Diisopropylbenzene hydroperoxide

Endpoint summary

Description of key information

Acute oral toxicity

DIHP, 81.2% Diisopropylbenzene hydroperoxide in diisoproylbenzene, was tested for acute oral toxicity according to OECD 401 guideline and in compliance with GLP (Murmann, 1994). In a pretest, 2 males and 2 females were treated with 2000 mg/kg body weight by gavage. The results of that stage gave a basis for the final test dose. As there were no deaths, 3 additional individuals of each sex were tested at the same dose as the two of the pretest in order to get a validated Limit test with as little killed animals as possible. Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. Some symptoms, like squatting posture gave indications of pain for the animals. The autopsy at the end of the test revealed however that the corrosive properties of the substance caused an ulceration of the stomach mucous membrane, which resulted in the adhesion of the stomach with the abdomen organs. No mortality was observed throughout the study. The acute oral LD0 of DIHP was found greater than 2000 mg/kg bw (1624 mg/kg bw as diisopropylbenzene hydroperoxide).

Acute dermal toxicity

The acute dermal toxicity of Luperox DH (diisopropylbenzene monohydroperoxide at 55.9% in diisopropylbenzene) was evaluated in rats according to OECD N°402 guideline (Ollivier, 2006). One groups of 5 male and 5 female Sprague Dawley rats was given a single dermal dose of Luperox DH at doses of 2000 mg/kg (equivalent to 1118 mg/kg of diisopropylbenzene monohydroperoxide). Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14). No systemic clinical signs and no deaths were observed during the study. Only dryness of the skin was noted in all animals from day 4 up to day 13. No other cutaneous reactions were recorded during the study. A slightly reduced weight gain was seen in 1/5 males and 2/5 females during the second week of the study. The overall body weight gain of the other animals was similar to that of historical control animals. No apparent abnormalities were observed at necropsy in any animal. The dermal LD0 in rats of the Luperox DH is higher than 2000 mg/kg (equivalent to 1118 mg/kg of diisopropylbenzene monohydroperoxide).

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:

1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The test is comparable to a guideline study, even if there is no certificat of analysis.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: HSD/Win: Wu (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Winkelmann GmbH
- Age at study initiation: no data
- Weight at study initiation: male: 151 to 174 g, female: 128 to 147 g
- Fasting period before study:
- Housing: conventionnal, separated by sex
- Diet (e.g. ad libitum): ad libitum until 16 h before application, 3 h after application, food ad libitum
- Water (e.g. ad libitum):yes
- Acclimation period:at least 5 days

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

IN-LIFE DATES: From: To: 01/08 to 18/08/1994

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.06 cm3 test substance/kg bodyweight

Doses:

2000 mg/Kg bodyweight corresponding to 2.06 cm3/kg body weight

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:
reseach of clinical symptoms: post administration: 1/2 h, 1h, 2h, 3h,4h, 5h and 6h, and every days the wo weeks after
bodyweigth measurement on day 0, 7 and 14
- Necropsy of survivors performed: yes

Preliminary study:

no death

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Remarks:

DIHP

Sex:

male/female

Dose descriptor:

LD0

Effect level:

1 624 mg/kg bw

Based on:

act. ingr.

Remarks:

diisopropylbenzene hydroperoxide

Mortality:

no mortality observed over the test duration

Clinical signs:

other: see table 2. The oral administration of a 2000 mg/kg bw dose of the test substance resulted in clearly toxic effects in the Wistar rats. Some symptoms, like squatting posture gave indications of pain for the animals. The animals were free of symptoms af

Gross pathology:

see table 3
The autopsy at the end of the test revealed however that the corrosive properties of the substance caused an ulceration of the stomach mucous membrane, which resulted in the adhesion of the stomach with the abdomen organs.

Table 1: Lethality and body weight development (Body weight and Limit test)

Male

Dosis (mg/kg body weight)	Animal	Application date	Bodyweight (g)			Mortality
			0	7	14	Time  after treatment	Body weight (g)
2000	1	02/08/1994	153	214	251	-	-
	2	02/08/1994	160	195	235	-	-
	3	04/08/1994	174	210	243	-	-
	4	04/08/1994	169	205	225	-	-
	5	04/08/1994	151	188	222	-	-

 

Female

Dosis (mg/kg body weight)	Animal	Application date	Bodyweight (g)			Mortality
			0	7	14	Time  after treatment	Body weight (g)
2000	1	02/08/1994	133	159	174	-	-
	2	02/08/1994	137	169	188	-	-
	3	04/08/1994	132	161	173	-	-
	4	04/08/1994	147	172	190	-	-
	5	04/08/1994	128	159	166	-	-

 

Table 2: Symptoms. Individuals data

Male (2000 mg/kg bw)

Symptoms	Hours after treatment (h)
	1/2	1	2	3	4	5	6	24	48	72	96
No symptoms	5								2	2	5
Abnormal gait		5	5	5
Squatting posture		5	5	5
Sudation					1	1	1
Motility increase								2
Motility decrease		5	5	5
Stagger		5	5	1	1	1	1
Breath sounds								1	1
Ruffled fur			5	5	5	5	5	5	3
Diarrhea								1	1
Body weight increase inhibition								2

 

Female (2000 mg/kg bw)

Symptoms	Hours after treatment (h)
	1/2	1	2	3	4	5	6	24	48	72	96
No symptoms	5								2	2	5
Abnormal gait		5	5	5		2	2
Squatting posture		5	5	5	2	4	3	1	1	1
Sudation				5	2	2	2
Motility increase								2	2	2
Motility decrease			5	5
Stagger		5	5	5	4	4	3
Ruffled fur			5	5	5	5	5	5	3	3
Hypothermia			5	5	4	4	3
Diarrhea					1	1	1	2	1	2
Body weight increase inhibition								4
Uncontrolled moves				5	2	2	2

Table 3: Observations after end of the observation period

Male (2000 mg/kg bw)

Total count	Autopsy
3 (3,4,5)	Adhesion of the liver with stomach
4 (1,3,4,5)	Adhesion of the stomach with the spleen, cartilaginous-like thickening of the gastric mucous membrane
3 (3,4,5)	Adhesion of the stomach with the peritoneum
1 (2)	cartilaginous-like thickening of the gastric mucous membrane

 

Female (2000 mg/kg bw)

Total count	Autopsy
3 (1,2,3)	Adhesion of the liver with stomach
3 (1,2,3)	Adhesion of the stomach with the spleen
5 (1,2,3,4,5)	cartilaginous-like thickening of the gastric mucous membrane
2(1,2)	Adhesion of the stomach with the peritoneum
1(3)	Adhesion of the stomach with the diaphragm
4(1,3,4,5)	Small intestine reddened

Interpretation of results:

GHS criteria not met

Conclusions:

Diisopropylbenzolhydroperoxid is not classified according to the Annex VI to the Directive 67/548/CEE and the CLP Regulation (1272/2008).

Executive summary:

DIHP, 81.2% Diisopropylbenzene hydroperoxide in diisoproylbenzene, was tested for acute oral toxicity according to OECD 401 guideline and in compliance with GLP. In a pretest, 2 males and 2 females were treated with 2000 mg/kg body weight by gavage. The results of that stage gave a basis for the final test dose. As there were no deaths, 3 additional individuals of each sex were tested at the same dose as the two of the pretest in order to get a validated Limit test with as little killed animals as possible. Examinations for mortality, clinical signs and body weight gain were performed during the 14-day observation period. All surviving animals were necropsied at the end of the observation period. Some symptoms, like squatting posture gave indications of pain for the animals. The autopsy at the end of the test revealed however that the corrosive properties of the substance caused an ulceration of the stomach mucous membrane, which resulted in the adhesion of the stomach with the abdomen organs. No mortality was observed throughout the study.

The acute oral LD0 of DIHP was found greater than 2000 mg/kg bw (1624 mg/kg bw as diisopropylbenzene hydroperoxide).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

1 624 mg/kg bw

Quality of whole database:

Key study, Klimisch 1

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:

experimental study

Adequacy of study:

key study

Study period:

2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
Species, strain: rat, Sprague-Dawley Rj: SD (IOPS Han).
Reason for this choice: rodent species generally accepted by regulatory authorities for this type of study.
Breeder: Janvier, Le Genest-Saint-Isle, France.
Number and sex: one group of ten animals (five males and five females).
Females were nulliparous and non-pregnant.
Age/weight: on the day of treatment, the animals were approximately 8 weeks old and had a mean body weight ± standard deviation of 312 ± 8 g for the males and 219 ± 8 g for the females.
Acclimation: at least 5 days before the beginning of the study.
Identification: individually by earnotches.

Environmental conditions:
The conditions in the animal room were set as follows:
• temperature: 22 ± 2°C
• relative humidity: 30 to 70%
• light/dark cycle: 12 h/12 h
• ventilation: approximately 12 cycles/hour of filtered, non-recycled air.
• food and water ad libitum

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

On the day before treatment, the dorsal area of each animal was clipped (i.e. approximately 5 cm x 7 cm for males and 5 cm x 6 cm for females) using an electric clipper. Only animals with healthy intact skin were used for the study. The test item was applied undiluted at the dose-level of 2000 mg/kg, taking into consideration that its specific gravity was 0.93 g/mL. The volume of administration was therefore 2.15 mL/kg.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw for diisopropylbenzene hydroperoxide in its solvent
1118 mg/kg bw for diisopropylbenzene hydroperoxide

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

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 until day 15.
Type, time of onset and duration of clinical signs were recorded for each animal individually. The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
The body weight gain of the treated animals was compared to that of CIT control animals with a similar initial body weight. On day 15, all animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death.
After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.

Sex:

male/female

Dose descriptor:

LD0

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Remarks:

Luperox DH

Sex:

male/female

Dose descriptor:

LD0

Effect level:

1 118 mg/kg bw

Based on:

act. ingr.

Remarks:

diisopropylbenzene hydroperoxide

Mortality:

No deaths occurred during the study.

Clinical signs:

other: No systemic clinical signs were observed during the study. Only dryness of the skin was noted in all animals from day 4 up to day 13. No other cutaneous reactions were recorded during the study.

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD0 of diisopropylbenzene hydroperoxide is higher than 1118 mg/kg in rats.

Executive summary:

The acute dermal toxicity of Luperox DH (diisopropylbenzene monohydroperoxide at 55.9% in diisopropylbenzene) was evaluated in rats according to OECD N°402 guideline. One groups of 5 male and 5 female Sprague Dawley rats was given a single dermal dose of Luperox DH at doses of 2000 mg/kg (equivalent to 1118 mg/kg of diisopropylbenzene monohydroperoxide). Following treatment, rats were observed daily and weighted weekly. A gross necropsy examination was performed at the time of scheduled euthanasia (Day 14).

No systemic clinical signs and no deaths were observed during the study. Only dryness of the skin was noted in all animals from day 4 up to day 13. No other cutaneous reactions were recorded during the study. A slightly reduced weight gain was seen in 1/5 males and 2/5 females during the second week of the study. The overall body weight gain of the other animals was similar to that of historical control animals. No apparent abnormalities were observed at necropsy in any animal.

Under these experimental conditions, the dermal LD0 in rats of the Luperox DH is higher than 2000 mg/kg (equivalent to 1118 mg/kg of diisopropylbenzene monohydroperoxide).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

1 118 mg/kg bw

Quality of whole database:

Klimisch 1 study.

Justification for classification or non-classification

The registered substance is not classified for acute and dermal toxicity according to the CLP Regulation (1272/2008).

For acute inhalation toxicity, a LC50 of 5.59 mg/l is reported, although the source is not reliable. Most of the hydroperoxydes are classified for acute inhalation toxicity (Cat 3 or 4), especially cumen hydroperoxide (CAS 80 -15 -9) which is classified Cat 3 (peroxide content around 90 %). Cumen hydroperoxide is heavier than diisopropylbenze hydroperoxide, and it is produced in a solvent (diisopropylbenzene) which is smaller and more volatile than itself. Other impurities are present in a large extent and the reported vapour pressure (6.7 hPa at 25 °C) is more likely related to diisopropylbenzene and impurities than to the hydroperoxide.

In conclusion a classification for diisopropylbenzen hydroperoxide in Cat 4 seems sufficient, regarding its corrosivity, its structure, its volatility, and other hydroperoxide data.