Registration Dossier

Toxicological information

Specific investigations: other studies

Currently viewing:

Administrative data

Endpoint:
specific investigations: other studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
Not specified; published in 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline or GLP followed.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
no guideline followed
Deviations:
not applicable
Principles of method if other than guideline:
The effects of glucose infusion on monochloroacetate (MCA) exposure were examined in male rats with a view toward effective clinical treatment for MCA intoxication. Rats were injected with 80 mg/kg sodium monochloroacetate (SMCA) (single lethal dose) and then infused with saline (control group) or 5% or 10% glucose solution at 2 mL/hour for ten hours. Survival rates in all groups were determined at 10 hours, 24 hours, and 14 days. Capillary blood samples for blood glucose and lactate levels were obtained at one-hour intervals for ten hours.
GLP compliance:
no
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Chemical pure grade SMCA purchased from Nakalai Tesque (Kyoto, Japan).
No further details specified.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Ten-week-old male Sprague-Dawley rats (mean weight 300 g) were used in this study. The rats were kept in a separate room that was maintained at a constant temperature (22.0± 1.0°C) under a 12- hour light/dark cycle. The animals were given free access to food and water for one week then starved for 14 hours just before the study.

Administration / exposure

Route of administration:
subcutaneous
Vehicle:
other: distilled water
Details on exposure:
Dosing solutions were prepared by dissolving SMCA in 2 mL distilled water.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data.
Duration of treatment / exposure:
Control group underwent ten hours of saline infusion therapy after subcutaneous administration of the LD99 dose of SMCA, and 5% glucose group and 10% glucose group rats underwent ten hours of glucose infusion therapy after administration of the LD99 dose of SMCA.
Frequency of treatment:
single subcutaneous injection
Post exposure period:
up to 14 days after injection
Doses / concentrations
Remarks:
Doses / Concentrations:
80 mg/kg (LD99)
Basis:
nominal conc.
No. of animals per sex per dose:
21
Control animals:
yes
Details on study design:
With the rats under phenobarbital anaesthesia, saline or glucose solution were infused intravenously by syringe pump via a catheter placed in the right cervical vein.

Examinations

Examinations:
Survival rates in all groups were determined at 10 hours, 24 hours, and 14 days. After SMCA administration, blood glucose and lactate levels were determined at one-hour intervals for ten hours.
Positive control:
No

Results and discussion

Details on results:
Survival:

- control group: 10% at ten hours, and close to 0% at 14 days
- 5% glucose group: 57% at ten hours and 14% at 14 days.
-10% glucose group: 78% at ten hours, and all these rats survived beyond 14 days.
Kaplan-Meier analysis showed the survival rates in 5% glucose group and 10% glucose group to be significantly better than that in the control group (P < 0.01 for 5% glucose group, P < 0.001 for 10% glucose group).

Blood glucose:

- control group: significant decreases in blood glucose concentrations during the first three hours after SMCA administration (0
- 5% glucose group: increase in blood glucose during the first hour. Blood glucose then decreased gradually to the baseline level, remaining constant until the six-hour time point. Beyond seven hours, a slight increase in glucose concentration was observed.
- 10% glucose group: significant increase in blood glucose concentration during the first hour. The glucose concentration gradually increased to 175 mg/dL by ten hours.

Blood lactate:

- control group: increased from 1 mmol/L to 7.6 mmol/L within three hours.
- 5% glucose group: significantly suppressed increase in lactate concentration. Concentration reached a maximum at four hours, although the peak value was lower than that of control group. It then decreased gradually to 2.5 mmol/L at ten hours.
- 10% glucose group: significantly suppressed increase in lactate concentration. Concentration reached a maximum at three hours (3.5 mmol/L) and gradually decreased to 2.3 mmol/L at six hours, then remained nearly constant.

A strong inverse linear relation was observed between concentration of infused glucose solution and blood lactate levels, between infused glucose and blood glucose concentrations, and between blood glucose and lactate levels.

Any other information on results incl. tables

None.

Applicant's summary and conclusion

Conclusions:
Rats were injected with 80 mg/kg sodium monochloroacetate (SMCA) (single lethal dose) and then infused with saline (control group) or 5% or 10% glucose solution at 2 mL/hour for ten hours. Glucose infusion following subcutaneous injection of SMCA at the LD99 level significantly improved the survival rate, and prevented a reduction in blood glucose levels. Although the blood lactate level increased in each group, there was an excellent inverse linear relation between blood glucose levels and blood lactate levels. Thus, the authors concluded that continuous parenteral infusion of glucose solution at an early stage after exposure may be an effective clinical therapy for the prevention of hypoglycaemia and metabolic lactic acidosis caused by MCA.