Benzylmagnesium chloride

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic 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:

study report

Title:

Unnamed

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: According to the specification of the National Toxicology Program for the conduct of toxicity and carcinogenicity studies on chemicals

GLP compliance:

yes

Remarks:

Study is conducted in compliance with Food and Drug Administration Good Laboratory Practice Regulations.

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

Test material form:

other:

Details on test material:

Lot WK8-6-86 was used during the 14-week studies; it was identified as tetrahydrofuran by infrared, ultraviolet/visible, and nuclear magnetic resonance spectroscopy. All spectra were consistent with the literature spectra of tetrahydrofuran. Lot WK8-6-86 contained less than 1.5 ppm peroxide and the overall purity was determined to be approximately 99%.
The bulk chemical was stored at room temperature in the original metal containers under a nitrogen atmosphere to ensure stability. Stability was monitored during the 14-week study using gas chromatography. No degradation of the bulk chemical was detected.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: air distribution line

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

5 days per week, for 14 weeks

Frequency of treatment:

6 hours plus T90 (12 minutes) per day

Doses / concentrations

Remarks:

Doses / Concentrations:
0 (chamber control), 66, 200, 600, 1800, 5000 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent no treatment

Results and discussion

Effect levels

Dose descriptor:

NOAEC

Effect level:

1 800 ppm

Basis for effect level:

other: level base on hemathology and clinical chemistry data of 5000 ppm group;

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Results of the 14 -week study

All rats survived until the end of the study. Final mean body weights and body weight gains of exposed groups of male and female rats were similar to those of the chamber controls. Immediately after exposure, male and female rats in the 5,000 ppm groups exhibited ataxia; animals had irregular movements with lack of coordination. Hematologic and biochemical data for rats demostrate minimal differences, with most values falling within physiologic ranges. The differences did not demonstrate an exposure relationship and only occurred in the 5000 ppm groups, but were not considered toxicologically relevant. In 5000 ppm rats, a minimal mature neutrophilia occurred, wich was evidenced by increased segmented neutrophil numbers. Microscopic evidence of a mild suppurative submucosal gastric inflammation could account for the neutrophilia. Minimal increase of of serum bile acid concentration occurred in 5000 ppm male and female rats and could be consistent with either cholestatic event or hepatocellular injury. There was no evidence of cholestasis or hepatocellular necrosis/leakage. Serum bile acid concentration can be affected by other mechanisms such as altered enterohepatic circulation and impaired hepatic function, and noncholestatic liver injury can increase circulating bile acid concentrations.

Absolute and relative thymus and spleen weights of male and female rats exposed to 5,000 ppm were significantly less than those of the chamber controls. Absolute and relative liver weights of female rats exposed to 5,000 ppm were significantly greater than those of the chamber controls. The decrease of spleen and thymus weights were not accompanied by readly appreciable histopathologic changes and may have been due to stress associated with tetrahydrofuran administration in these groups. No exposure-related gross lesions were observed in male or female rats at necropsy. Mimal suppurative inflammation characterized by submucosal neutrophilic infiltrates and edema was associated with areas of forestomach hyperplasia in two male and four female rats exposed to 5,000 ppm. The gastric lesions may have been due to the irritant effect of tetrahydrofuran ingested during exposure.

Applicant's summary and conclusion

Conclusions:

In this study, groups of 10 male and 10 female rats have been exposed to 0, 66, 200, 600, 1800, 5000 tetrahydrofuran inhalation for 14 weeks, 5 days per week. Immediately after exposure, rats in the 5000 ppm group exhibited ataxia, with irregular movements and lack of coordination. Hematology and clinical chemistry data differences between exposure groups did not demonstrate a strong exposure relationship and only occurred in the 5000 ppm group. However, these data were considered not toxicologically relevant. The decrease of thymus and spleen weights were not associated with readly appreciable histopathological changes and may have been due to stress associated with tetrahydrofuran administration. The gastric lesion observed may have been due to the irritant effect of tetrahydrofuran ingested during exposure. The only effect on liver of rats was the increase of absolute and relative weight of 5000 ppm.

Executive summary:

In this study, groups of 10 male and 10 female rats have been exposed to 0, 66, 200, 600, 1800, 5000 tetrahydrofuran inhalation for 14 weeks, 5 days per week All rats survived until the end of the study. Final mean body weights and body weight gains of exposed groups of male and female rats were similar to those of the chamber controls. Immediately after exposure, male and female rats in the 5,000 ppm groups exhibited ataxia; animals had irregular movements with lack of coordination. Hematologic and biochemical data for rats demostrate minimal differences, with most values falling within physiologic ranges. The differences did not demonstrate an exposure relationship and only occurred in the 5000 ppm groups, but were not considered toxicologically relevant. In 5000 ppm rats, a minimal mature neutrophilia occurred, wich was evidenced by increased segmented neutrophil numbers. Microscopic evidence of a mild suppurative submucosal gastric inflammation could account for the neutrophilia.

Absolute and relative thymus and spleen weights of male and female rats exposed to 5,000 ppm were significantly less than those of the chamber controls. Absolute and relative liver weights of female rats exposed to 5,000 ppm were significantly greater than those of the chamber controls. The decrease of spleen and thymus weights were not accompanied by readly appreciable histopathologic changes and may have been due to stress associated with tetrahydrofuran administration in these groups. No exposure-related gross lesions were observed in male or female rats at necropsy. Mimal suppurative inflammation characterized by submucosal neutrophilic infiltrates and edema was associated with areas of forestomach hyperplasia in two male and four female rats exposed to 5,000 ppm. The gastric lesions may have been due to the irritant effect of tetrahydrofuran ingested during exposure.