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Diss Factsheets

Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No data
4 (not assignable)
Rationale for reliability incl. deficiencies:
There were extremely limited details on the methodology, and the report was just on the histopathology findings.

Data source

Reference Type:
study report
Report date:

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:

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)
EC Number:
Cas Number:
Molecular formula:
HEDP-2Na C2H6Na2O7P2 HEDP-3Na C2H5Na3O7P2
Sodium Salts of (1-Hydroxyethylidene)bisphosphonic acid (2-3 Na:1)

Test animals


Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
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:
Details on study design:
Post-exposure period: 14 days

Results and discussion

Results of examinations

Clinical signs:
not specified
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:
Effect level:
>= 5 mg/m³ air

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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.