Diisopropyl ether

Neurotoxicity

Description of key information

A NOAEC of 7060 ppm (29500 mg/m3), the highest concentration tested, was derived from the results of a 13-week diisopropyl ether inhalation neurotoxicity study in Sprague-Dawley rats (similar to OECD Test Guideline 424).

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: sub-chronic inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 424 (Neurotoxicity Study in Rodents)

Deviations:

yes

Remarks:

source of test material not reported, and ophthalmology was not performed

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days/week for 6 hours/day

Remarks:

Doses / Concentrations:
450, 3250, 7060 ppm
Basis:
other: measured

No. of animals per sex per dose:

10 animals/sex/dose

Control animals:

yes

Dose descriptor:

NOAEL

Remarks on result:

not determinable

Remarks:

no NOAEL identified

Body weights and clinical observations were not affected by exposure to DIPE. The pinna reflex was significantly reduced in the low dose males when compared to the controls during week 2. Unperturbed activity level was significantly decreased in low- and high-dose females when compared to the controls in week 4. Rectal temperature in the low-dose males was significantly increased in week 4 when compared to the controls. Although motor activity of control animals tended to decrease as the animals aged, there was a significant decrease in high-dose females when compared to the control animals in week 4. Motor activity in the high-dose group (males and females) remained consistant throughout the study but tended to be lower than the controls until week 13. In contrast, motor activity was significantly increased in low dose females in week 8. No effects were observed in the central or peripheral nervous system of the high-dose group, however, in one female in the low-dose group, a large cavity was noted in the cerebrum. In the same female, microscopic examination revealed focal hypoplasia of the cortex and the white matter tracks serving this area of the cortex. The dorsolateral region of the thalamus adjacent to the dilated ventricle was also hypoplastic. There was no evidence of neuronal degeneration, inflammation, or gliosis within the brian sections of this rat.

Executive summary:

A NOAEC value was not reported by the study authors. Review of the study data suggests that the NOAEC can be considered to be 7060 ppm (29500 mg/m³), the highest concentration tested. This consideration is based on the observation that the effects that were noted in the study were small in magnitude, did not occur in both sexes, were not concentration-dependent, and were transient in nature (i.e., did not occur at all time points investigated). This is consistent with the authors’ statement that “…some nonbiologically significant changes were observed in both the FOB and motor activity.”

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

29 500 mg/m³

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Rodriguez and Dalbey (1997) conducted a 13-week diisopropyl ether inhalation neurotoxicity study in Sprague-Dawley rats. The study design was similar to OECD Test Guideline 424 but was not conducted per GLP. Ten rats/sex/group were exposed to diisopropyl ether at concentrations of 0, 450, 3250, or 7060 ppm (equivalent to 0, 1900, 13600, or 29500 mg/m³, respectively) for 13 weeks (6 hours/day for 5 days/week). Rats were observed daily for signs of toxicity and body weights were recorded weekly. The animals were evaluated in a functional observational battery (FOB) followed by a determination of motor activity prior to initiation of exposures, in an FOB following 2, 4, 8, and 13 weeks of exposure, and for motor activity following 4, 8, and 13 weeks of exposures. Following the final determination of motor activity, the animals were anesthetized and the brain, spinal cord, and peripheral nerves were removed for microscopic examination.

Body weights and clinical observations were not affected by exposure to diisopropyl ether. The pinna reflex was significantly reduced in the low dose males when compared to the controls during week 2. Unperturbed activity level was significantly decreased in low- and high-dose females when compared to the controls in week 4. Rectal temperature in the low-dose males was significantly increased in week 4 when compared to the controls. Although motor activity of control animals tended to decrease as the animals aged, there was a significant decrease in high-dose females when compared to the control animals in week 4. Motor activity in the high-dose group (males and females) remained consistent throughout the study but tended to be lower than the controls until week 13. In contrast, motor activity was significantly increased in low dose females in week 8. No effects were observed in the central or peripheral nervous system of the high-dose group, however, in one female in the low-dose group, a large cavity was noted in the cerebrum. In the same female, microscopic examination revealed focal hypoplasia of the cortex and the white matter tracks serving this area of the cortex. The dorsolateral region of the thalamus adjacent to the dilated ventricle was also hypoplastic. There was no evidence of neuronal degeneration, inflammation, or gliosis within the brain sections of this rat.

A NOAEC value was not reported by the study authors.  Review of the study data suggests that the NOAEC can be considered to be 7060 ppm (29500 mg/m³), the highest concentration tested.  This consideration is based on the observation that the effects that were noted in the study were small in magnitude, did not occur in both sexes, were not concentration-dependent, and were transient in nature (i.e., did not occur at all time points investigated).  This is consistent with the authors’ statement that “…some nonbiologically significant changes were observed in both the FOB and motor activity.”