Xylitol

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Safety Assessment of Nebulized Xylitol in Beagle Dogs

Author:

Reed MD, McCombie BE, Sivillo AE, Thorne PS, Welsh MJ, March TH, McDonald JD, Seilkop SK, Zabner J, and Durairaj L

Year:

2012

Bibliographic source:

Inhal. Toxicol., 24(6):365-372

Materials and methods

Principles of method if other than guideline:

Beagle dogs were exposed to the nebulized test substance to evaluate the potential toxicity/recovery from a 14-consecutive day (7 days/week) exposure vial facemask.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Xylitol

EC Number:

201-788-0

EC Name:

Xylitol

Cas Number:

87-99-0

Molecular formula:

C5H12O5

IUPAC Name:

(2R,3r,4S)-pentane-1,2,3,4,5-pentol

Test material form:

solid

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

snout only

Remarks:

veterinary anaesthesia mask

Vehicle:

water

Duration of treatment / exposure:

14 consecutive days with 14-day recovery period

Frequency of treatment:

1, 0.5, or 0.25 hour daily for high, mid, and low exposure, respectively

Doses / concentrations

Dose / conc.:

3.5 mg/m³ air

No. of animals per sex per dose:

Main Study: 3/sex/concentration
Recovery: 2/sex from control and high exposure concentrations

Control animals:

yes

Results and discussion

Effect levels

Dose descriptor:

NOAEC

Based on:

test mat.

Remarks on result:

other: 3.5 mg/L for 1 hour

Remarks:

no effects observed

Any other information on results incl. tables

Mean test substance aerosol concentrations for all groups were ~3.5 mg/L. Mean total deposited doses to the pulmonary region were estimated as 21, 11, and 5 mg/kg, for the high-, mid-, and low-exposure groups, respectively. All dogs survived to the scheduled necropsy. No treatment-related findings were observed dur to test substance exposure in any endpoint examined. Lung findings (mild interstitial infiltration, macrophage hyperplasia, alveolitis, and bronchitis) were consistent among exposed and control groups. No exposure-related effect of test substance in any parameter assessed was observed during or after the 14-day exposure in dogs. 

Applicant's summary and conclusion

Conclusions:

The NOEL was the high-exposure level (`3.5 mg/L for 1 hour) and suggests that inhaled test substance is safe for clinical administration.

Executive summary:

The study objective was to evaluate the potential toxicity/recovery from a 14-consecutive day (7 days/week), facemask inhalation administration of nebulized test substance solution in Beagle dogs. Aerosolized test substance was generated through three Aerotech II nebulizers operating at ~40 psi driving pressure. Test article groups were exposed to the same concentration of aerosolized test substance for 1, 0.5, or 0.25 hour for the high, mid, and low exposures, respectively. A control group was exposed for 1 hour to a nebulized normal saline solution. Animals were sacrificed the day following the last exposure or subsequently after 14 non-exposure days. Study endpoints included clinical observations, body weights, ophthalmology, and physical examinations, food consumption, clinical pathology, urinalyses, organ weights, and histopathology. Mean test substance aerosol concentrations for all groups were ~3.5 mg/L. Mean total deposited doses to the pulmonary region were estimated as 21, 11, and 5 mg/kg, for the high-, mid-, and low-exposure groups, respectively. All dogs survived to the scheduled necropsy. No treatment-related findings were observed dur to test substance exposure in any endpoint examined. Lung findings (mild interstitial infiltration, macrophage hyperplasia, alveolitis, and bronchitis) were consistent among exposed and control groups. No exposure-related effect of test substance in any parameter assessed was observed during or after the 14-day exposure in dogs. The NOEL was the high-exposure level (3.5 mg/L for 1 hour) and suggests that inhaled test substance is safe for clinical administration.