Registration Dossier

Administrative data

Description of key information

The dermal and oral LD0 of structurally analogous [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide are more than 2000 mg/kg in Sprague Dawley rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
from 06 November 2009 to
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: compliant to GLP and testing guideline; adequate coherence between data, comments and conclusions
Justification for type of information:
see read across rationale in Section 13.2
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Breeder: Janvier, Le Genest-Saint-Isle, France.
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation: 204 +/- 5 g
- Fasting period before study: approximately 18 hours
- Housing: polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm)
- Diet (e.g. ad libitum): conventional laboratory diet (SSNIFF R/M-H pelleted maintenance diet)
- Water (e.g. ad libitum): drinking water filtered by a FG Millipore membrane (0.22 micron), provided ad libitum
- Acclimation period: at least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 30 to 70%
- Air changes (per hr): 12 cycles/hour
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: From 13 November 2009 to 01 December 2009.
Route of administration:
oral: gavage
Vehicle:
other: 0.5% methylcellulose
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: standard vehicle used for specific routes of administration (the test item was not soluble in purified water)
- Lot/batch no. (if required): 066K0129

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: at the request of the Sponsor, the starting dose-level was 2000 mg/kg.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: the animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day. The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: no.
Sex:
female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Mortality:
None.
Clinical signs:
None.
Body weight:
When compared to CIT historical control data, a lower body weight gain was noted in 2/6 animals (6 and 8 g vs. 17 ± 8 g in historical data base) between day 8 and day 15.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Other findings:
None.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The oral LD0 of the test item 1,3(4) bis(tert butylperoxyisopropyl)benzene (batch No. 307090713) was higher than 2000 mg/kg in rats.
Executive summary:

The acute oral toxicity of the test item, 1,3(4)‑bis(tert-butylperoxyisopropyl)benzene (batch No. 307090713), was evaluated in rats according to OECD (No. 423, 17th December 2001) and Commission Regulation (EC) (No. 440/2008, B.1tris, 30 May 2008) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. The test item was prepared in 0.5% methylcellulose and was administered by oral route (gavage), under a volume of 10 mL/kg, to groups of three fasted female Sprague-Dawley rats. The study design was as follows:

 

Dose-level

(mg/kg)

Volume

(mL/kg)

Female

2000

10

3

2000

10

3

Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item.

 

All animals were subjected to necropsy.

Neither mortality nor clinical signs were observed during the study. When compared to CIT historical control data, a lower body weigh gain was noted in 2/6 animals (6 and 8 g vs. 17 ± 8 g in historical data base) between day 8 and day 15. 

At necropsy, no apparent abnormalities were observed in any animals. Under the experimental conditions of this study, the oral LD0of the test item 1,3(4)‑bis(tert‑butylperoxyisopropyl)benzene (batch No. 307090713) was higher than 2000 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
GLP guideline study

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 1a : GLP guideline study
Justification for type of information:
see read across rationale in Section 13.2
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, 69210 L'Arbresle, France
- Age at study initiation: 8 weeks old
- Weight at study initiation: 237-257 g (males) and 244-252 (females)
- Housing: individually (during the treatment period) in polycarbonate cages
- Diet (A04C pelleted diet) and water: ad libitum (filtred drinking water)
- Acclimation period: at least 5 days before the begining of the study

ENVIRONMENTAL CONDITIONS
- Temperature : 19-23 °C
- Humidity: 30-70 %
- Air changes : 12 per hr
- Photoperiod: 12/12 hrs light
Type of coverage:
semiocclusive
Vehicle:
other: Before the application, the substance was pre-moistened with 2 ml water
Details on dermal exposure:
TEST SITE
- Area of exposure: 6 x 8 cm (on the day before tratment, the dorsal area of each animal was clipped using electric clippers; only animals with healthy intact skins were used for the study)
- % coverage: 10 %
- Type of wrap if used: The gauze was held in contact with the skin by mean of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage (in order to avoid the ingestion of the test substance by the animal).

TEST MATERIAL
- Amount applied: a single dose of 2000mg/kg of the test substance (fine powder) was placed on an hydrophilic gauze pad pre-moistened with 2 ml of water and the applied to the skin.
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: frequently during the hours following administration of test substance, then at least once a day until day 15. Body weight were recorded just before the administration of test substance on day 1, then on days 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: a macroscopic examination of the main organs (digestive tract, heart, kidney, liver, lungs, pancreas, spleen and any organ with obvious abnormalities was performed)
Statistics:
not appropriate
Preliminary study:
No preliminary study because the substance was anticipated to be non-toxic at 2000 mg/kg.
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality.
Clinical signs:
No clinical signs and no cutaneous reactions were observed during the study.
Body weight:
A slight bodyweight loss was seen in 4/5 females betwwen day 1 and day 8.
Gross pathology:
No abnormal observations.
Other findings:
No other relevant findings.
Interpretation of results:
other: not classified
Remarks:
Criteria used for interpretation of results: other: Directive 67/548/EEC, and EU Regulation (EC) N0. 1272/2008 (CLP)
Conclusions:
Under these experimental conditions, the dermal LD50 of Peroximon F is assumed to be more than 2000 mg/kg in Sprague Dawley rats.
Executive summary:

The acute dermal toxicity of Perximon F ( 1,3 & 1,4-di-(2-t-butylperoxyisolpropyl)benzene) was evaluated in rats according to OECD N° 402 guideline and EC 92/69/EEC B.3 guidelines (Acute Toxic Standard Method). Peroximon F was applied to the skin of groups of 5 male and 5 female Sprague Dawley rats at doses of 2000 mg/kg in a semi-occlusive dressing for 24 hours. Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14).

No mortality and no abnormal clinical signs were observed. Only a slight bodyweight loss was seen in 4/5 females between day 1 and day 8. At necropsy, no abnormal gross pathology was observed.

Under these experimental conditions, the dermal LD50 of Peroximon F is assumed to be more than 2000 mg/kg in Sprague Dawley rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
GLP guideline study

Additional information

Oral route

The acute oral toxicity of structurally analogous [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide was evaluated in rats according to OECD (No. 423, 17th December 2001) and Commission Regulation (EC) (No. 440/2008, B.1tris, 30 May 2008) guidelines (Gerbeix, 2010). The study was conducted in compliance with the principles of Good Laboratory Practice Regulations. The test item was prepared in 0.5% methylcellulose and was administered by oral route (gavage) at the dose level of 2000 mg/kg bw, under a volume of 10 mL/kg, to six fasted female Sprague-Dawley rats. Clinical signs, mortality and body weight gain were checked for a period of up to 14 days following the single administration of the test item. All animals were subjected to necropsy. Neither mortality nor clinical signs were observed during the study. When compared to CIT historical control data, a lower body weight gain was noted in 2/6 animals (6 and 8 gvs. 17 ± 8 g in historical data base) between day 8 and day 15. At necropsy, no apparent abnormalities were observed in any animals. The oral LD0of [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide was higher than 2000 mg/kg in rats.

Dermal route

The acute dermal toxicity of structurally analogous [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide was evaluated in rats according to OECD N° 402 guideline and EC 92/69/EEC B.3 guidelines (Acute Toxic Standard Method) (Manciaux, 1999). [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide was applied to the skin of groups of 5 male and 5 female Sprague Dawley rats at doses of 2000 mg/kg in a semi-occlusive dressing for 24 hours. Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14). No mortality and no abnormal clinical signs were observed. Only a slight bodyweight loss was seen in 4/5 females between day 1 and day 8. At necropsy, no abnormal gross pathology was observed. The dermal LD0 of [1,3(or 1,4)-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide was assumed to be more than 2000 mg/kg in Sprague Dawley rats.

Justification for selection of acute toxicity – oral endpoint

key study

Justification for selection of acute toxicity – dermal endpoint

key study

Justification for classification or non-classification

According to regulation (CE) n°1272/2008, [1,3-phenylenebis(1-methylethylidene)]bis[tert-butyl] peroxide is not classified for acute oral and dermal toxicity