test:In two animals, topical adminitration caused no irritation, neither 100 % neor 50 %.

MAIN STUDY
A. INDUCTION EXPOSURE
* Intradermal induction:
- On day 1, 3 injections are realized on the scapular area:
- 0.1mL of Freund's complete adjuvant at 50 % in 0.9% NaCl
- 0.1mL of the test item at (10) % (for treated group) or 0.1mL of vehicle (for control group)
- 0.1mL of a mixture 50/50 (V/V) of Freund's complete adjuvant in 0.9% NaCl and the test item at (10 ) % (for treated group) or the vehicle (for control group).

* Cutaneous induction:
- On day 7, local irritation is induced by application of Sodium Laurylsulfate 10% in Vaseline
- On day 8, occlusive application on the scapular area of 0.5mL of the undiluted test item (for treated group) or vehicle (for control group) for 48 hours

B. CHALLENGE EXPOSURE D22
On day 22, 24hours occlusive application on the scapular area of 0.5mL of the undiluted test item 10% on the right flank and 0.5mL of the vehicle on the left flank.
Reactions are evaluated 24 and 48 hours after removal of the dressing
Challenge controls:
There were no challenge controls
Positive control substance(s):
yes
Remarks:
2,4-Dinitrochlorobenzene
Positive control results:
Valid, with DNCB
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
0.5 ml undiluted
No. with + reactions:
7
Total no. in group:
20
Clinical observations:
only erythema was observed (6 animals with a score of 1, one animal with a score of 2)
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
0.5 ml undiluted
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
only erythema was observed (3 animals with a score of 1 with dryness of the skin, 2 animals with a score of 2)
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0.5 ml undiluted
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0.5 ml undiluted
No. with + reactions:
0
Total no. in group:
10

Individual scoring:

Group

Sex

Animal

24h

48h

Erythema

Oedema

Erythema

Oedema

LF

RF

LF

RF

LF

RF

LF

RF

Control

M

 31

 0

 0

0

 0

 0

 0

 0

 0

 32

 0

 0

 0

 0

 0

 0

 0

 0

 33

 0

 0

 0

 0

 0

 0

 0

 0

 34

 0

 0

 0

 0

 0

 0

 0

 0

 35

 0

 0

 0

 0

 0

 0

 0

 

Control

F

46 

 0

 0

 0

 0

 0

 0

 0

 0

47 

 0

 0

 0

 0

 0

 0

 0

 0

48 

 0

 0

 0

 0

 0

 0

 0

 0

 49

 0

 0

 0

 0

 0

 0

 0

 0

 50

 0

 0

 0

 0

 0

 0

 0

 0

 

Treated

M

36 

 0

 1

 0

 0

 0

 0

 0

 0

 37

 0

 0

 0

 0

 0

 0

 0

 0

 38

 0

 0

 0

 0

 0

 0

 0

 0

 39

 0

 0

 0

 0

 0

 0

 0

 0

 40

 0

 1

 0

 0

 0

 1/S

 0

 0

 41

 0

 2

 0

 0

 0

 1/S

 0

 0

 42

 0

 0

 0

 0

 0

 0

 0

 0

 43

 0

 1

 0

 0

 0

 0

 0

 0

 44

 0

 0

 0

 0

 0

 0

 0

 0

 45

 0

 0

 0

 0

 0

 0

 0

 0

 

Treated

F

 51

 0

 1

 0

 0

 0

 0

 0

 0

 52

 0

 1

 0

 0

 0

 1

 0

 0

 53

 0

 0

 0

 0

 0

 0

 0

 0

 54

 0

 0

 0

 0

 0

 0

 0

 0

 55

 0

 0

 0

 0

 0

 0

 0

 0

 56

 0

 0

 0

 0

 0

 1

 0

 0

 57

 0

 1

 0

 0

 0

 1/S

 0

 0

 58

 0

 0

 0

 0

 0

 0

 0

 0

 59

 0

 0

 0

 0

 0

 0

 0

 0

 60

 0

 0

 0

 0

 0

 0

 0

 0

 

LF=left flank

RF=right flank

A=crusts

S=dryness of the skin

no visible change.............................................................................................0

discrete or patchy erythema.............................................................................1

moderate and confluent erythema.....................................................................2

intense erythema..............................................................................................3

No cutaneous reactions were observed in the animals of the control group.

ln the treated group, at the 24-hour reading, a very slight or well-defined erythema (grade 1 or 2) was noted in 6/20 and 1/20 animals, respectively.

At the 48-hour reading, a very slight erythema (grade 1) persisted in 5/20 animals and dryness of the skin was recorded in 3/20 animals.

 

The slight cutaneous reactions observed at the 24-hour reading and which persisted at the 48-hour reading are most probably attributable to a weak sensitizing potential of the test substance.

Positive controls were also run per standard protocol. The positive control, DNCB resulted in 90% of guinea pigs showing positive reaction in the GPMT (Study Report).

Interpretation of results:
GHS criteria not met
Conclusions:
Peroximon 801 induced delayed contact hyper sensitivity in 5/20 (25%) guinea-pigs but as the skin reactions are slight a classification is not warranted.
Executive summary:

The delayed contact hypersensivity of Peroximon 801 (96.8% tert-buty-cumyl peroxide) was evaluated in Guinea pigs according to OECD N°406 guideline (Magnusson and Kligman test). The induction phase has been realized both by intradermal route on day 1 (10 % in vehicle) and by cutaneous route on day 8 (undiluted) in 2 groups of guinea pigs: 5 males and 5 females for control group and 10 males and 10 females for treated group. The challenge phase was realized on day 22 by cutaneous application of the undiluted test material on one flank (vehicle on the other flank); the cutaneous reactions were scored 24 and 48 hours after the challenge phase.

No cutaneous reactions were observed in the animals of the control group. ln the treated group, at the 24-hour reading, a very slight or well-defined erythema (grade 1 or 2) was noted in 6/20 and 1/20 animals, respectively. At the 48-hour reading, a very slight erythema (grade 1) persisted in 5/20 animals and dryness of the skin was recorded in 3/20 animals. The sligh cutaneous reactions observed at the 24-hour reading and which persisted at the 48-hour reading are most probably attributable to a weak sensitizing potential of the test substance. Paroximon 801 induced delayed contact hyper sensitivity in 5/20 (25%) guinea-pigs. Nevertheless, a classification is not warranted since only 25 % of animals were supposed sensitized and since topical application was done with the undiluted substance.

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to EU Regulation (EC) N0. 1272/2008 (CLP), Tert-butyl-a,a-dimethylbenzyl peroxide (TBCP) is not classified for skin sensitisation.