5-[(4-carboxybutanoyl)peroxy]-5-oxopentanoic acid

Endpoint summary

Description of key information

The LD50 value for acute oral toxicity of the test item in Wistar rats was established to be 1276 mg/kg bw.

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:

1998

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Hanlbm: WIST (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wblferstrasse 4, CH-4414 Fullinsdorf / Switzerland
- Age at study initiation: Males: 8 weeks; Females: 10 weeks
- Weight at study initiation: Males: 184 - 193 g, Females: 165 - 185 g
- Fasting period before study: overnight fasting period prior to intubation
- Housing: Groups of three in Makrolon type-4 cages with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet: Pelleted standard Kliba 3433, batch no. 25/98 rat maintenance diet (Kliba Mühlen AG, CH-4303 Kaiseraugust) available ad libitum.
- Water: Community tap water from Fiillinsdorf, available ad libitum.
- Acclimation period: One week under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24 °C
- Humidity (%): humidity between 43-82 %
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour artificial fluorescent light, 12-hour dark cycle
- Music was played during the light period

IN-LIFE DATES:
Acclimatization: 04- AUG-1998 to 10-AUG-1998 (2000 mg/kg; males) 19-AUG-1998 to 25-AUG-1998 (2000 mg/kg; females) 01-SEP-1998 to 07-SEP-1998 (200 mg/kg; females)
Treatment: 11-AUG-1998 (2000 mg/kg; males) 26-AUG-1998 (2000 mg/kg; females) 08-SEP-1998 (200 mg/kg; females)
Observation: 11-AUG-1998 to 25-AUG-1998 (2000 mg/kg; males) 26-AUG-1998 to 27-AUG-1998 (2000 mg/kg; females) 08-SEP-1998 to 22-SEP-1998 (200 mg/kg; females)
Termination Report: 25-AUG-1998 (2000 mg/kg; males) 22-SEP-1998 (200 mg/kg; females)

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

PEG 400

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg body weight
- Justification for choice of vehicle: Stable and homogeneous in PEG 400 for at least 2 hours (was determined at RCC Umweltchemie AG under non-GLP RCC project no. 690208).
- Lot/batch no.: not specified
- Purity: not specified

MAXIMUM DOSE VOLUME APPLIED:
2000 mg/kg body weight

DOSAGE PREPARATION
The test article was placed into a glass beaker on a tared Mettler PM 460 balance and the vehicle (PEG 400) was added. A weight by volume dilution was prepared using a magnetic stirrer as homogenizer. Homogeneity of the test article in the vehicle was maintained during treatment. The preparation was made shortly before dosing.

CLASS METHOD
- Rationale for the selection of the starting dose: Oral administration was used as this is one possible route of human exposure during manufacture, handling and use of the test article. The top-down approach was assessed based on information of the sponsor.

Doses:

200 and 2000 mg/kg body weight

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: The animals were examined for clinical signs four times during test day 1 and once daily during test days 2-15. Mortality/viability were recorded together with clinical signs at the same time intervals. Body weights were recorded on day 1 prior to administration and on days 8 and 15.
- Necropsy of survivors performed: yes

Statistics:

The LOGJT-Model (COX, Analysis of Binary Data, London 1977) was used to calculate the median lethal dose. The 90 %, 95 % and 99 % confidence limits for the toxicity value and the slope of the dose response line were calculated.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 200 - < 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 276 mg/kg bw

Based on:

test mat.

Mortality:

The following animals were treated and percentage mortality was observed:
Females: Group 1 (200 mg/kg) 0 %
Females: Group 3 (2000 mg/kg) 100% (one female was found dead after 2h, two females after day 2)
Males: Group 2 (2000 mg/kg) 33% (one male was found dead after day 3)

Clinical signs:

The following clinical signs were observed:
Group 1 ( 200 mg/kg; females) no clinical signs noted (3)*
Group 2 (2000 mg/kg; males) sedation (3), hunched posture (3), dyspnea (3), ruffled fur (3), cyanosis (1), poor condition (1)
Group 3 (2000 mg/kg; females) ventral recumbency (1), lateral recumbency (1), hunched posture (2), uncoordinated movements (2), dyspnea (2), labored respiration (3), ruffled fur (2), poor condition (2), rolling spasms (1)
* () = number of male or female animals affected, respectively.

Body weight:

The body weight of the surviving animals was within the range commonly recorded for animals of this strain and age.
Females mean: 213g; Males mean: 267g

Gross pathology:

The following macroscopic findings were observed at necropsy:
Group 1 ( 200 mg/kg; females): Scheduled necropsy: no findings noted (3)*
Group 2 (2000 mg/kg; males): Scheduled necropsy: no findings noted (2)
Spontaneous death: gray-white discoloration in the lungs, stomach distended with gas and hemorrhagic fluid content in the abdominal cavity (1)
Group 3 (2000 mg/kg; females): Spontaneous death: greenish foci on both sides of the lungs, black-brown isolated crateri-form retractions in the gray-white distended stomach, gray-white duodenum distended with ingesta, gray-white liquid content in the jejunum and ileum, violet caecum reduced in size, dark-red foci in the liver, yellowish foci on the left side of the kidneys (1), greenish foci in the lungs, black-brown foci in the gray-white distended stomach, pale liquid contents in the duodenum, yellowish liquid contents in the jejunum, greenish caecum reduced in size (1), greenish foci on both sides of the lungs, gray-white foamy fluid released from bronchi, several black crateri-form retractions in the stomach, gray-white liquid contents and black-brown foci in the duodenum, black-brown foci in the gray-white jejunum distended with ingesta, black-brown foci in the gray-white ileum distended with ingesta, dark-red foci in the liver (1)
* () = number of male or female animals affected, respectively.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Under the conditions of the present study, the LD50 value of the test item in Wistar rats was established to be 1276 mg/kg bw.

Executive summary:

In an acute oral toxicity study according to OECD guideline 423, test item was administered by oral gavage to groups of 3 Wistar rats of each sex at 2000 mg/kg body weight and 3 females at 200 mg/kg bw. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). At 2000 mg/kg bw, all females and 1 of 3 males dies. At 200 mg/kg bw no mortality was observed. Sedation, hunched posture, dyspnea, ruffled fur, cyanosis and poor condition were observed in the male animals of the 2000 mg/kg dose group. Ventral and lateral recumbency, hunched posture, uncoordinated movements, dyspnea, labored respiration, ruffled fur, poor condition and rolling spasms were observed in the females of the 2000 mg/kg dose group. No clinical signs were observed in the female animals of the 200 mg/kg dose group during the observation period. The body weight of the surviving animals was within the range commonly recorded for animals of this strain and age. Gray-white discoloration in the lungs, stomach distended with gas and hemorrhagic fluid content in the abdominal cavity were observed in one male animal. Greenish foci on both sides of the lungs and gray-white foamy fluid released from bronchi, several black or black-brown crateri-form retractions in the gray-white distended stomach, gray-white duodenum distended with ingesta, gray-white liquid content and black-brown foci in the jejunum and ileum distended with ingesta, violet or greenish caecum reduced in size, dark-red foci in the liver, yellowish foci on the left side of the kidneys, pale or gray-white liquid contents and/or black-brown foci in the duodenum and yellowish liquid contents in the jejunum were observed in the female animals of the 2000 mg/kg dose group. At scheduled necropsy, no macroscopic findings were observed in two males of the 2000 mg/kg dose group and in all females of the 200 mg/kg dose group. Based on these observations, the median lethal dose (LOGIT-Model) for the acute oral toxicity of the test item in rats of both sexes observed fo a period of 15 days is: LD50 = 1276 mg/kg bw.

he oral LD50 value of the test item in Wistar rats was established to exceed 2000 mg/kg bw. 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 276 mg/kg bw

Quality of whole database:

OECD Guideline study according to GLP

Additional information

OECD 423

In an acute oral toxicity study according to OECD guideline 423, test item was administered by oral gavage to groups of 3 Wistar rats of each sex at 2000 mg/kg body weight and 3 females at 200 mg/kg bw. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (day 15). At 2000 mg/kg bw, all females and 1 of 3 males dies. At 200 mg/kg bw no mortality was observed. Sedation, hunched posture, dyspnea, ruffled fur, cyanosis and poor condition were observed in the male animals of the 2000 mg/kg dose group. Ventral and lateral recumbency, hunched posture, uncoordinated movements, dyspnea, labored respiration, ruffled fur, poor condition and rolling spasms were observed in the females of the 2000 mg/kg dose group. No clinical signs were observed in the female animals of the 200 mg/kg dose group during the observation period. The body weight of the surviving animals was within the range commonly recorded for animals of this strain and age. Gray-white discoloration in the lungs, stomach distended with gas and hemorrhagic fluid content in the abdominal cavity were observed in one male animal. Greenish foci on both sides of the lungs and gray-white foamy fluid released from bronchi, several black or black-brown crateri-form retractions in the gray-white distended stomach, gray-white duodenum distended with ingesta, gray-white liquid content and black-brown foci in the jejunum and ileum distended with ingesta, violet or greenish caecum reduced in size, dark-red foci in the liver, yellowish foci on the left side of the kidneys, pale or gray-white liquid contents and/or black-brown foci in the duodenum and yellowish liquid contents in the jejunum were observed in the female animals of the 2000 mg/kg dose group. At scheduled necropsy, no macroscopic findings were observed in two males of the 2000 mg/kg dose group and in all females of the 200 mg/kg dose group. Based on these observations, the median lethal dose (LOGIT-Model) for the acute oral toxicity of the test item in rats of both sexes observed fo a period of 15 days is: LD50 = 1276 mg/kg bw.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on acute oral toxicity, the test item is classified and labelled as acute oral tox. 4 (H 302: Harmful if swallowed) according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.