dimethyl 1,2-benzenedicarboxylate;reaction mass of: 1,2-dimethylpropylidene dihydroperoxide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

07 August 2001 - 30 August 2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

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

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

442-480-8

EC Name:

-

Cas Number:

182893-11-4

Molecular formula:

Mixture of C5H12O4 and C10H22O6

IUPAC Name:

reaction mass of 1,2-dimethylpropylidene dihydroperoxide and dimethyl 1,2-benzenedicarboxylate

Details on test material:

Identification: Trigonox R-938
Chemical name: Methylisopropylketonperoxide in dimethylphthalata (DMP)
CASRN: Not asisgned yet
Description: Clear colourless liquid
Batch: VRS01048
Test substance storage: In refrigerator in the dark
Stability under storage conditions: NA
Expiry date: 12 July 2002

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 7-8 weeks
- Weight at study initiation: mean 192g
- Fasting: Food was withheld overnight (for a maximum of 20 hours) prior to dosing until approximately 3-4 hours after administration of the testsubstance
- Housing: Group housing of 3 animals per sex per cage in labelled Macrolon cages (type IV; height 15 cm.) containing purified sawdust as bedding material (SAWI, Jelu Werk, Rosenberg, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (from Altromin (code VRF 1), Lage, Germany). Certificates of analysis were examined and then retained in the NOTOX archives.
- Water (e.g. ad libitum):Free access to tap-water. Certificates of quarterly analysis were examined and then retained in the NOTOX archives.
- Acclimation period: Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 07 August 2001 - 30 August 2001

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED:
2000 mg/kg (1.74 ml/kg) body weight.
200 mg/kg (0.174 ml/kg) body weight.
Dose volume calculated as dose level: density.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: none

Doses:

2000 and 200 mg/kg

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality: Twice daily. The time of death was recorded as precisely as possible. Body weight: Days 1 (pre-administration), 8 and 15 and at death (if found dead after day 1).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs:
At periodic intervals on the day of dosing (day 1) and once daily thereafter, until day 15. The symptoms were graded according to
fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
For females and males given 200 mg/kg no clinical observations were performed on day 13 and 11, respectively. Since sufficient data on clinical observations were available, this protocol deviation was considered not to have affected the study integrity.

Statistics:

No statistical analysis was performed.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 200 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All females given 2000 mg/kg were found dead. The decedents were found on day 1 or 2 posttreatment. No further mortality occurred.

Clinical signs:

other: Lethargy, uncoordinated movements, alopecia, hunched posture and/or piloerection were noted on day 1 among the females given 2000 mg/kg. Piloerection or hunched posture was noted on day 1 among the females given 200 mg/kg and males given 200 mg/kg showed

Gross pathology:

At post mortem examination, dark red discolouration of the medulla of the kidneys was found in one female given 2000 mg/kg. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

The oral LD50 value of MIPKP in Wistar rats was established to be within the range of 200-2000 mg/kg body weight.

Executive summary:

Assessment of acute oral toxicity in the rat (Acute Toxic Class Method). The study was carried out based on the guidelines described in: EC Commission Directive 96/54/EC, Part B.1 tris "Acute Toxicity-Oral, Acute Toxic Class Method" and OECD No.423, "Acute Oral Toxicity - Acute Toxic Class Method".

Initially, the test substance was administered by oral gavage to three female Wistar rats at 2000 mg/kg body weight. In a stepwise procedure additional groups of animals were dosed at 200 (females) and 200 (males) mg/kg body weight. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (day 15).

All females given 2000 mg/kg were found dead, on day 1 or 2 post-treatment. No further mortality occurred. Lethargy, uncoordinated movements, alopecia, hunched posture and/or piloerection were noted on day 1 among the females given 2000 mg/kg. Piloerection or hunched posture was noted on day 1 among the females given 200 mg/kg and males given 200 mg/kg showed lethargy on day 1.

The mean body weight gain shown by the surviving animals over the study period was considered to be normal. At post mortem examination, dark red discolouration of the medulla of the kidneys was found in one female given 2000 mg/kg. Macroscopic post mortem examination of the other animals that died during the study and of the surviving animals at termination did not reveal any abnormalities.

The oral LD50 value MIKP in Wistar rats was established to be within the range of 200-2000 mg/kg body weight.