Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

No data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Remarks:

There were extremely limited details on the methodology, and the report was just on the histopathology findings.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

Materials and methods

Principles of method if other than guideline:

There are insufficient details on the method to judge compliance with test guidelines. The two reports available for this study only contain histopathological results.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

EC Number:

701-238-4

Cas Number:

29329-71-3

Molecular formula:

HEDP-2Na C2H6Na2O7P2 HEDP-3Na C2H5Na3O7P2

IUPAC Name:

Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: No data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

14 days (plus 14 day recovery period)

Frequency of treatment:

Daily, but period not stated.

Doses / concentrations

Dose / conc.:

5 mg/m³ air

No. of animals per sex per dose:

10 in test group, 5 in control groups

Control animals:

yes

Details on study design:

Post-exposure period: 14 days

Results and discussion

Results of examinations

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Examination of the cornea and conjunctiva did not reveal any adverse effects (except one control male for which corneal and conjunctival keratitis was observed).

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Eosinophilic leukocytes were observed. The edges were either reactionless epithelium or hyperplastic epithelium. This alteration spread between the surrounding epithelium on the one hand and the epiglottis, and adjacent salivary glands on the other. Swelling in this area caused by cellular infiltrates and oedema. Foreign body giant cell formation was evident after the 14 day treatment-free period. Overall, after 14 days of inhalation of 5 mg/m3 CA2, there was erosion of the large mucosa with central necrosis and fibrin deposition. The cell infiltration was mainly monocytes, eosinophils, granulocytes and macrophages. After a further 14 days without treatment, the effect on the epithelium was reversed. However, ions of foreign body giant cells and macrophages were observed clearly in subepithelial areas and consequently, alterations were considered to be clearly treatment-related.

Clinical biochemistry findings:

not specified

Endocrine findings:

not examined

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

The cutaneous mucosa of the nose, skin of the nose and nostrils had occasional incisions. In seven males of the controls and one animal of the test group, the tongue-base was inflamed. Trachea and lung showed only spontaneous alveolar proteinosis (one male animal of the test group and one female control) and occasional calcification diseases (one male of the control group and two females of the test group). Consequently, there was very little evidence of respiratory irritation. The majority of female animals of the test and control groups showed varying degrees of corticomedullary calcification of the kidney. There was evidence of viral inflammation in pancreas and salivary glands.
While the base of the tongue, hard and soft palate and the proximal sections of the esophagus and trachea and the proximal portion of the epiglottis were normal, erosions were found in the distal third of the trachea (side facing the epiglottis) in the treated group.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No detectable histological alterations in the nose, larynx or trachea were observed.

Histopathological findings: neoplastic:

not specified

Other effects:

not examined

Effect levels

Dose descriptor:

NOAEL

Effect level:

>= 5 mg/m³ air

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

In a subacute repeated dose toxicity study (reliability score 4), unknown if conducted according to any OECD Test Guidelines and pre-GLP, salt of HEDP (2-3Na) was administered to Wistar rats, nose-only at a concentration of 5 mg/m3. A NOAEL was concluded to be ≥5 mg/m3 based on no detectable histological alterations in the nose, larynx and trachea.