Benzylmagnesium chloride

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

other: Reliability score is not applicable because available data are on stabilizer agent (as described in sect. 1.2) and not on the benzylmagnesium chloride as such.

Data source

Reference

Reference Type:

publication

Title:

ACUTE AND SUBCHRONIC NEUROTOXICOLOGICAL EVALUATION OF TETRAHYDROFURAN BY INHALATION IN RATS

Author:

Linda A. Malley, Greg R. Christoph, Judith C. Stadler, John F. Hansen, John A. Biesemeier and Sree L. Jasti

Year:

2001

Bibliographic source:

DRUG AND CHEMICAL TOXICOLOGY, 24(3), 201–219 (2001)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: U. S. EPA, Toxic substances Control Act Health Effects Testing guideline, 40 CFR Part 798 Subpart G, Neurotoxicity (1985) and USEPA/FIFRA Neurotoxicity Pesticide Assessment Guidelines F, PB 91-154617 (1991)

GLP compliance:

not specified

Test type:

other: acute and subchronic inhalation studies

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydrofuran

EC Number:

203-726-8

EC Name:

Tetrahydrofuran

Cas Number:

109-99-9

Molecular formula:

C4H8O

IUPAC Name:

tetrahydrofuran

Details on test material:

Purity of tetrahydrofuran was assessed by gas chromatography as 99.98 % or greater. Known impurities were trace quantites of water, stabilizers and spontaneously-forming peroxides.

Test animals

Species:

rat

Strain:

other: Crl:CD BR

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air distribution line

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

0, 500 ppm, 2500 ppm, 5000 ppm

No. of animals per sex per dose:

12

Control animals:

yes

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

other: no-observed-effect concentration

Effect level:

500 ppm

Any other information on results incl. tables

Results of the study of acute exposure to tetrahydrofuran.

Body Weight and Body Weight Gain. There were no significant differences between the mean weights of control and treatment groups on test days 1, 2, 8, and 15. However, analysis of weight change indicated that 5000 ppm males lost significantly more relative to control between test days 2 and 8. Female rats showed a similar weight gain (loss) pattern, but none of the differences relative to control were statistically significant.

Food Consumption. Daily food consumption for male rats in the 5000 ppm group (17.2 ±3.5 g; mean ±SD) was significantly less than control (24.6 ± 2.8 g) for the day 1–2 interval. Food consumption for other intervals did not differ from control. Food consumption for 5000 ppm female rats followed a similar pattern, but the differences were not significant.

Startle Responses During Exposure. Startle behavior in response to an unexpected stimulus was diminished during acute exposure to 2500 ppm and was diminished or absent during exposure to 5000 ppm. The overall results show that the effects on startle behavior appeared to be more pronounced with increasing exposure time. Exposure to 500 ppm had no effect.

Clinical Observations. Signs of sedation were apparent immediately after the rats were removed from the inhalation chambers. All 12 male rats and 11/12 female rats in the 5000 ppm group exhibited lethargy; abnormal gait or mobility was noted for 4/12 males and 4/12 females. These incidence values were significantly different ( p<0.05) from control rats which had no adverse signs. The increased incidence of splayed rear feet in the 5000 ppm group (2/12 males and 2/12 females) was not statistically significant,

but the observations are toxicologically relevant. No clinical observations in the 2500 ppm groups were statistically significant, although observations of lethargy (2/12 females) and splayed rear feet (1/12 females, 1/12 males) suggest adverse behavioral effects in a subset of the rats. No unusual clinical signs were identified in rats exposed to 500 ppm, and no treatment-related abnormalities were detected in any group on test days 2 through 15.

Motor Activity. All groups had comparable motor activity scores prior to exposure. Females exposed to 5000 ppm had reduced (not statistically significant) number and duration of total movements after exposure on test day 1. The reduction, however, was statistically significant only during the second 10-min block of the 60-min test session. Male rats exposed to 5000 ppm appeared to have reduced motor activity at the beginning of the session and elevated activity at the end of the session, but the differences relative to control were not statistically significant. There were no compound-related effects on motor activity of female rats on day 2 or for male and female rats on days 8 and 15.

Functional Observational Battery. There were no differences between treatment groups and control during baseline FOB assessments. Males exposed to 5000 ppm had a significantly lower incidence of palpebral closure in the adaptation cage compared to control; this result may suggest that exposure to 5000 ppm reduced sleeping behavior after exposure. There was an increased incidence of slow or absent righting reflex in the 5000 ppm males and females, and although the incidence values were not significantly different from control, this result is toxicologically relevant. None of the FOB assessments conducted during test days 2, 8 and 15 provided statistical or suggestive evidence of compound-related effects. Abnormal gait and splayed limbs were not observed during the FOB (conducted subsequent to clinical observations) indicating rapid recovery from the acute effects.

Discussion.

Acute exposure to 2500–5000 ppm of THF produced signs of behavioral sedation during and after exposure. Post-exposure

clinical observations and neurobehavioral assessments indicated that THF’s sedative properties waned rapidly after termination of exposure. Despite obvious signs of sedation in most rats immediately after acute exposure to 5000 ppm, the subsequent motor activity test detected only slightly reduced activity. Furthermore, FOB assessments after the 60-minute motor activity test included only a few findings of residual sedation. Furthermore, behavioral sedation results indicate that that the effects are concentration-dependant, comparing 2500 ppm group to the 5000 ppm one. Clinical observations, motor activity tests, and FOB assessments conducted on the day following acute exposure did not reveal indications of continuing sedation. 5000 ppm males had slightly increased motor activity and altered body weight change one day after acute exposure. However, all neurobehavioral parameters and body weight gains were normal within one week, indicating that the rats fully recovered from all identified effects of acute THF exposure. Acute exposure of rats to 500 ppm had no identifiable effects during or after exposure.

Applicant's summary and conclusion

Conclusions:

Groups of male and female rats received tetrahydrofuran inhalation exposure at concentrations of 0, 500, 2500 and 5000 ppm. The principal neurobehavioral effects of exposure to 1500 ppm or greater is acute behavioral sedation which dissipates rapidly after termination of exposure. Clinical observations, motor activity tests, and functional observational battery assessments conducted on the day following acute exposure did not reveal indications of continuing sedation. Two effects of acute THF exposure that were evident one day after exposure involved slightly increased motor activity and altered body weight change for 5000 ppm males. Acute exposure of rats to 500 ppm had no identifiable effects during or after exposure.

Executive summary:

In this study, four groups of 12 male and 12 female Crl:CD BR rats received tetrahydrofuran acute (6 hours) exposure through inhalation at concentrations 0, 500, 2500 and 5000 ppm. Evaluations conducted immediately after exposure included clinical observations, motor activity assessments (MA), and a battery of functional tests (FOB) designed to reveal nervous system dysfunction. During exposure to 2500 and 5000 ppm, rats had a diminished or absent startle response to a punctate auditory alerting stimulus.

Following exposure to 5000 ppm, male and female rats were lethargic, exhibited abnormal gait or mobility, and splayed rear feet. Lethargy and splayed rear feet were also observed in females esposed to 2500 ppm. During the subsequent FOB, males exposed to 5000 ppm had a lower incidence of palpebral closure, higher incidences of slow or absent righting reflex, and a biphasic pattern of reduced motor activity followed by increased motor activity. Females exposed to 5000 ppm had increased incidences of palpebral closure in the open field, increased incidences of slow or absent righting reflex, and decreased motor activity.

Post-exposure clinical observations and neurobehavioral assessments indicated that THF’s sedative properties waned rapidly after termination of exposure. Acute exposure of rats to 500 ppm had no identifiable effects during or after exposure. The demonstrated no-observed-effect level of tetrahydrofuran exposure is 500 ppm.