2-Propenoic acid, 1,1'-[7,13-dimethyl-10-(3-methyl-11-oxo-2,4,7,10-tetraoxatridec-12-en-1-yl)-10-[[2-[(9-oxo-9H-thioxanthen-2-yl)oxy]acetyl]amino]-3,6,8,12,14,17-hexaoxanonadecane-1,19-diyl] ester

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Between February the 12th 2002 and March 15th 2002

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles, possibly with incomplete or methodological deficiencies, which do not affect the quality of relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2002

Report date:

2002

Materials and methods

Test guideline

Qualifier:

no guideline followed

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

86273-46-3

Cas Number:

86273-46-3

IUPAC Name:

86273-46-3

Constituent 2

Reference substance name:

-

EC Number:

451-690-9

EC Name:

-

Constituent 3

Reference substance name:

2-Propenoic acid, 2-[2-(ethenyloxy)ethoxy]ethyl ester

IUPAC Name:

2-Propenoic acid, 2-[2-(ethenyloxy)ethoxy]ethyl ester

Details on test material:

- Name of test material (as cited in study report): HBM-AV
- Substance type: Colourless transparent liquid
- Physical state: liquid
- Analytical purity: 99.7%
- Impurities (identity and concentrations): see section 1.2
- Composition of test material, percentage of components: see section 1.2
- Lot/batch No.: FX-IT30-AV
- Expiration date of batch number: 30th June 2002
- Storage condition of test material: Cold storage and protected from light

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc, Atsugi Breeding centre, 795 Shimofurusawa, Atsugi-shi, Kanagawa, Japan
- Age at study initiation: 6 weeks
- Weight at study initiation:
Male: 204g to 228g
Female: 141 to 166g
- Fasting period before study:
- Housing: Animals were housed individually in stainless steel bracket cages for rats (260W x 380D x 180Hmm)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: acclimitised for 7 days prior to experiments


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 deg C
- Humidity (%): 50 +/- 20%
- Air changes (per hr): 10 or more per hour
- Photoperiod (hrs dark / hrs light): 12 hours light followed by 12 hours of darkness.


IN-LIFE DATES: From: Day 1 Up to: Day 15

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: not stated
- Amount of vehicle (if gavage):
- Justification for choice of vehicle: not stated
- Lot/batch no. (if required): V9K2502
- Purity: not stated


MAXIMUM DOSE VOLUME APPLIED:
10 mL/kg suspensions

DOSAGE PREPARATION (if unusual):


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:

Doses:

1024, 1280, 1600, 2000 and 2500 mg/kg suspensions

No. of animals per sex per dose:

1024 mg/kg Male: 5 Female: 5
1280 mg/kg Male: 5 Female: 5
1600 mg/kg Male: 5 Female: 5
2000 mg/kg Male: 5 Female: 5
2500 mg/kg Male: 5 Female: 5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: days 1, 2, 3, 4, 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs at 30 minutes, 1, 3, 6 hours and then daily up to day 15.

Statistics:

Mean values and standard deviations of body weights obtained in this study were calculated for each group. The LD50 and 95% confidence limit for each group were calculated by Probit method.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

LD50

Effect level:

1 790 mg/kg bw

95% CL:

>= 1 494 - <= 2 160

Effect levels 2

Sex:

male

Dose descriptor:

LD50

Effect level:

2 026 mg/kg bw

95% CL:

>= 1 725 - <= 2 614

Mortality:

All of the deaths were observed on day 2. Deaths occurred in 1 male and 2 females at 1600 mg/kg, 1 male an 3 females at 2000 mg/kg and all males and females at 2500 mg/kg. Meanwhile, no death occurred in the 1024 and 1280 mg/kg group.
The Ld50 values were calculated by Probit method. As a result, the LD50 of HBM-AV values were 2026 mg/kg (95% confidence limit: 1725-2614 mg/kg) for males and 1790 mg/kg (95% confidence limit: 1494-2160 mg/kg) for females.

Clinical signs:

other: In the 1024 mg/kg group, no abnormal findings were noted through the observation period in both males and females. In the 1280 mg/kg group, at 3-6 hours after administration, decreased locomotor activity was observed in 3 males and 3 females. In the 1600

Gross pathology:

In all animals that died, stomach distension and dark redness of glandular stomach were observed, but in the animals that survived, no special changes were noted in males and females in any groups.

Other findings:

not reported

Any other information on results incl. tables

Discussion:

HBM-AV was administered by gavage to SD [Crj:CD(SD)] rats (five rats of each sex group) at doses of 1024, 1280, 1600, 2000 and 2,500 mg/kg. After administration, observations were performed for 15 days (including the day of treatment) and the potential acute toxicity and the LD₅₀ of HBM-AV were studied.

All of the deaths in any groups were observed on day 2. Deaths occurred in 1 males and 2 females at 1600 mg/kg, 1 male and 3 females at 2000 mg/kg and all males and females at 2500 mg/kg. Meanwhile, no death occurred in the 1024 and 1280 mg/kg group.

The LD50 values were calculated by Probit method. As a result, the LD50 values of HBM-AV were 2026 mg/kg (95% confidence limit: 1725 -2614 mg/kg) for males and 1790 mg/kg (95% confidence limit: 1494 -2160 mg/kg) for females.

At clinical signs, in 1280 mg/kg or higher groups decreased locomotor activity and abnormal gait were observed in both males and females at 3 -6 hours after administration. In 2000 mg/kg or higher groups, prone position, panting, sedation and hypothermia were observed in either males or females at 6 hours, and in severe cases of these symptoms, animals resulted in death. But in the surviving animals., these symptoms disappeared quickly. These symptoms were considered to be caused by administration of the test substance. Meanwhile in the 1024 mg/kg group, no abnormal findings were noted through the observation period in both males and females.

The body weights of all surviving animals in each group increased satisfactorily throughout the observation period.

At necropsy, in all animals that died, stomach distension and dark redness of glandular stomach considered congestion/hemorrhage were observed. But in the animals that survived, no special changes were noted in both males and females in any groups.

Based on the above results, the LD₅₀ of HBM-AV was estimated to be 2026 mg/kg for males and 1790 mg/kg for females under the conditions of the study.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the results as detailed in the discussion above, the LD50 of HBM-AV was estimated to be 2026mg/kg for males and 1790 mg/kg for females under the conditions of the study. The substance VEEA can be classified as Acute Tox 4.

Executive summary:

HBM-AV was administered by gavage to SD [Crj:CD(SD)] rats (five rats of each sex/group) at doses of 1024, 1280, 1600, 2000 and 2500 mg/kg. After administration, observations were performed for 15 days (including the day of treatment) and the potential acute toxicity and the LD₅₀ of HBM-AV were studied.

All of the deaths were observed on day 2 after administration. Deaths occurred in 1 male and 2 females at 1600 mg/kg, 1 male and 3 females at 2000 mg/kg. Meanwhile, no death occurred in the 1024 nor the 1280 mg/kg group.

Based on the results of the test VEEA is classified as harmful according to the EU classification and labelling system..

At clinical signs, in 1280 mg/kg or higher groups decreased locomotor activity and abnormal gait were observed in both males and females at 3 - 6 hours after administration. In 2000 mg/kg or higher groups, prone position, panting sedation and hypothermia were observed in either males or females. Meanwhile, in the 1024 mg/kg group, no adnormal findings were noted through the obsevration period.

The body weights of all survivng animals in each group increased satisfactorily throughout the observation period.

At necropsy, in all animals that died, stomach distention and dark redness of glandular stomach were observed. But in the animals that survived, no special changes were noted in both males and females in any groups.

Based on the above results, the LD50 of HBM-AV was estimated to be 2026mg/kg for males and 1790 mg/kg for females under the conditions of the study.

The substance VEEA can be classified as R22 harmful according to the EU labelling and classification guidelines.