Registration Dossier

Administrative data

Description of key information

Based on the results obtained from testing the acute oral LD50 was determined to be greater than 2000 mg/kgbw. The 4 hour LC50 value determined in an acute inhalation toxicity study was considered to be greater than 2.53 mg/L and below 6.8 mg/L.

No acute dermal toxicity study was conducted as no hazard after short-term exposure is expected based on experimental data of another 41 organic peroxides. This assumption is supported by a LD50 value > 2500 mg/kgbwdetermined in an acute dermal toxicity study with tert-butylperoxypivalate(read-across). It is therefore assumed that tert-butylperoxyisobuytratealso revealed a LD50 value > 2000 mg/kgbw after short-term exposure due to structure similarity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995-08-24 until 1995-09-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Version / remarks:
1992
Deviations:
no
GLP compliance:
yes
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: 6 weeks old
- Weight at study initiation: mean body weight of 184 ± 5 g for the males and 136 ± 4 g for the females
- Fasting period before study: 1 day
- Housing: The animals were housed individually in polystyrene cages
- Diet: A04 C pelleted diet (U.A.R., 91360 Villemoisson-sur-Orge, France)
- Water: drinking water filtered by a F.G. Millipore membrane (0.22 micron) was provided ad libitum.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21 ± 2°C
- Humidity: 30 to 70 %
- Air changes: about 12 cycles/hour of filtered, non-recycled air
- Photoperiod: 12 h/12 h

IN-LIFE DATES: 1995-08-24 to 1995-09-07
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE
- The test substance was administered in its original form taking into consideration that its density was 0.86. The volume administered to each animal was adjusted according to body weight determined on the day of treatment.
Doses:
2000 mg/kg in active material (i.e. corresponding to 2642 mg/kg in finished product)
No. of animals per sex per dose:
5 rats per sex
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observation of the animals was made at least once a day. The animals were weighed individually just before administration of the test substance on day 1 and then on days 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic examination
Statistics:
No
Preliminary study:
No
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
Two out of five females were found dead on day 2 or 3.
Clinical signs:
In the males, sedation was observed one hour after treatment, and then piloerection and hypoactivity which persisted for four hours. Thereafter, no clinical signs were noted. In the females, sedation was noted one hour after treatment, in addition to piloerection and dyspnea two hours after; then, hypoactivity and piloerection were noted after four hours. Thereafter, no clinical signs were noted, except coma in one out of five females on day 2 prior to death on day 3.
Body weight:
The body weight gain of the animals was not influenced by treatment.
Gross pathology:
Macroscopic examination of the main organs of the animals demonstrated no apparent abnormalities.
Other findings:
None
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the study LD50 of > 2000 mg/kg was determined.
Executive summary:

The test substance, tert-butyl peroxyiisobutyrate (TBPIB) 75.7 % in hydrocarbon was administered by oral route to one group of ten fasted Sprague-Dawley rats (five males and five females). according to OECD 401 and EU method B1 guidelines. The test substance was administered in its original form, by gavage, at a dose of 2000 mg/kg in active material. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single administration of the test substance. All animals were subjected to necropsy.

The body weight gain of the animals was not affected by treatment with the test substance. Two out of five females were found dead on day 2 or 3. In the males, sedation was observed one hour after treatment, and then piloerection and hypoactivity which persisted for four hours. Thereafter, no clinical signs were noted. In the females, sedation was noted one hour after treatment, in addition to piloerection and dyspnea two hours after; then, hypoactivity and piloerection were noted after four hours. Thereafter, no clinical signs were noted, except coma in one out of five females on day 2 prior to death on day 3. No abnormalities were observed at necropsy.

Under the study experimental conditions, the oral LD50 of the test substance 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 and guideline study of current date.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013-04-11 to 2013-04-26
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Version / remarks:
07 September 2009
Deviations:
yes
Remarks:
only one animal group was treated in the Main Study.
Qualifier:
according to guideline
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
Version / remarks:
30 May 2008
Deviations:
yes
Remarks:
only one animal group was treated in the Main Study.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1300 (Acute inhalation toxicity)
Version / remarks:
August 1998
Deviations:
yes
Remarks:
only one animal group was treated in the Main Study.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
Stabilizer: isododecane
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt., Cserkesz u. 90., H-1103 Budapest, Hungary
- Age at study initiation: Young adult rats, 8 weeks old
- Weight at study initiation: Male: 267-282 g, Female: 204-217 g
- Housing: individually
- Diet: ssniff® SM R/M-Z+H complete diet for rats and mice produced by ssniff Spezialdiäten GmbH, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 7 days
- Acclimatisation to the test apparatus: 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 – 70
- Air changes (per hr): 8-12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2013-06-11 To: 2013-06-26
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: anodised aluminium Flow Past Exposure Chamber (CR Equipment SA, Switzerland).
- Exposure chamber volume: 1.66 L
- Method of holding animals in test chamber: animals were held in polycarbonate restraining tubes and exposed “nose-only” under dynamic air flow conditions
- Source and rate of air: The air was supplied by an oil-free air compressor and was filtered in a two-stage filter set. The air was not humidified in order to avoid false results at gravimetry of the sampling tubes produced by adsorbed water vapour.
- Method of conditioning air: In the particular set-ups according to the pre-set total airflow rate the proper number of the radial tubes were plugged, and in such a way was ensured 1 L/min fresh test atmosphere to each animal port, sufficient to exclude re-breathing of the animals and to maintain natural oxygen concentration in the breathing zones.
- System of generating vapour atmosphere: The vapour of the test item was generated in a gas washing bottle (bubbler) with an airstream of 5 L/min. The bubbler was attached through a T junction to the input port on the top of the exposure chamber. In the first sighting exposure the other input branch of the junction was closed, while in the second sighting exposure and in the main study exposure the concentration of test atmosphere was set by additional clear air of 15 L/min and 8 L/min, respectively.

TEST ATMOSPHERE
- Brief description of analytical method used:
During these experiments it was found that due to different evaporation rates of the two components (TBPIB, active ingredient and Isododecane, stabilizer) the composition of the test item's vapour may be different from the composition of the liquid form. Therefore study concentration measurement via gravimetry was not sufficient and chemical analysis was also performed.
For sampling of the test atmosphere charcoal-filled sorbent tubes type Anasorb 747 (SKC Inc., Lots: 7006 and 7599) were implemented based on OSHA Sampling and Analytical Methods: Organic Vapors, 07, May 2000. At the time of the technical trials sampling procedure and method for chemical analysis were developed and validated. The mass of the test item's vapour adsorbed in the sampling tubes was measured both via gravimetry and chemical analysis. The analytical method implemented was reverse phase HPLC technique using UV absorption of TBPIB at 210 nm. In such a way the results did not depend on the amount of Isododecane in the samples. However, the method was calibrated directly with 75% TBPIB, therefore the mass of samples given by chemical analysis is test item equivalent mass (i.e. 74.3% TBPIB plus 25.7% Isododecane, according to the Test Item Characterization Sheet). Isododecane in excess does not appear in the result of chemical analysis, and was calculated as the difference of gravimetric mass of the sample and of the mass of TBPIB. This latter was determined as 74.3% of the test item's mass given by chemical analysis.
Investigation of sample stability at 6 and 24 hours revealed a reproducible temporal degradation (recovery rate: 75 and 65 %, respectively). Accordingly in the study the samples were analyzed after about 6 hours and the corresponding recovery correction factor (1/0.75) was implemented.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle: air

TEST ATMOSPHERE
- Particle size distribution: Since no condensation of the test item from vapour to aerosol was detected by the light scattering aerosol photometer that is part of the exposure system, particle size analysis was neither planned nor performed in the study.
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
First sighting study: 6.8 mg/L 75% TBPIB
Second sighting study: 1.51 mg/L 75% TBPIB
Main Study: 2.53 mg/L 75% TBPIB
No. of animals per sex per dose:
First sighting study: 1/1
Second sighting study: 1/1
Main Study: 5/5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days in the Main Study
- Observation for Morbidity / mortality: twice daily
- Frequency of observations: after one, two and three hour exposure whilst the animals are still restrained; as soon as practicable after removal from restraint on completion of the exposure; approximately one hour after completion of the exposure and then at least once daily for fourteen days.
- Frequency of weighing: Individual body weights were recorded with an accuracy of 1 g on the day of exposure Day 0 (prior to exposure) and Days 1, 3, 7 and 14.
- Necropsy of survivors performed: yes
Statistics:
not applicable
Preliminary study:
One group of animals (1 male and 1 female) was exposed to test item atmosphere at the highest attainable concentration. The achieved total vapour concentration was 9.5 mg/L (gravimetry) with test item (i.e. 75% TBPIB) concentration of 6.81 mg/L (chemical analysis). Both animals died within 24 hours post-exposure.
A second sighting exposure at the total vapour concentration of 2.10 mg/L (gravimetry) was performed. Chemical analysis failed and the 75% TBPIB concentration was calculated from the total vapour concentration as 1.51 mg/L, based on the test item vs. total vapour ratio of 0.72 obtained in the first sighting exposure. 1 male and 1 female rat were tested, and no mortality appeared in 5 days postexposure.
Key result
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 2.53 - < 6.8 mg/L air (analytical)
Based on:
test mat.
Remarks:
75% TBPIB
Exp. duration:
4 h
Remarks on result:
other: One male animal died on day of exposure.
Mortality:
One animal died one day after completion of the exposure.
Clinical signs:
other: In the male and female animals test item related clinical signs were found between the fourth hour of inhalation exposure and on Day 1 of observation period. Clinical signs were decreased activity, bloody discharge around the nose, dyspnoea, tremor, vocal
Body weight:
In both genders body weight loss was observable on the day of inhalation exposure. In both sexes a compensation of body weight loss was found from Day 3 of observation period. On basis of body weight and body weight gain data, there was no notable test item effect observable in the exposed animals.
Gross pathology:
In the male dose group of 2.53 mg 75% TBPIB/L (5 animals): One animal died during the study. In this case the lungs were reddish mottled and the liver was dark coloured. In the surviving animals macroscopic alteration could not be found.
In the female dose group of 2.53 mg 75% TBPIB/L (5 animals): In one case hydrometra occurred.

In the male animal died on Day 1 of post-exposure period the reddish mottled lungs and dark coloured liver was considered as test item related effect.
The hydrometra is an alteration with sporadic occurrence in experimental rats without toxicological meaning.
In the surviving animals no macroscopic alterations in connection with the toxicological effect of the test item could be observed. 75% TBPIB did not cause local irritancy in the respiratory tract.
Other findings:
not applicable
Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
Under the experimental conditions of the present Acute Inhalation Toxicity Study, one of ten animals exposed to a mean achieved atmospheric test item vapour concentration of 2.53 mg/L for four hours died. Due to mortalitiy of both animals in the first sighting study at a test atmosphere concentration of 6.8 mg/L the acute inhalation median lethal concentration (4 hr LC50) of test item in Wistar Crl:(WI) BR rats was considered to be greater than 2.53 mg/L and below 6.8 mg/L. The test item was therefore shown to fulfill the criteria of Acute Toxicity Category 3 of the GHS/CLP system.
Executive summary:

The study was designed to assess the acute inhalation toxicity of test item. The results of the study are believed to be of value in predicting toxicity in humans by the inhalation route and the data obtained may serve as a basis for classification, labelling and hazard assessment according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS, United Nations 2011) and Regulation (EC) No 1272/2008 (CLP). The method used followed that described in the US Environmental Protection Agency (EPA) Health Effects Test Guidelines, OPPTS 870.1300, Acute Inhalation Toxicity, August 1998. The method was also designed to meet OECD guideline 403 (May 1981 and continuous series) and Commission Regulation (EC) No 440/2008, Annex Part B, B.2: "Acute Toxicity (Inhalation)", Official Journal of the European Union No. L 142, dated May 31st, 2008, in line with the Sponsor requirements.

A group of ten Wistar Crl:(WI) BR rats (five males and five females) was exposed to an atmosphere containing the vapour of the test item. The animals were exposed for four hours using a nose-only exposure system, followed by a fourteen day observation period. The concentration of the test item in the test atmosphere was determined by chemical analysis of samples gathered on charcoal sorbent tubes. Test item concentration for the Main study exposure was selected according to the result of two sighting exposures.

Following the first sighting exposure with the highest technically attainable test item concentration of 6.8 mg/L both treated animals died, while the second exposure at the concentration of 1.51 mg/L did not cause mortality. The Main study exposure was performed at the test item concentration elevated above the 2 mg/L border of GHS/CLP categories 2 and 3. The mean atmospheric concentration (achieved) and the nominal concentration of the test item was as follows:

 

Mean Achieved Concentration ± SD (mg/L air): 2.53±065 mg/L air

Nominal concentration: 4.87 mg/L air

 

Test item related clinical signs were found between the fourth hour of inhalation exposure and Day 1 of the observation period. Clinical signs were decreased activity, bloody discharge around the nose, dyspnoea, tremor, vocalisation, incoordination, crouching position and piloerection. One male animal died one day after completion of exposure. In this animal decreased activity, tremor, piloerection and dyspnoea were found in the fourth hour of inhalation exposure and one hour after completion of exposure. The surviving animals were symptom–free from Day 2 of observation period. In both genders body weight loss was observable on the day of inhalation exposure. In both sexes a compensation of body weight loss was found from Day 3 of the observation period. On basis of body weight and body weight gain data, there was no notable test item effect observable in the exposed animals. In the surviving animals macroscopic alteration in connection with the toxicological effect of the test item could not be observed. The test item did not cause local irritancy in the respiratory tract. In the male animal died on Day 1 of post-exposure period the reddish mottled lungs and dark coloured liver were considered as test item related effect.

Under the experimental conditions of the present Acute Inhalation Toxicity Study, one of ten animals exposed to a mean achieved atmospheric test item vapour concentration of 2.53 mg/L for four hours died. Due to mortalitiy of both animals in the first sighting study at a test atmosphere concentration of 6.8 mg/L the acute inhalation median lethal concentration (4 hr LC50) of test item in Wistar Crl:(WI) BR rats was determined to be greater than 2.53 mg/L and below 6.8 mg/L. The test item was therefore shown to fulfill the criteria of Acute Toxicity Category 3 of the GHS/CLP system.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating conc.
Value:
2 530 mg/m³
Quality of whole database:
The study was conducted in compliance with GLP and OECD guideline. However, in the main study, only one animal group was treated due to animal welfare reasons as the outcome of the first treatment in the Main Study provided sufficient information for classification according to Regulation (EC) No 1272/2008.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available
Dose descriptor:
discriminating dose

Additional information

Acute oral toxicity

In the key study the test substance, tert-butyl peroxyisobutyrate (TBPIB) 75.7 % in hydrocarbon was administered by oral route to one group of ten fasted Sprague-Dawley rats (five males and five females) according to OECD 401 and EU method B1 guidelines. The test substance was administered in its original form, by gavage, at a dose of 2000 mg/kg in active material. After an observation time of 14 days following a single administration of the test substance the body weight gain of the animals was not affected by treatment with the test substance. Two out of five females were found dead on day 2 or 3. In the males, sedation was observed one hour after treatment, and then piloerection and hypoactivity which persisted for four hours. Thereafter, no clinical signs were noted. In the females, sedation was noted one hour after treatment, in addition to piloerection and dyspnea two hours after; then, hypoactivity and piloerection were noted after four hours. Thereafter, no clinical signs were noted, except coma in one out of five females on day 2 prior to death on day 3. No abnormalities were observed at necropsy. Under the study experimental conditions, the oral LD50 of the test substance was higher than 2000 mg/kg in rats.

 

In the other study (supporting study), similar results were obtained although no mortality occured. The test substance, tert-butyl peroxyisobutyrate (TBPIB) 75 % in mineral spirit was investigated in a group of five male and five female CD rats at a dosage of 2000 mg/kg. The animals were fasted overnight prior to dosing and the test material was administered at a constant volume-dosage of 10 mL/kg in maize oil. Mortality and signs of reaction to treatment were recorded during a subsequent 14-day observation period. The animals were killed on the following day and subjected to necropsy. No mortality occurred and signs of reaction to treatment comprised underactivity, piloerection and hunched posture. All animals were overtly normal on the second day. The animals achieved expected bodyweight gains and necropsy revealed no significant macroscopic lesion. Under the conditions of this study, the acute oral median lethal dosage (LD50) of the test material was greater than 2000 mg/kg. For the pure substance (100 %) a LD50 value of 1500 mg/kg was calculated.

 

Acute inhalation toxicity

The study was designed to assess the acute inhalation toxicity of test item. The results of the study are believed to be of value in predicting toxicity in humans by the inhalation route and the data obtained may serve as a basis for classification, labelling and hazard assessment according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS, United Nations 2011) and Regulation (EC) No 1272/2008 (CLP). The method used followed that described in the US Environmental Protection Agency (EPA) Health Effects Test Guidelines, OPPTS 870.1300, Acute Inhalation Toxicity, August 1998. The method was also designed to meet OECD guideline 403 (May 1981 and continuous series) and Commission Regulation (EC) No 440/2008, Annex Part B, B.2: "Acute Toxicity (Inhalation)", Official Journal of the European Union No. L 142, dated May 31st, 2008, in line with the Sponsor requirements.

A group of ten Wistar Crl:(WI) BR rats (five males and five females) was exposed to an atmosphere containing the vapour of the test item. The animals were exposed for four hours using a nose-only exposure system, followed by a fourteen day observation period. The concentration of the test item in the test atmosphere was determined by chemical analysis of samples gathered on charcoal sorbent tubes. Test item concentration for the Main study exposure was selected according to the result of two sighting exposures.

Following the first sighting exposure with the highest technically attainable test item concentration of 6.8 mg/L both treated animals died, while the second exposure at the concentration of 1.51 mg/L did not cause mortality. The Main study exposure was performed at the test item concentration elevated above the 2 mg/L border of GHS/CLP categories 2 and 3. The mean atmospheric concentration (achieved) and the nominal concentration of the test item was as follows:

 

Mean Achieved Concentration ± SD (mg/L air): 2.53±065 mg/L air

Nominal concentration: 4.87 mg/L air

 

Test item related clinical signs were found between the fourth hour of inhalation exposure and Day 1 of the observation period. Clinical signs were decreased activity, bloody discharge around the nose, dyspnoea, tremor, vocalisation, incoordination, crouching position and piloerection. One male animal died one day after completion of exposure. In this animal decreased activity, tremor, piloerection and dyspnoea were found in the fourth hour of inhalation exposure and one hour after completion of exposure. The surviving animals were symptom–free from Day 2 of observation period. In both genders body weight loss was observable on the day of inhalation exposure. In both sexes a compensation of body weight loss was found from Day 3 of the observation period. On basis of body weight and body weight gain data, there was no notable test item effect observable in the exposed animals. In the surviving animals macroscopic alteration in connection with the toxicological effect of the test item could not be observed. The test item did not cause local irritancy in the respiratory tract. In the male animal died on Day 1 of post-exposure period the reddish mottled lungs and dark coloured liver were considered as test item related effect.

Under the experimental conditions of the present Acute Inhalation Toxicity Study, one of ten animals exposed to a mean achieved atmospheric test item vapour concentration of 2.53 mg/L for four hours died. Due to mortalitiy of both animals in the first sighting study at a test atmosphere concentration of 6.8 mg/L the acute inhalation median lethal concentration (4 hr LC50) of test item in Wistar Crl:(WI) BR rats was determined to be greater than 2.53 mg/L and below 6.8 mg/L. The test item was therefore shown to fulfill the criteria of Acute Toxicity Category 3 of the GHS/CLP system.

 

Acute dermal toxicity

No acute dermal toxicity study was conducted as no hazard after short-term exposure is expected based on experimental data of another 41 organic peroxides. This assumption is supported by a LD50 value > 2500 mg/kg bw determined in an acute dermal toxicity study with tert-butyl peroxypivalate. It is therefore assumed that tert-butyl peroxyisobuytrate (read-across) also revealed a LD50 value > 2000 mg/kg bw after short-term exposure due to structure similarity.

Justification for classification or non-classification

The test item is classified for acute inhalation toxicity, Category 3, H331: Toxic if inhaled according to Regulation (EC) No 1272/2008.

Based on the results obtained, tert-butyl peroxyisobutyrate was not classified and labelled for acute oral and dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP).

The substance contains up to 25 % isododecane as stabilizer which is classified as aspiration toxicity cat. 1. Based on the kinematic viscosity of the substance and in accordance with the section 3.10.3 of Annex I of Regulation (EC) No 1272/2008 (CLP) the substance has to be classified as aspiration toxicity cat. 1, H304: May be fatal if swallowed and enters airways.