Butyl 4,4-bis(tert-butyldioxy)valerate

Endpoint summary

Description of key information

Acute oral toxicity

The potential acute toxicity of4,4-bis(tert-butyldioxy)valerate(Luperox 230) was evaluated following asingle oral administration (gavage) to rats (Gerbeix, 2016). The study was conducted in compliance with the OECD guideline No. 423 and the principles of Good Laboratory Practice. The test item was administered once by oral route (gavage) to two groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil. Based on available test item toxicity data, the starting dose-level of 2000 mg/kg was chosen. After the first assay, as no toxicity was observed, the results were confirmed in other females. Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on Day 1 and then on Days 8 and 15.On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. Macroscopic lesions preserved in 10% buffered formalin were destroyed at the finalization of the study report.

No unscheduled deaths occurred during the study. At 2000 mg/kg, hunched posture together with dyspnea were observed on Day 1, 1 to 3 hours and 4 hours after treatment in 1/6 females. Hunched posture persisted from Day 2 to Day 6 in this animal. No clinical signs were noted in the other 5/6 females treated at the same dose-level. No relevant differences from historical control data were noted in the body weight and body weight change of test item-treated animals over the study period. There were no macroscopic findings related to treatment in the study. Under the experimental conditions of this study, the oral LD0 of 4,4-bis(tert-butyldioxy)valerate (Luperox 230) was higher than 2000 mg/kg in rats.

 

Acute dermal toxicity

The acute dermal toxicity of 4,4-bis(tert-butyldioxy)valerate (LUPEROX 230M50) was evaluated in rats according to OECD guideline No. 402 and the principles of Good Laboratory Practice Regulations (Manciaux, 2001). The test substance was applied at the dose-levels of 2000 mg/kg and 4000 mg/kg (as LUPEROX 230M50) to the skin of groups of ten Sprague-Dawley rats (five males and five females each). The application was performed with the undiluted test substance, taking into consideration that its specific gravity was 0.84 g/ml. The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test substance. All animals were subjected to necropsy.

No clinical signs and no deaths were observed during the study. No cutaneous reactions were observed. A reduced weight gain or a slight body weight loss was seen in females given 4000 mg/kg. The body weight gain of the other animals was not affected by treatment with the test substance. No apparent abnormalities were observed at necropsy in any animal.

The dermal LD0  of LUPEROX  230M50 is equal to or higher than 4000 mg/kg in rats, which corresponds to a dose-level of 2000 mg/kg of 4,4-bis(tert-butyldioxy)valerate.

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:

05 January 2016 -- 10 February 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Compliant to GLP and testing guidelines; adequate consistence between data, comments and conclusions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (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/Weight: on the day of treatment, the females were approximately 8 weeks old and had a mean body weight of 216 g (range: 196 g to 226 g).
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: at least 5 days before the beginning of the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: 19 January 2016 to 10 February 2016

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL

- Maximum dose-volume applied: 10 mL/kg

DOSAGE PREPARATION (if unusual): fresh dose formulations were prepared by the CiToxLAB France Pharmacy on the day of each administration and kept at room temperature prior to administration.

CLASS METHOD (if applicable):
- Rationale for the selection of the starting dose: 2000 mg/kg based on available toxicity data before initiation of the study.

Doses:

2000 mg/kg

No. of animals per sex per dose:

six nulliparous and non-pregnant female rats per treatment step

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

> 2 000 other: mg/kg

Based on:

test mat.

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

At 2000 mg/kg, hunched posture together with dyspnea were observed on Day 1, 1 to 3 hours and 4 hours after treatment in 1/6 females. Hunched posture persisted from Day 2 to Day 6. No clinical signs were noted in the other 5/6 females treated at the same dose-level.

Body weight:

No relevant differences from CiToxLAB France historical control data were noted in the body weight and body weight change of test item-treated animals over the study period.

Gross pathology:

There were no macroscopic findings related to treatment with LUPEROX® 230 in the study.

One unilateral renal cyst was noted in one female treated at 2000 mg/kg (group 2).
It was considered to be incidental and not related to treatment, as it is a common background finding for the species.

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

Under the experimental conditions of this study, the oral LD0 of the test item was higher than 2000 mg/kg in rats.

Executive summary:

The potential acute toxicity of Luperox 230 was evaluated following a single oral administration (gavage) to rats. This study was conducted in compliance with the OECD guideline No. 423 and the principles of Good Laboratory Practice. The test item was administered once by oral route (gavage) to two groups of three fasted female Sprague-Dawley rats under a dosage-volume of 10 mL/kg. The test item was prepared in corn oil.

Based on available test item toxicity data, the starting dose-level of 2000 mg/kg was chosen. After the first assay, as no toxicity was observed, the results were confirmed in other females. Each animal was observed at least once a day for mortality and clinical signs for 15 days. Body weight was recorded on Day 1 and then on Days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. Macroscopic lesions preserved in 10% buffered formalin were destroyed at the finalization of the study report.

No unscheduled deaths occurred during the study. At 2000 mg/kg, hunched posture together with dyspnea were observed on Day 1, 1 to 3 hours and 4 hours after treatment in 1/6 females. Hunched posture persisted from Day 2 to Day 6 in this animal. No clinical signs were noted in the other 5/6 females treated at the same dose-level. No relevant differences from CiToxLAB France historical control data were noted in the body weight and body weight change of test item-treated animals over the study period. There were no macroscopic findings related to treatment withLUPEROX 230 in the study.

Under the experimental conditions of this study, the oral LD0 of Luperox 230 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:

Key study

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

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: of 252 ± 10 g for the males and 225 ± 11 g for the female
- Housing: individually in polycarbonate cage
- Diet: A04 C pelleted diet, ad libitum
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 30-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back, approximately 7 cm x 5 cm for males and 6 cm x 5 cm for females
- % coverage: ca. 10
- Type of wrap if used: aerated hypoallergenic dressing

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

Duration of exposure:

24 hours

Doses:

2000 and 4000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not required

Details on study design:

CLINICAL EXAMINATIONS
Morbidity and mortality
Each animal was checked for mortality and morbidity, once a day during the acclimation period, frequently during the hours following administration, then once a day until the end of the observation period, including weekends.

Clinical signs
Each animal was observed after treatment as follows:
at least once during the first 30 minutes, periodically during the first 4 hours, then once a day, at approximately the same time, for the recording of clinical signs.
Any clinical signs observed were recorded individually for each animal, along with the times of onset and recovery.

Body weight
The body weight of each animal was recorded on the day of group allocation then on the day of treatment and on Days 8 and 15.
The body weight gain of the test item-treated animals was compared to that of CiToxLAB France historical control data generated from animals of the same strain and age treated with drinking water treated by reverse osmosis under similar experimental conditions.

PATHOLOGY
Euthanasia
On completion of the observation period, all animals were deeply anesthetized by an intraperitoneal injection of pentobarbital sodium and euthanized by exsanguination.

Macroscopic post-mortem examination
A macroscopic post-mortem examination was performed on all animals. 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. All gross observations were recorded individually for each animal.

Preservation of tissues
For all animals, the macroscopic lesions were preserved in 10% buffered formalin.
Any histological specimens (tissues in fixative) were destroyed at the finalization of the study report.

Microscopic examination
No microscopic examination was performed.

Statistics:

None

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 4 000 mg/kg bw

Based on:

test mat.

Remarks on result:

no indication of skin irritation up to the relevant limit dose level

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

act. ingr.

Remarks:

Di-n-butyl-4,4'-Di(tert-butylperoxy)

Mortality:

No unscheduled deaths occurred during the study.

Clinical signs:

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

Body weight:

A reduced weight gain or a slight body weight loss was seen in females given 4000 mg/kg.
The body weight gain of the other treated animals was similar to that of CIT historical control animals

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information

Conclusions:

The derrnal LD0 of LUPEROX 230M50 is equal to or higher than 4000 mg/kg in rats, which corresponds to a dose-level of 2000 mg/kg of Di-n-butyl-4,4'-Di(tert-butylperoxy).

Executive summary:

The  acute  dermal  toxicity  of  LUPEROX 230M50 was evaluated in rats according to OECD guideline No. 402 and the principles of Good Laboratory Practice Regulations. The test substance was applied at the dose-levels of 2000 mg/kg and 4000 mg/kg to the skin of groups of ten Sprague-Dawley rats (five males and five females each). The application was performed  with the undiluted test substance, taking into consideration that its specific gravity was 0.84 g/ml. The test site was then covered by a semi-occlusive dressing for 24 hours. Clinical signs, mortality and body weight gain were checked for a period of 14 days following the single application of the test substance. All animals were subjected to necropsy.

No clinical signs and no deaths were observed during the study. No cutaneous reactions were observed. A reduced weight gain or a slight body weight loss was seen in females given 4000 mg/kg. The body weight gain of the other animals was not affected by treatment with the test substance. No apparent abnormalities were observed at necropsy in any animal.

The dermal LD0  of LUPEROX  230M50 is equal to or higher than  4000 mg/kg in rats, which corresponds to a dose-level of 2000 mg/kg of Di-n-butyl-4,4'-Di(tert-butylperoxy).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

Key study

Justification for classification or non-classification

No classification is warranted for the acute oral and dermal toxicity according to CLP/GHS criteria.