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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Original data on the aluminum content of the lungs not (yet) available. However, study meets generally accepted scientific principles, documentation sufficient for assessment.

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
study report
Report date:
Reference Type:
study report
Report date:

Materials and methods

Principles of method if other than guideline:
Chronic inhalation study in cynomolgus monkeys during 24 m (interim sacrifice: 6 and 12 months)
GLP compliance:
Limit test:

Test material

Constituent 1
Reference substance name:
Automatically generated during migration to IUCLID 6, no data available
Automatically generated during migration to IUCLID 6, no data available
Details on test material:
- Name of test material (as cited in study report): UDL-1362 (P&G code), Type A Zeolite
- Chemical name: Zeolite, cuboidal, crystalline, synthetic, non-fibrous
- Framework: cuboidal
- Related CAS number: 1318-02-1
- Analytical purity: no data

Test animals

other: Macaca fascicularis

Administration / exposure

Route of administration:
Type of inhalation exposure:
whole body
other: air
Details on inhalation exposure:
In a study with cynomolgus monkeys (Macaca fascicularis), groups of 3 females and 3 males each were exposed to 0, 1, 6 and 50 mg/m³ zeolite dust (A-type) for 6 hours per day, 5 days a week for a period of 6, 12 or 24 months.
6000-L glass chamber, airflow through the chambers: 1000 L/minute; control animals were exposed to filtered room air, animals lived continuously in the chambers.
As a positive control quartz dust was used in an exposure concentration of 50 mg/m³. The exposure of the animals of the positive control and of the high exposure group was discontinued after 55 weeks.
Following the 24-month exposure period some animals were held for a 3 month recovery period (1 mg/m3: 2 animals for recovery; 6 mg/m3: 4 animals held for recovery).
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Chamber atmospheres were sampled daily during exposures to determine gravimetric dust concentrations and particle size distributions were obtained at regular intervals throughout the study.
Concentration: The mean measured concentrations were 1.17, 6.14 and 44.37 mg/m³ for the 6-months study, 1.25, 6.28, and 53.29 mg/m³ for the 12-months study, and 1.29, 6.04 and 48.95 mg/m³ for the 24-months study, respectively.
The particles were micronized.
Group mean values for mass median diameter (with ranges of geometric standard deviations) were
for the 6 month study: 2.79 (1.43 - 3.27), 3.39 (1.40 - 1.76), and 3.44 (1.34 - 1.91) µm, respectively.
For the 12 month study: 3.62 (1.32-2.58), 3.61 (1.24 - 3.72), and 3.84 µm (1.3 - 5.2)
For the 24-month study: 3.48 (1.32-3.27), 3.48 (1.32-3.27), 3.63 µm (1.3-5.2).
Duration of treatment / exposure:
24 m (interim sacrifice: 6 and 12 months)
Frequency of treatment:
6 hours per day, 5 days a week
Doses / concentrations
Doses / Concentrations:
0, 1, 6 and 50 mg/m³ zeolite dust
nominal conc.
No. of animals per sex per dose:
Control animals:
Positive control:
As a positive control quartz dust was used in an exposure concentration of 50 mg/m³.


Observations and examinations performed and frequency:
Physical Examination: rectal temperatures, heart and lung sounds, abdominal palpation, gross skin examination, eye examination (prior to exposure and prior to sacrifice), skin test on tuberculosis and chest radiographs were performed at pre-exposure and thereafter monthly until study term. Body weights were determined weekly for the first month and monthly thereafter. Pharmacotoxic signs were recorded daily.
Hematology was performed twice before exposure and tri-monthly thereafter until termination of the experiment: red blood cells, white blood cells, differential leukocyte count, haemoglobin concentration, hematocrit.
Serum Chemistry: Na, Cl, K, SGPT, alkaline phosphatase, total serum protein, arterial blood gas (PO2, PCO2) were investigated bi-monthly with pulmonary function test, which determined the respiratory rate and tidal volume, the multiple breath nitrogen wash out and single breath CO diffusion as well as the dynamic compliance.
Urine Analysis were performed twice before exposure and tri-monthly thereafter (protein, pH, occult blood, glucose, billirubin, specific gravity, and microscopic examinations).
Sacrifice and pathology:
Following organs were gross pathological examined: brain, thyroids, lungs, spleen, gonads, heart, adrenals, liver, stomach, pituitary, eyes, thymus, peripheral nerves, tonsils, oesophagus, small intestine, cervical lymph node, skeletal muscle, bone marrow, nasopharynx, trachea, pancreas, large intestine, mesenteric lymph node, skin, urinary bladder, ureters, kidneys, external nares, larynx, nasal turbinates, and peribronchial lymph node.
Following organs were examined histopathologically: brain, stomach, eyes with lids, pituitary, thymus, heart, peripheral nerves, kidneys, parathyroid, oesophagus, thyroids, small intestine, cervical lymph nodes, skeletal muscle, spleen, bone marrow, aorta, lumbar spinal cord, adrenals, pancreas, large intestine, mesenteric lymph node, gonads, liver, skin, urinary bladder, ureters, external nares, lungs, larynx, nasopharynx, trachea, nasal turbinates, and peribronchial lymph node.
In special lung studies the pulmonary tissues were examined for UDL 1362 deposition by determine aluminum content. The lungs were analyzed also for hydroxylin and ash content.
In all statistical analyses, the level of probability chosen for rejecting the null hypothesis was r = 0.05.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Details on results:
Some animals revealed soft stools up to diarrhoea which was treated medically. Two animals revealed broken arms and were sacrificed at the 6 month interval.
There were neither compound related effects on body weight, hematology, serum chemistry, urinalysis, ophthalmic parameters, or organ/body weight ratios in any exposure group. The ash content of the lungs of the highest dose level was elevated over control, but hydroxyprolin levels were not increased even after 55 weeks of exposure (with or without recovery). The other groups showed any change at any time. Compound-induced histo-morphological changes were neither seen in the upper airways nor in any non-respiratory tract organs examined.
Exposure to 50 mg/m³ zeolite dust produced some focal nonsuppurative inflammatory reactions of the lungs after 29 and 55 weeks of exposure which were not completely resolved in individual monkeys after a 90-day recovery period (sporadic inflammatory changes in one monkey after 29-weeks of exposure and little change other than macrophage accumulation after the last exposure at 55 week; however, three months after exposure one of three monkeys had multifocal to diffuse nonsuppurative bronchiolitis and alveolitis; the other two monkeys exposed to 55 weeks and held three months did not have any compound-related inflammatory response to the macrophage accumulations).
Exposure to 6 mg/m³ zeolite dust produced free alveolar and septal wall macrophages after 26 weeks. Similar macrophage accumulations were present after 52 and 104 weeks. They were accompanied by sporadic nonsuppurative bronchiolitis and alveolitis in the lungs of three of the six monkeys exposed for 52 weeks and the one monkey exposed for 104 weeks. Primarily in lobes of the lungs there was residual damage from the lung parasite Pneumonyssus sp. (lung mites) or from kaolin (a component of a therapeutic compound utilised to control diarrhoea). These changes had not completely reversed after a 90-day recovery period in two of four monkeys. However, no compound-related inflammatory reaction was observed after the 90-day recovery period in the two other monkeys.
Exposure to 1mg/m³ zeolite dust produced free alveolar and septal wall macrophage accumulations after 26, 52 and 104 weeks. Sporadic areas of nonsuppurative bronchiolitis and alveolitis were present in the lungs of three of the four monkeys. Following the recovery period of 90 days, primarily macrophage accumulations without any inflammatory response were observed. The sporadic non-suppurative inflammatory reactions, which occurred in individual monkeys after 104 weeks, were not evident after the 90-day recovery period.

No evidence of progressive pulmonary fibrosis was observed. Dose-related nonsuppurative inflammatory reactions were observed in animals of all dose groups. These reaction had diminished in severity but had not fully disappeared in the mid and high dose group. In the 1 mg/m³ dose group, these effects were not evident after the 90-day recovery period. The LOAEL for inhalation is 1 mg/m³.

Effect levels

Dose descriptor:
Effect level:
1 mg/m³ air

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion