Diallyl 2,2'-oxydiethyl dicarbonate

Endpoint summary

Description of key information

Acute toxicity: oral: Wil Research Laboratories, Inc. Acute Oral Toxicity Study in Albino Rats with CR-39 (479-768) (1981); GLP; comparable to the OECD Guideline 401.
Acute toxicity: dermal: Wil Research Laboratories, Inc. Acute Dermal Toxicity Study in Albino Rabbits with CR-39 (1981); comparable to the OECD Guideline 402.
Acute toxicity: inhalation: Industrial BIO-TEST Laboratories, Inc. Acute vapor inhalation toxicity study with CR-39, 62310-31-151-1006 in albino rats (1971); comparable to the OECD Guideline 403.

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:

1980-12-30 to 1981-03-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Study

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

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

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).

Sex:

male

Dose descriptor:

LD50

Effect level:

416 mg/kg bw

95% CL:

342 - 506

Sex:

female

Dose descriptor:

LD50

Effect level:

> 400 - < 600 mg/kg bw

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

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

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

515 mg/kg bw

Quality of whole database:

Good quality, guideline studies.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1971-06-28 to 1971-08-16

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: equivalent to guideline study; no GLP study, but acceptable, well-documented study report

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

the study was performed prior to the adoption of the OECD Guideline

Deviations:

yes

Remarks:

see below "Principles of method if other than guideline"

Principles of method if other than guideline:

One concentration level for a one-hour period was tested.

GLP compliance:

no

Test type:

other: Acute Inhalation Toxicity

Limit test:

no

Species:

rat

Strain:

other: Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Concentrations:

The average nominal vapor concentration, calculated by dividing the generator weight loss by the total volume of air used during the test, was 0. 73 mg/L air at 29. 92 inches Hg and 25 °C

No. of animals per sex per dose:

5 males/5 females

Control animals:

no

Sex:

male/female

Dose descriptor:

other: average nominal vapor concentration

Effect level:

0.73 mg/L air (nominal)

Exp. duration:

1 h

Remarks on result:

other: No deaths and no treatment realted effects

No deaths or untoward behavioral reactions were noted during the exposure period. The 14-day observation period was uneventful.

The average 14-day body weight gain was 48 grams which is within normal limits.

Necropsy did not reveal any gross pathologic alterations which could be attributed to inhalation of test material vapors.

Interpretation of results:

other: EU GHS criteria not met

Remarks:

Single exposure level tested might be unsufficient to interpret the results

Conclusions:

No toxic effects of test material could be determined in test animals after the single level acute inhalation.

Executive summary:

An acute inhalation toxicity study was conducted (prior to the adoption of the OECD Guideline) wherein a group of ten albino rats was exposed to the vapors of CR-39 for a one-hour period at an average nominal concentration of 0.73 mg/L air. After exposure, the test animals were observed for the following 14 days.

No deaths, untoward behavioral reactions or gross pathologic alterations were noted in any of the test animals. Body weight gains were within the normal limits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

365 mg/m³ air

Physical form:

inhalation: vapour

Quality of whole database:

Good quality, similar to guideline.

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

Study period:

1981-03-03 to 1981-03-17

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report which meets basic scientific principles (Klimish et al., 1997). The study was performed prior to the adoption of the OECD Guidelines. Purity of test material was not noted.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Eight test animals were used in the present study (4/sex). Environmental conditions are reported not completely.

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Langshaw Farms, Augusta, Michigan
- Age at study initiation: young adult animals
- Weight at study initiation: ranged from 2.25 to 2.50 kilograms.
- Fasting period before study: no
- Housing:individually housed in steel wire-bottomed cages suspended above the droppings.
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow, 5322 ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The rabbits were quarantined and acclimated to laboratory conditions for 13 days prior to initiation of the study


ENVIRONMENTAL CONDITIONS
data not available

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Approximately 24 hours prior to the dermal application the backs of the rabbits were clipped free of hair. The twenty-four hour waiting period allowed recovery of the stratum corneum from the disturbance that accompanies the close clipping procedure and also permitted healing of any microscopic abrasions possibly produced during this process.

TEST SITE (approximately 240 cm^2).
- Area of exposure: back
- % coverage: 10
Each test site was immediately occluded with a layer of 4-ply gauze, two single layers thick.
- Type of wrap if used: rubber latex dental dam and the dental dam taped at the edges with 1 inch Micropore tape to form an airtight occlusive wrap.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was wiped off.
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): not reported (see Doses)
- Concentration (if solution): no
- Constant volume or concentration used: no; individual dose amounts were calculated using day 0 body weights.


VEHICLE
- Amount(s) applied (volume or weight with unit): not applicable
- Concentration (if solution): not applicable
- Lot/batch no. (if required): not applicable
- Purity: not applicable

Duration of exposure:

24 hours

Doses:

undiluted 10 mL/kg bw

No. of animals per sex per dose:

4males /4 females

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. All surviving animals selected for the study were weighed one day prior to dosing, on day of dosing, 6 and 13 days after dosing.
- Necropsy of survivors performed: yes (as well as of animals foud dead) on the visceral and thoracic cavities
- Other examinations performed: clinical signs, body weight,organ weights, 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:

The WIL computer program based on the techniques of Litchfield and Wilcoxon were used to calculate the LD50 if mortality occurred at an adequate number of dose levels [Litchfield, J. J. and F. Wilcoxon, "A Simplified Method of Evaluation of Dose-Effect Experiments," J. Pharm. and Exp. Ther., 99-113 (1949)].

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 10 mL/kg bw

Remarks on result:

other: mortality in 3/8 animals

Mortality:

Three females were found dead on day 2 of the study.

Clinical signs:

other: Surviving animals appeared slightly emaciated with anorexia, adipsia, decreased defecation and tufts of hair on the cage paper. Evaluation of local skin reactions revealed moderate to slight erythema and edema during days 1-3.

Gross pathology:

Examination of the visceral and thoracic cavities of the test animals at necropsy by the pathologist revealed:
Intraperitoneal fluid red, spleen mottled light (240F).
Exterior surface of stomach reddened and interior hemorrhagic, vaginal area congested (red black in color and passage not distinguishable for examination (244F). Irregular, pale, yellow foci noted over the liver (243F and 229M). No significant gross pathologic findings (all others).

Other findings:

no

Table 1: Means and statistics of individual body weights (kg)

	Males		Females
	Statistic	Value	Statistic	Value
Day -1	Mean S.D. S.E. N	2.400 0.082 0.0041 4	Mean S.D. S.E. N	2.400 0.108 0.054 4
Day 0	Mean S.D. S.E. N	2.425 0.104 0.052 4	Mean S.D. S.E. N	2.375 0.150 0.075 4
Day6	Mean S.D. S.E. N	2.067 0.247 0.142 3	Mean S.D. S.E. N	2.200 0.424 0.300 2
Day13	Mean S.D. S.E. N	2.417 0.208 0.120 3	Mean S.D. S.E. N	2.525 0.177 0.125 2

Interpretation of results:

other: EU GHS criteria not met

Conclusions:

As only one dose level was dosed and produced mortality in 3/8 of the test animals, an LD50 could not be calculated. From the data presented the LD50 is greater than 10 mL/kg of body weight.

Executive summary:

When CR-39 was administered dermally at one dose level of 10 mL/kg bw to the nonabraded skin of 8 New Zealand White rabbits (4 males and 4 females), signs of systemic toxicity occurred (anorexia, adipsia, emaciation and decreased defecation) during the post dose observation period of 14 days. Three/eight animals were found dead on day 2 of the study. Positive gross pathologic findings were observed in four/eight of the test animals. From the data presented in the report the LD50 of CR-39 is greater than 10 mL/kg bw (11,430 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

11 430 mg/kg bw

Quality of whole database:

Good quality, guideline studies.

Additional information

Acute oral toxicity of carbonic acid, oxydiethylene diallyl ester to rats is moderate. The study " Acute Oral Toxicity Study in Albino Rats with CR-39 (479-768)" (dated 1981 -10 -22) was chosen as the key study for acute oral toxicity assessment because of its GLP compliance, a clear dose dependent responce (four dose levels tested) and LD50 which was calculated for both sexes.

Acute dermal toxicity to rabbits is low. When CR-39 was administered dermally at one dose level of 10 mL/kg bw to the nonabraded skin of 8 New Zealand White rabbits (4 males and 4 females), signs of systemic toxicity occurred (anorexia, adipsia, emaciation and decreased defecation) during the post dose observation period of 14 days. Three of eight animals were found dead on day 2 of the study. Positive gross pathologic findings were observed in four of eight of the test animals. From the data presented in the report the LD50 of CR-39 is greater than 10 mL/kg bw (11,430 mg/kg).

Conversion of existing inhalation toxicity data which have been generated using a 1 hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

Thus the inhalation discriminating dose for 4h was 375 mg/m³. No LC50(4h) can be determined based on the single concentration exposure.

Justification for classification or non-classification

The classification is warranted according to the criteria of Regulation (EC) No 1272/2008.

GHS: Acute tox. oral Cat. 4