Di-tert-butyl α,α,α',α'-tetramethyl-(p-phenylenedimethylene) diperoxide

Endpoint summary

Description of key information

From the read across with 1,(3)4-bis(tert-butylperoxyisopropyl)benzene, the dermal and oral LD0 of 1,4-bis(tert-butylperoxyisopropyl)benzene 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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2009-2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: compliant to GLP and testing guideline; adequate coherence between data, comments and conclusions

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system 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 females

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:

other: None.

Gross pathology:

Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.

Other findings:

None.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions of this study, the oral LD50 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 LD₅₀of 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:

Klimisch 1 study, GLP compliant

Acute toxicity: via inhalation route

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:

migrated 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

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system 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:

other: No clinical signs and no cutaneous reactions were observed during the study.

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:

Klimisch 1 study, GLP compliant

Additional information

There is no data on 1,4-bis(tert-butylperoxyisopropyl)benzene. A read across approach is proposed with 1,(3) 4-bis(tert-butylperoxyisopropyl)benzene.

Acute oral toxicity

The acute oral toxicity of 1, (3) 4-bis(tert-butylperoxyisopropyl)benzene was evaluated in Sprague Dawley female rats according to OECD N° 423 guideline (CIT, 2010).Neither mortality nor clinical signs were observed during the study.

When compared to laboratory historical control data, only a lower body weigh gain was noted in 2/6 animals between day 8 and day 15. 

The LD0 by oral exposure is therefore over 2000 mg/kg/day in Sprague Dawley female rats.

Acute dermal toxicity:

The acute dermal toxicity of 1, (3) 4-bis(tert-butylperoxyisopropyl)benzene was evaluated in rats according to OECD N° 402 guideline and EC 92/69/EEC B.3 guidelines (Acute Toxic Standard Method). The substance 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.

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 LD0 of 1, (3) 4-bis(tert-butylperoxyisopropyl)benzene is

assumed to be more than 2000 mg/kg in Sprague Dawley rats.

Justification for selection of acute toxicity – oral endpoint
Key study, Klimisch 1

Justification for selection of acute toxicity – dermal endpoint
Key study, Klimisch 1

Justification for classification or non-classification

According to regulation (EC) 1272/2008 and according to the directive 67/548/EEC: 1,4-bis(tert-butylperoxyisopropyl)benzene is not classified for acute toxicity.