Diisopropyl ether

Endpoint summary

Description of key information

The oral LD50 values were reported to be 4600 mg/kg body weight for 14-day old males and females, 12000 mg/kg body weight for young adult males, and 11900 mg/kg body weight for older adult males in rats administered isopropyl ether (Kimura et al., 1971).  No data was provided on mortality or clinical effects.  However, clinical effects observed in rabbits include narcosis and respiratory depression among others.  Anesthesia was observed following acute inhalation exposure in monkeys, rabbits, and guinea pigs at concentrations greater than 1.0%. The lowest lethal dose for a 1-hour exposure in these species was reported to be greater than 30000 ppm (corresponding to 64 mg/L).  The authors did not report an LD50 value following acute dermal exposure in rabbits; however, an LD50 value of greater than 2000 mg/kg body weight was reported in the high production volume (HPV) report (2008).  

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:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

-Observed for up to 7 days after dosing

Principles of method if other than guideline:

16 solvents administered orally (via syringe) to newborn, immature, young adult, and older adult rats. LD50 values were calculated by the method of Litchfield and Wilcoxon (1949).

GLP compliance:

no

Remarks:

Study pre-dates GLP requirements.

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Four different ages were tested - 24 to 48-hour old (newborn rats); 14-day old (immature rats); age not reported for young adults and older adults.
- Weight at study initiation: 5 to 8 g (newborn rats); 16 to 50 g (immature rats); 80 to 160 g (young adults); 300 to 470 g (older adults).
- Fasting period before study: Non-fasted rats were used.

Route of administration:

other: Orally via straight needle or microsyringe

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: Not reported

Doses:

Not reported

No. of animals per sex per dose:

-6 to 12 mixed sex animals per study in newborn and immature 14-day old rats
-6 male animals per study on young and older adults

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 7 days
- Necropsy of survivors performed: No

Statistics:

The LD50 and associated confidence limits were calculated both by the method of Litchfield and Wilcoxon (1949) and by a probit analysis statistical program via an IBM-1800 calculator. Parallel probit analyses (Finney, 1952), programmed for the IBM-1800 computer, were carried out on the LD50 values to compare the potencies within the 3 to 4 age groups for each of the solvents tested.

Preliminary study:

Not applicable.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

6.4 mL/kg bw

95% CL:

4.7 - 8.6

Remarks on result:

other: 14-day old

Sex:

male

Dose descriptor:

LD50

Effect level:

16.5 mL/kg bw

95% CL:

15.3 - 17.7

Remarks on result:

other: young adult

Sex:

male

Dose descriptor:

LD50

Effect level:

16 mL/kg bw

95% CL:

14.1 - 18.4

Remarks on result:

other: older adult

Mortality:

No information available

Clinical signs:

other: No information available

Gross pathology:

No information available

Other findings:

- Other observations: Able to obtain only a rough approximation of the acute oral LD50 values for newborn rats due to minimum administration volumes (generally < 1 mL/kg body weight).

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: CLP (EC 1272/2008)

Conclusions:

Based on a di-isoproply ether density of 723 g/L:
LD50 (male/female 14-day old) = 4600 mg/kg bw
LD50 (male young adult) = 12000 mg/kg bw
LD50 (male older adult) = 11900 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 600 mg/kg bw

Quality of whole database:

Both studies available show consistent finding, although the key study was performed using rats and the supporting stdy used rabbits as test animals. The acute LD50 however was in the same range.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

64 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1938

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Significant methodological deficiencies, information in published paper is insufficient

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

not specified

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Duration of exposure:

The material was continuously dripped onto the shaved skin to keep it wet for one hour, while continuously evaporating.

Doses:

Approximately 150 ml of material was used over the course of the hour.

No. of animals per sex per dose:

1 animal

Control animals:

no

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Remarks on result:

other: LD50 reported by HPV (2008), no LD50 reported by study authors

The procedure resulted in no general ill effect.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: CLP (EC 1272/2008)

Conclusions:

The procedure resulted in no general ill effect upon dermal exposure. LD50 of > 2000 mg/kg body weight reported by HPV (2008), no LD50 reported by study authors.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute oral:

The potential oral toxicity of isopropyl ether was evaluated in male and female Sprague-Dawley rats in a study similar in methodology to OECD Guidelines for the Testing of Chemicals No. 401 (Kimura et al., 1971). Groups of new-born (24 to 48 hours old), immature (14 days old), young adults, and older adult rats were orally administered isopropyl ether by gavage (dose not reported) and observed for 7 days. Although no data were reported on mortality or clinical effects, the LD50 values were determined as 6.4 mg/kg body weight for 14-day old males and females, 16.5 mg/kg body weight for young adult males, and 16 mg/kg body weight for older adult males mL/kg body weight (corresponding to 4600, 12000, and 11900 mg/kg body weight, respectively based on a density of 423 g/L). Isopropyl ether was not classified as acutely toxic following oral exposure according to CLP criteria.

 

Furthermore, the acute oral toxicity of isopropyl ether was assessed in rabbits (Machle et al.,1938). One animal per dose group received a dose of 1.62, 3.3, 5.2, 6.0, 7.2, or 8.2 g/kg body weight of isopropyl ether via gavage. A lack of coordination and unsteadiness were reported from 5 to 20 minutes, followed by intoxication and light narcosis from 14 to 40 minutes. In the animals that received 7.2 to 8.2 g isopropyl ether/kg body weight, the onset of symptoms was more rapid and deep narcosis followed. Other symptoms reported for these 2 animals include loss of corneal reflex, evidence of medulla depression, slow and irregular respiration, reduced body temperature, partial shock and cyanosis, and deep comatose state, followed by death. These early deaths were due to respiratory failure caused by the depressant action of the material upon the respiratory center. One animal, which had received 6.0 g/kg body weight of isopropyl ether experienced unsteadiness and short periods of intoxication and died within 15 hours as a result from the irritation of the intestinal tract by the test article. The 3 surviving rats (i.e., those administered 1.62, 3.3, or 5.2 g isopropyl ether/kg body weight) had a decrease in body weight 7 days after administration of the test substance and this initial weight loss was regained in every case during the succeeding week. The authors reported the minimal lethal dose to be between 7 and 9 g/kg body weight of isopropyl ether for rabbits via oral administration. It should also be noted that this study contains significant methodological deficiencies and the results are only provided as supporting data. 

 

Acute inhalation:

The inhalation toxicity of isopropyl ether was investigated in monkeys, rabbits, and guinea pigs in a study conducted by Machle et al. (1938). Although limited information is available for each of the experiments conducted in this publication, the results reported on each animal provides details regarding the toxicity of isopropyl ether via the inhalation route. Macacus rhesus female monkeys (1/group), New Zealand White rabbits (1 or 2/group), and guinea pigs (1 or 2/group) were exposed to isopropyl ether vapour by whole body inhalation for up to 180 minutes at concentrations of 0.1, 0.3, 1.0, 3.0, or 6.0%. At a concentration of 0.3% isopropyl ether (approximately 3000 ppm), no visible indication of anesthetic action was reported in any species. At higher concentrations of 1.0 and 3.0% isopropyl ether (approximately 10000 and 30000 ppm, respectively), signs of anesthesia were reported in all species.  Overall, death as a result of respiratory failure was reported in the 6% dose groups in each experiment (monkeys, rabbits, and guinea pigs). No LD50 value was reported by the authors for each of these experiments conducted on monkeys, rabbits, and guinea pigs; however, from these 3 experiments the authors concluded that the lowest lethal dose for a 1-hour exposure was greater than 30000 ppm (equivalent to 64 mg/L, assuming a temperature of 20°C and an atmospheric pressure of 1 atm). Isopropyl ether was not classified as acutely toxic following oral exposure according to CLP criteria.

 

Acute dermal:

One New Zealand White rabbit was dermally administered isopropyl ether to determine the acute dermal toxicity of isopropyl ether (Machle et al., 1938). The test material was continuously dripped onto the shaved skin to keep it wet for one hour, while continuously evaporating. Over the course of one hour, approximately 150 mL of the test material was used. No general ill effects were reported during this procedure and no further details were available. No LD50 value was reported by the authors; however, the LD50 was reported by the HPV (2008) to be greater than 2000 mg/kg body weight. Thus, isopropyl ether was not classified as acutely toxic following dermal exposure according to CLP criteria. 

Justification for selection of acute toxicity – oral endpoint

Reliable study supported by unreliable finding from a study dated 1938.

Justification for selection of acute toxicity – inhalation endpoint

A weight of evidence approach was followed using results from experiments made in 1938 using monkeys, rabbits and guinea pigs (whole body exposure).

Justification for selection of acute toxicity – dermal endpoint

supportive study for dermal exposure, in line with effects seen by other routes of exposure.

Justification for classification or non-classification

Acute Toxicity, oral: The submission substance has an acute oral LD50 of greater 2000 mg/kg bw (acute oral LD50 of 4600 mg/kg bw). As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

 

Acute Toxicity, dermal: The submission substance has an acute dermal LD50 of greater 2000 mg/kg bw. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

 

Acute Toxicity, inhalative: The submission substance has an acute inhalative 4h LC50 of greater than 20 mg/L (1h LC50 > 64 mg/L corresponds to a 4h LC50 of >32 mg/L). As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008, Annex I section 3.1.

 

Specific Target Organ Toxicity– Single Exposure: The submission substance produced transient anaesthesia effects in an oral and multiple inhalative exposure studies below the toxic level. Human data reported by ACGIH (1991) indicate that at 800 ppm for five minutes, most subjects reported irritation of the eyes and nose. Therefore, based on the human data, coupled with the animal data that showed this substance was likely causing respiratory tract irritation (albeit at concentrations in excess of the LC50), the submission substance meets the criteria for respiratory irritation effects. As a result, the substance meets the criteria for category 3 for narcotic and respiratory irritation effects classification according to Regulation (EC) No 1272/2008, Annex I section 3.8.

 

ACGIH. 1991. Isopropyl Ether. In: Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III.. American Conference of Governmental Industrial Hygienists (ACGIH); Cincinnati. pp. 835