(4-amino-1-hydroxy-1-phosphonobutyl)phosphonic acid;hydrate

Additional toxicological data

Administrative data

Endpoint:

additional toxicological information

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11-04-2001 to 09-05-2001

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2001

Report date:

2001

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

To evaluate the esophageal irritation potential of an oral buffered formulation of
alendronate sodium following weekly esophageal infusion for 4 weeks.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

sodium;(4-amino-1-hydroxy-1-phosphonobutyl)-hydroxyphosphinate

Cas Number:

121268-17-5

Molecular formula:

C4H12NaNO7P2 · 3 H2O

IUPAC Name:

sodium;(4-amino-1-hydroxy-1-phosphonobutyl)-hydroxyphosphinate

Test material form:

solid: particulate/powder

Results and discussion

Any other information on results incl. tables

Results

1. Mortality, Physical Signs, Body Weight, and Food Consumption

All dogs survived to the termination of the experiment.  There were no

treatment-related physical signs.  Emesis was seen in some drug-treated dogs

during the recovery from anesthesia.  This was not considered related to drug

treatment.  There were no drug-related effects on body weight or food

consumption.

2. Gross and Light Microscopic Changes

There were no drug-related gross or light microscopic changes in the esophagi

of dogs exposed weekly to the oral buffered formulation of alendronate sodium at

a concentration of 3.73 mg/mL.  In contrast, there was gross and/or histologic

evidence of esophageal irritation in dogs infused at the highest concentration

(7.47 mg/mL); at necropsy, in 2 dogs, there was focal reddening of the distal

esophageal mucosa and histologically there was very slight to moderate

esophagitis (erosive or ulcerative) in all dogs.

Conclusions

This study has demonstrated that the oral buffered formulation of alendronate sodium, at a concentration of 3.73 mg/mL, is not irritating to the esophageal mucosa in dogs. At the highest concentration (7.47 mg/mL) studied, there was gross and light microscopic evidence of esophageal irritation in dogs after weekly exposure for 4 weeks.

Applicant's summary and conclusion

Conclusions:

There were no drug-related antemortem changes in dogs. In dogs infused with 3.73 mg/mL,
there was no gross or light microscopic evidence of esophageal irritation. At a higher
concentration (7.47 mg/mL), esophagitis (erosive or ulcerative) was evident in all dogs.
This finding is relevant for classification of the substance as a respiratory irritant using the criteria set out in the Classificaiton, Labelling and Packaging Regulations 1272/2008/EC.