Diallyl 2,2'-oxydiethyl dicarbonate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1980-12-30 to 1981-03-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

see below "Principles of method if other than guideline"

Principles of method if other than guideline:

No environmental conditions are reported.

GLP compliance:

yes (incl. QA statement)

Test type:

other: The study was performed prior to the adoption of the OECD Test Guideline 401

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diallyl 2,2'-oxydiethyl dicarbonate

EC Number:

205-528-7

EC Name:

Diallyl 2,2'-oxydiethyl dicarbonate

Cas Number:

142-22-3

Molecular formula:

C12H18O7

IUPAC Name:

3-({[2-(2-{[(prop-2-en-1-yloxy)carbonyl]oxy}ethoxy)ethoxy]carbonyl}oxy)prop-1-ene

Details on test material:

- Name of test material (as cited in study report): CR-39 (479-768)
- Substance type: organic
- Physical state: liquid
- Analytical purity: 100%
- Impurities (identity and concentrations): data not available
- Composition of test material, percentage of components: data not available
- Isomers composition: data not available
- Purity test date: data not available
- Lot/batch No.: 1979-12-12
- Expiration date of the lot/batch: data not available
- Radiochemical purity (if radiolabelling): not applicable
- Specific activity (if radiolabelling): not applicable
- Locations of the label (if radiolabelling): not applicable
- Expiration date of radiochemical substance (if radiolabelling): not applicable
- Stability under test conditions: A test material stability statement was provided by the sponsor.
- Storage condition of test material: at room temperature in a locked test compound cabinet.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan.
- Age at study initiation: Young adult rats
- Weight at study initiation: ranged from 174 to 251 grams.
- Fasting period before study: 24 hours
- Housing: individually in wire-bottomed cages suspended above the droppings.
- Diet (e.g. ad libitum): Purina Certified Rodent Chow, 5002 was offered ad libitum, except during the 24 hour period immediately prior and 1 hour after to oral intubation when food was withheld.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The rats were quarantined and acclimated to laboratory conditions for 7 to 13 days prior to initiation of the study. Animals were observed twice daily during the quarantine period.

ENVIRONMENTAL CONDITIONS
data not available

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.75%, 3.00%, 4,50% and 6.00%
- Amount of vehicle (if gavage): 1,33 mL/kg bw
- Justification for choice of vehicle: corn oil is a suitable vehicle for carbonic acid, oxydiethylene diallyl ester
- Lot/batch no. (if required): data not available
- Purity: data not available


MAXIMUM DOSE VOLUME APPLIED: not reported


DOSAGE PREPARATION (if unusual): Initially this study utilized two dose levels of 100 mg/kg and 800 mg/kg with ten rats (5 males and 5 females) per dose level. As mortality occurred at the 800 mg/kg dose level the sponsor was contacted and requested that two additional dose levels of 400 and 600 mg/kg with ten rats (5 males and 5 females) each be dosed.
Individual dose amounts were calculated by using fasted body weights (Day 0, Mean: Males = 211.25, Females = 167.75) taken prior to dosing. The test material vehicle solution was measured in a plastic disposable syringe and administered directly into the rat's stomach using a rubber catheter and tubing adapter.

Doses:

100, 400, 600 and 800 mg/kg bw

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: at frequent intervals during the day of dosing and at least twice daily thereafter for a total of 14 days. Animals were weighed the day before dosing, the day of dosing, and 7 and 13 days following dosing.
- Necropsy of survivors performed: yes (as well as in animals found dead). Gross necropsy was performed on the visceral and thoracic cavities.
- Other examinations performed: All animals were observed closely for gross signs of systemic toxicity and mortality. Room conditions, as well as availability of adequate food and water, were checked and any noteworthy conditions recorded.

Statistics:

Calculation of LD50
The WIL computer program based on the techniques of Litchfield and Wilcoxon would have been used to calculate the LD50 when mortality occurred.
Litchfield, J. J. and F. Wilcoxon, "A Simplified Method of Evaluation of Dose-Effect Experiments", J. Pharm. and Exp. Ther., 99-113 (1949).

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

416 mg/kg bw

95% CL:

342 - 506

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

> 400 - < 600 mg/kg bw

Effect levels 3

Sex:

male/female

Dose descriptor:

LD50

Effect level:

515 mg/kg bw

95% CL:

435 - 611

Mortality:

Mortalities are presented in Table 1 in "Any other information on results incl. tables". At the 800 mg/kg bw dose level deaths occurred on day 0, the day of dosing (all females) and on day 1, 2 and 3 (all males). Clinical signs persisted for the survivors (days 1-3) until all were dead. At the 600 mg/kg dose level deaths occurred on day 0 (3 females) and on day 1 (2 females, 1 male). At the 400 mg/kg dose level deaths occurred on day 1 (1 female) and day 2 (female). No males died in the 400 mg/kg - dose group. No deaths occurred at the 100 mg/kg bw dose level.

Clinical signs:

other: All animals exhibited signs of systemic toxicity which were first observed 1 minute after dosing. At the 800 mg/kg dose level clinical signs consisted of inactivity, lethargy, bodies cool to touch, ataxia, glassy eyes, lacrimation, eyes half shut, salivat

Gross pathology:

Examination of the thoracic and visceral cavities of animals at necropsy by the pathologist revealed:
Dose Level: - 100 mg/kg bw: No significant gross pathologic findings (all animals).
- 400 mg/kg bw: No significant gross pathologic findings: Congestion of the gastric mucosa, healed gastric perforation with a chronic,
organized peritonitis.
- 600 mg/kg bw: Localized thickened area in the forestomaeh (in two females). No significant gross pathologic findings (all others).
- 800 mg/kg bw: Generalized visceral congestion, hemorrhage of the hind stomach and duodedum, mottled liver, stomach mottled dark
red.

Other findings:

data not available

Any other information on results incl. tables

Table 1: Mortality

Dose Group (mg/kg bw)	Sex	Total Died/Tested
100	M F	0/5 0/5
400	M F	0/5 2/5
600	M F	1/5 5/5
800	M F	5/5 5/5

Table 2: Body weight - summary of means (g)

Dose Group (mg/kg bw)	Males				Females
	100	400*	600	800	100	400*	600	800
Day -1	238.0	215.0	222.6	238.8	179.6	181.6	178.2	178.8
Day 0	220.8	198.6	202.8	222.8	171.6	167.0	166.6	165.8
Day 7	251.6	213.2	208.5	-	182.4	178.3	-	-
Day 13	264.8	233.4	244.5	-	186.8	191.7	-	-
Day 14	-	-	197.0	214.8	-	161.0	163.4	162.4

* Group (400 mg/kg bw) body weights taken on day 6

Applicant's summary and conclusion

Interpretation of results:

other: Acute tox 4 based on EU GHS criteria

Conclusions:

The LD50 for CR-39 was calculated to be 416 mg/kg for males (95% confidence limits 342-506) and a slope of 1.17, and greater than 400 mg/kg and less than 600 mg/kg for females and 515 mg/kg for both sexes (95% confidence limits 435-611) and a slope of 1.31 (95% confidence limits 1.22 - 1.40).

Executive summary:

When CR-39 (479-768) was administered orally at four dose levels of 100, 400, 600, 800 mg/kg bw to 10 rats (5 males and 5 females) each, signs of systemic toxicity occurred at all dose levels increasing in incidence and severity with dose level.

Clinical signs ranged from lacrimation, salivation, loose feces and excreta stains to inactivity, lethargy, ataxia, bodies cool to touch, prostration, clonic convulsions and death. Mortality occurred at the 400 mg/kg bw dose level (2/10), 600 mg/kg bw dose level (6/10) and at the 800 mg/kg bw dose level (10/10). Positive gross pathologic findings were observed at the 400 mg/kg bw dose level (congestion of gastric mucosa or gastric healed perforation with chronic organized peritonitis), at the 600 mg/kg bw dose level (localized thickened area in the forestomaeh) and at the 800 mg/kg bw dose level (generalized visceral congestion, hemorrhage of hindstomach and/or mottled liver, or stomach mottled dark red).

From the data presented the LD50 of CR-39 (479-768) was determined to be 515 mg/kg for both sexes.