Registration Dossier

Administrative data

Description of key information

The oral LD50 for BPTC under the conditions of this study is estimated to be higher than 2000 mg/kg in female and male rats.

The LC50 of di-tert-butyl 3,3,5-trimethylcyclohexylidene diperoxide obtained in this study was estimated to be greater than 5.6 mg/L air (chemically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

The median lethal dose of di-tert-butyl-3,3,5-trimethylcyclohexylidene diperoxide (CAS# 6731-36-8) after single dermal administration to rats of both sexes (LD 50), observed over a period of 14 days, is greater than 2000 mg/kg body weight.

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:
14 days
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study according to OECD 401 and Japanese "Chemical Substance GLP". Could easily be a K1 if study appendices located, QA and GLP statement provided, and C of A.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Remarks:
"Chemical Substances GLP" Japan
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
Animals used and raising method
4-week-old female and male Sprague-Dawley [Crj:CD(SD)IGS, SPF] rats were purchased from Japan Charles River K.K. Tsukuba Breeding Center and the animals were preconditioned for 8 days for acclimatization to the raising condition as well as for quarantine. No abnormalities were observed in general condition in the animals during the preconditioning period. 15 males and 5 females were used for the study. The males were divided randomly into 3 groups with 5 per group based on the body weights at the end of quarantine, and a group of 5 females was selected from the group of animals in the most recent shipment. The age was 5 weeks for both the females and males at the start of administration (note).
___________________________________________________________
(Note) Animals received: January 27, 1999
Number of animals received: 17 males and 6 females
Body weights when received: 79.8-90.1 g for males and 79.3-84.0 g for females
Date of administration: February 4, 1999
Body weights at the time of administration: 123.8-144.3 g for males and 109.6-121.4 g for females

Each animal was housed in a metal mesh cage (WDH; 220 mm x 270 mm x 190 mm) in a breeding room at standard temperature of 24 ± 1°C, standard humidity of 50-65%, 15 ventilations/h and 12 h illumination (illumination 7:00 a.m. to 7:00 p.m.), and solid feed (CE 2, product of Japan Clea K.K.) and water (city water from Hatano City Water Department) were given freely. In this regard, the measured temperature and humidity were 24.0-24.5°C and 48.5 65.5%, respectively. The humidity deviated slightly from the standard humidity but the deviation lasted less than 1 h and the rest was within thestandard range. Also, the diet and water given contained no foreign matter that could cause disruption of the study.

Oil-based felt-tip pens were used to mark sequence numbers on the tails of the animals for identification. Also, an animal card labeled with the study protocol number, dose, sex and animal number was attached to each cage to aid identification of each individual animal.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Preparation of administration samples
The administration samples were prepared by weighing the test substance for each dose and dissolving it in corn oil (product name: corn oil, Lot No. V8P7069, product of Nakarai K.K.) to a given concentration. The samples were stored in a cold area away from light until administration, which was 3 days after preparation.

Samples of 2 and 20% w/v of the test substance were validated as being stable for 12 days in a cold area away from light (Appendix A-not part of translation) by means of a 28-day multiple oral toxicity study of this test substance in rats that was previously conducted at Hatano Research Institute (study protocol No.: C-98-017). Also, the content of the test substance in each sample for administration was tested and verified to be within specifications (Appendix B-not part of translation). In this case, a uniformity test was not performed because the administration samples were all in liquid form.The concentration of the test substance in the prepared samples was determined by gas chromatography (Appendix C-not part of translation).

Establishment of doses and administration method
The doses for the present study were established based on the result of a literature survey (RTECS No.: SD8600000), as well as on the results from a preliminary study (study protocol No.: C-98-016) of the 28-day multiple oral toxicity of the present substance conducted for dose setting. Specifically,the LD50 found from the literature survey for the present test substance was 12,918 mg/kg [1], and 2 doses, namely, 1000 and 2000 mg/kg, were established for 1 sex (male) because a mild inhibitory effect on the body weight was observed in the females at 1000 mg/kg dose in the initial stage of the preliminary study, while a vehicle control group was established to which corn oil was administered at the same volume as the test substance solution. Also, 1 dose at 2000 mg/kg was established for the females because no gender difference was observed in the preliminary study.

The volume administered was 10 mL per 1 kg body weight and the quantity administered was calculated based on the body weight measured immediately prior to administration, which was after the animal had been fasted for about 18 h. One single forcible oral administration was conductedusing a gastric tube for rats. Administration was conducted at 9:43-9:55 a.m. and food was given about 3 h after administration.

Doses:
1000 and 2000 mg/kg, were established for 1 sex (male)
Also, 1 dose at 2000 mg/kg was established for the females.
No. of animals per sex per dose:
5
Control animals:
yes
Preliminary study:
The doses for the present study were established based on the result of a literature survey (RTECS No.: SD8600000), as well as on the results from a preliminary study (study protocol No.: C-98-016) of the 28-day multiple oral toxicity of the present substance conducted for dose setting. Specifically, the LD50 found from the literature survey for the present test substance was 12,918 mg/kg [1], and 2 doses, namely, 1000 and 2000 mg/kg, were established for 1 sex (male) because a mild inhibitory effect on the body weight was observed in the females at 1000 mg/kg dose in the initial stage of the preliminary study, while a vehicle control group was established to which corn oil was administered at the same volume as the test substance solution. Also, 1 dose at 2000 mg/kg was established for the females because no gender difference was observed in the preliminary study. The volume administered was 10 mL per 1 kg body weight and the quantity administered was calculated based on the body weight measured immediately prior to administration, which was after the animal had been fasted for about 18 h. One single forcible oral administration was conducted using a gastric tube for rats. Administration was conducted at 9:43-9:55 a.m. and food was given about 3 h after administration.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
None
Clinical signs:
For males, diarrhea or loose stools were observed on the day of administration in 2 cases in the vehicle control group, 4 cases in the 1000 mg/kg group and 3 cases in the 2000 mg/kg group, and perianal soiling was observed on the day of administration or observation day 2 in 3 cases in the 2000 mg/kg group.

Diarrhea or loose stools were also observed on the day of administration in 3 females in the 2000 mg/kg group. No other abnormalities were observed.
Body weight:

Normal body weight increases were observed in the females and males after administration.
Gross pathology:
No abnormalities were observed in the organs/tissues in any female or male during the necropsy performed on observation day 15.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The LD50 for BPTC under the conditions of this study is estimated to be higher than 2000 mg/kg in female and male rats.
Executive summary:

Acute single oral toxicity of 1,1-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane (abbreviated as BPTC hereafter) was investigated in Sprague-Dawley [Crj:CD(SD)IGS, SPF] rats. Single oral doses of BPTC were administered to 5-week-old male rats in groups of 5 at 1000 and 2000 mg/kg, respectively, and to 5-week-old female rats in a group of 5 at 2000 mg/kg, and the rats were observed from observation day 1 (the day of administration) for 14 days, followed by necropsy on observation day 15. In addition, 10 mL/kg corn oil was administered to 5 males in a vehicle control group and they were observed in the same manner. Diarrhea or loose stools were observed in all administration groups, with slightly higher incidence in the BPTC administration groups. No abnormal changes were observed in any case in body weight changes or in observations in necropsy performed on observation day 15. From these findings, the LD50for BPTC under the conditions of this study is estimated to be higher than 2000 mg/kg in female and male rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
There is a key study which is relable with minor restrictions.

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:
Experimental Starting Date: 28-Jul-2010, Experimental CCCCompletion Date: 11-Aug-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological defiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to
Guideline:
OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories Ltd, Kreuzelweg 53, 5961 NM Horst / Netherlands
- Age at study initiation: 10 weeks
- Weight at study initiation: Males: 290.1 to 295.4 g, females: 191.1 to 192.7 g
- Fasting period before study: none
- Housing: Animals were housed in groups of 3 of the same sex in Makrolon® type-IV cages with wire mesh tops and standard softwood bedding ("Lignocel" J. Rettenmaier & Söhne GmbH & Co KG, 73494 Rosenberg / Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst / Switzerland) including paper enrichment (Enviro-dri from Lillico, Biotechnology, Surrey, UK)
- Diet (e.g. ad libitum): Animals had ad libitum access to a pelleted standard Harlan Teklad 2914C rat maintenance diet (Provimi Kliba AG, 4303 Kaiseraugst, Switzerland) batch no. 20/10 except during the period when the animals were restrained in exposure tubes.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf ad libitum in water bottles, except during the period when they were restrained in exposure tubes.
- Acclimation period: for 13 days under laboratory conditions, after a clinical health examination

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

Animal Welfare: This study was performed in an AAALAC-accredited laboratory in accordance with the Swiss Animal Protection Law under license no. 397

IN-LIFE DATES: From: To: 28-Jul-2010 to 11-Aug-2010
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The test atmosphere was generated using a Hospitak N°950 nebulizer connected to a syringe pump. The polyethylene injector inside the nebulizer was replaced by a stainless steel injector
- Exposure chamber volume: not applicable
- Method of holding animals in test chamber: The animals were confined separately in restraint tubes which were positioned radially around the exposure chamber.
- Source and rate of air: compressed air was supplied by means of an oil free compressor and passed respiratory quality filters before it was introduced into the exposure system
- Method of conditioning air: respiratory quality filters
- System of generating particulates/aerosols: The test atmosphere was generated using a Hospitak N°950 nebulizer connected to a syringe pump. The polyethylene injector inside the nebulizer was replaced by a stainless steel injector
- Method of particle size determination: Mercer impactor
- Treatment of exhaust air: filtered
- Temperature, humidity, pressure in air chamber: 22.8 °C, 3.5 % rel. humidity, 20.4 % oxygen

TEST ATMOSPHERE
- Brief description of analytical method used: Gravimetric determinations of aerosol concentration were performed four times during exposure. The samples were collected on a Millipore®durapore filter, Type HVLP loaded in a 47 mm in-line stainless steel filter sampling device. The filters were weighed before and immediately after sampling using a calibrated balance. The test aerosol concentration was calculated from the amount of test item present on the filter and the sample volume.
Chemical determinations of aerosol concentration were performed four times during exposure. The samples were collected on a Millipore®durapore filter, Type HVLP loaded in a 47 mm in-line stainless steel filter sampling device. The filters were transferred into appropriate labeled vials containing 5 mL of Acetonitrile, forwarded on dry ice to the scientist responsible for formulation analysis and stored at -20 ± 5 °C until analysis. The samples were analyzed using a GC method provided by the Sponsor and implemented at Harlan Laboratories Ltd.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): no vehicle used
- Concentration of test material in vehicle (if applicable):
- Justification of choice of vehicle:
- Lot/batch no. (if required):
- Purity:

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution:
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): MMAD: 1.98/2.17/2.10 µm, GSD: 1.96/1.97/2.08

CLASS METHOD (if applicable)
- Rationale for the selection of the starting concentration:
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4
Concentrations:
gravimetric: 5.3 mg/L air
chemical: 5.6 mg/L air
nominal: 6.1 mg/L air
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: Observations for viability were recorded once before exposure on the day of exposure (test day 1), three times during exposure, immediately and 1 h after exposure on test day 1 and twice daily during the observation period. Each animal was examined three times during exposure, immediately and 1 h after exposure on test day 1 and once daily during the observation period. Observations were detailed and carefully recorded using explicitly defined scales as appropriate. Only grossly abnormal signs were detectable during exposure as the animals were restrained in the exposure tubes. The body weight of each animal was recorded on test days 1 (before exposure), 2, 4, 8 and 15 (before necropsy).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.6 mg/L air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
none
Clinical signs:
other: (See Individual Tables in attachement) Salivation was observed during and immediately after exposure in all animals. Decreased activity, hunched posture, bradypnea and ruffled fur were recorded in all animals after the end of exposure on day 1. Ruffled f
Body weight:
(See Individual Tables in attachement).

From test day 1 to test day 2, slight body weight loss was noted in all animals. Thereafter normal body weight development was recorded.
Gross pathology:
(See Individual Tables in attachement).

There were no macroscopic findings.
Other findings:
none

    Test Atmosphere Conditions

Temperature, relative humidity and oxygen concentration during exposure were considered to be satisfactory for this type of study.

 

Data on temperature, relative humidity and oxygen concentration are presented in the following table:

 

Recording Time

[hours:min]

O2Concentration

[Vol %]

Temperature

[°C]

Relative Humidity

[% RH]

07:30

20.3

22.7

7.6

08:00

20.4

22.8

5.8

08:30

20.4

22.9

2.3

09:00

20.4

22.9

2.2

09:30

20.4

22.8

2.2

10:00

20.3

22.8

4.1

10:30

20.4

22.8

2.4

11:00

20.4

22.8

2.4

11:30

20.4

22.8

2.2

Mean

20.4

22.8

3.5

St. Dev.

0.0

0.0

2.0

N

9

9

9

 

 

   Determination of Nominal Aerosol Concentration

The nominal aerosol concentration was 6.1 mg/L air.

 

 

  Gravimetric Determination of Aerosol Concentrations

The mean gravimetric aerosol concentration determined was 5.3 mg/L air as targeted. The aerosol concentration was stable during the exposure period. Data on gravimetric aerosol concentrations are presented in the following table:

 

Sampling Time

[hours:min]

Sampling Volume

[L]

Amount of Test Item on the Filter

[mg]

Gravimetric Aerosol Concentration

[mg/L air]

8:00 – 08:04

4.0

20.847

5.5

9:00 – 09:03

3.0

14.620

5.1

10:00 – 10:03

3.0

14.978

5.2

11:00 – 11:03

3.0

15.404

5.4

Mean

 

 

5.3

St. Dev.

 

 

0.2

N

 

 

4

 

  Chemical Determination of Aerosol Concentrations

The mean chemical aerosol concentration determined was 5.6 mg/L air as targeted. The aerosol concentration was stable during the exposure period. The chemical aerosol concentration compared favourably with the gravimetrically determined concentration. This was in accordance with the high purity of the test item. Details on chemically determined aerosol concentrations are presented in the following table:

Sampling Time

[hours:min]

Sampling Volume

[L]

Amount of Test Item on the Filter

[mg]

Chemical Aerosol Concentration

[mg/L air]

8:00 – 08:04

4.0

22.72

5.9

9:00 – 09:03

3.0

15.04

5.2

10:00 – 10:03

3.0

15.48

5.4

11:00 – 11:03

3.0

16.78

5.9

Mean

 

 

5.6

St. Dev.

 

 

0.3

N

 

 

4

Particle Size Distribution:

The Mass Median Aerodynamic Diameters (MMAD) obtained from three gravimetric measurements of particle size distribution during the exposure were similar (MMAD between 1.98µmand 2.17µm). This led to the conclusion that the particle size of the generated aerosol was stable during the whole exposure period. The MMADs were well within the target range of 1 to 4mm, thus deposition of the particles can be assumed to have occurred in both the upper and the lower respiratory tract. In addition, the Geometric Standard Deviations (GSD) were within the target range of 1.5 to 3. Hence, the particle size distributions obtained were considered to be appropriate for acute inhalation toxicity testing.

 

Data on particle size distribution are presented in the following table:

 

Time

Total Amount Collected
[µg]

Percentages:
Stage No.
Effective Cut-Off Diameter [µm]

MMAD
[µm]

GSD

Corr. Coeff.
(R)

% <
4 µm

1
--

2
4.6

3
3.0

4
2.13

5
1.6

6
1.06

7
0.715

8
0.325

08:01

947

9.3

17.3

17.4

21.1

22.1

10.6

0.1

2.1

1.98

1.96

0.965

85.3%

09:45

954

11.2

18.0

22.3

23.5

16.1

6.8

0.0

2.0

2.17

1.97

0.957

81.6%

11:10

820

11.7

17.4

20.6

24.4

14.8

7.6

0.0

3.5

2.10

2.08

0.952

81.0%

 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In conclusion, the LC50 of di-tert-butyl 3,3,5-trimethylcyclohexylidene diperoxide obtained in this study was estimated to be greater than 5.6 mg/L air (chemically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.


Executive summary:

A group of three male and three female albino rats [RccHanTM:WIST(SPF)] was exposed by nose-only, flow-past inhalation for four hours to the test item at a chemically determined mean concentration of 5.6 mg/L air. All animals were observed for clinical signs and mortality during the inhalation exposure and the subsequent 14-day observation period. Body weights were recorded prior to exposure on test day 1, and during the observation period on test days 2, 4, 8 and 15 before necropsy. On test day 15 all animals were sacrificed and necropsied. The ranges of aerosol concentration, temperature, relative humidity, oxygen content and airflow rate measured during the exposure were considered to be satisfactory for a study of this type. In addition, the test item was considered to be respirable to rats. All animals survived the scheduled observation period. Salivation was observed during exposure in all animals. Decreased activity, hunched posture, bradypnea, ruffled fur and salivation were recorded in all animals after exposure. There were no clinical signs from day 3 onwards. There were no effects on body weight that were considered to be related to treatment with the test item. There were no macroscopic findings in any animal.

In conclusion, the LC50 of di-tert-butyl 3,3,5-trimethylcyclohexylidene diperoxide obtained in this study was estimated to be greater than 5.6 mg/L air (chemically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
5 600 mg/m³
Quality of whole database:
The key study is reliable without restrictions.

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08-Dec to 31-Dec 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
other: Standard acute dermal method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
Animals: Rat, RccHanTM: WIST(SPF)
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Harlan Laboratories B.V. / Kreuzelweg 53 / 5961 NM Horst / The Netherlands
Number of Animals per Group: 5 males and 5 females
Age at Treatment: Males: 8 weeks / Females: 12 weeks
Body Weight Range at Treatment: 227.2 g – 249.8 g (males) / 208.1 g – 211.2 g (females)
Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70% (values above 70% during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The test item was applied undiluted as delivered from the Sponsor. The doses were calculated based upon the rats’ body weight.

One day before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10% of the total body surface. Only those animals without injury or irritation on the skin were used in the test.

On test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

Application volume/kg body weight: 2 mL

Twenty-four hours after the application the dressing was removed and the skin was flushed with lukewarm tap water and drapped off with disposable paper towels. Thereafter, the reaction sites were assessed.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5 males / 5 females
Control animals:
not required
Details on study design:
Five male and five female RccHan:WIST (SPF) rats were treated with di-tert-butyl-3,3,5-trimethylcyclohexylidene diperoxide (CAS# 6731-36-8) at 2000 mg/kg by dermal application. The test item was applied undiluted as delivered from the Sponsor at a volume dosage of 2 mL/kg. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2 - 15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded within the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2 - 15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied andexamined macroscopically.
Statistics:
No statistical analysis was used.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were evident during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
Dermal sores were noted on the skin of two males and one female.
Other findings:
Generalized erythema, slight in degree, was noted in four males and one female after removal of the semi-occlusive bandage 24 hours afteradministration. This finding was reversible by the following observation. In two additional females, slight erythema was noted from day 4 - 7 of observation and on days 2 - 8 of observation, respectively.

Dermal sores, slight to moderate in degree, were noted in three males (days 10 - 13, days 6 - 15 and days 9 - 15) and in one female (days 9 - 15). Desquamation (slight to moderate) was noted in four males, beginning on day 5 of observation and persisting until the end of the observation period. Desquamation was also seen in three females. In two females, this was already evident on days 3 or 5 of observation and persisted until the end of the observation period, whereas one female showed slight desquamation on day 7 of observation only.

Please see attachment "Local Dermal Signs"

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The median lethal dose of di-tert-butyl-3,3,5-trimethylcyclohexylidene diperoxide (CAS# 6731-36-8) after single dermal administration to rats of both sexes (LD 50), observed over a period of 14 days, is greater than 2000 mg/kg body weight.
Executive summary:

Five male and five female RccHan:WIST (SPF) rats were treated withdi-tert-butyl-3,3,5-trimethylcyclo hexylidene diperoxide (CAS# 6731-36-8)at 2000 mg/kg by dermal application. The test item was applied undiluted as delivered from the Sponsor at a volume dosage of 2 mL/kg. The application period was 24 hours. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs withinthe first 30 minutesand at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2 - 15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded withinthe first 30 minutesand at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2 - 15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

 

No deaths occurred during the study. No clinical signs were evident during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age.

 

Local effects included slight generalized erythema in four males and one female after removal of the semi-occlusive bandage 24 hours after administration. This finding was reversible by the following observation. In two additional females, slight erythema was noted from day 4 - 7 of observation and on days 2-8 of observation, respectively.

Dermal sores were noted in three males (days 10 - 13, days 5 - 15 and days 9 - 15) and in one female (days 9 - 15). Desquamation was noted in four males from day 4 of observation and persisting until the end of the observation period. Desquamation was also seen in three females. In two females, this was already evident on days 3 or 5 of observation and persisted until the end of the observation period, whereas one female showed slight desquamation on day 7 of observation only.

 

At necropsy, dermal sores were noted on the skin of two males and one female.

The median lethal dose of di-tert-butyl-3,3,5-trimethylcyclohexylidene diperoxide (CAS# 6731-36-8) after single dermal administration to rats of both sexes (LD 50), observed over a period of 14 days, is greater than 2000 mg/kg body weight.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
The key study is reliable without restrictions.

Additional information

The oral LD50for BPTC under the conditions of this study is estimated to be higher than 2000 mg/kg in female and male rats.

The LC50 of di-tert-butyl 3,3,5-trimethylcyclohexylidene diperoxide obtained in this study was estimated to be greater than 5.6 mg/L air (chemically determined mean aerosol concentration). There was no indication of relevant sex-related differences in toxicity of the test item.

The median lethal dose of di-tert-butyl-3,3,5-trimethylcyclohexylidene diperoxide (CAS# 6731-36-8) after single dermal administration to rats of both sexes (LD 50), observed over a period of 14 days, is greater than 2000 mg/kg body weight.

Justification for selection of acute toxicity – oral endpoint

Well documented study according to OECD 401 and Japanese "Chemical Substance GLP".

Justification for selection of acute toxicity – inhalation endpoint

Apparently well conducted GLP study.

Justification for selection of acute toxicity – dermal endpoint

Apparently well conducted GLP study.

Justification for classification or non-classification

All key acute toxicity values are above minimum classification criteria.