Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

experimental phase: Sep. 5, 1975 - Mar. 3, 1976; final report dated: Jun. 10, 1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

study in potential urinary bladder or renal toxicological effect, 2 dose levels and control, 160- or 200-day administration (via feed)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Zeolite, cuboidal, crystalline, synthetic, non-fibrous

EC Number:

930-915-9

Cas Number:

1318-02-1

Molecular formula:

M2/nO • Al2O3 • ySiO2 • wH2O (n is the valency of the cation M, predominantly Na, y can range from 0.64 to 8.8, and w is the number of water molecules (general formula) Na: 1.34 - 24.02%, Al: 2.20 - 39.51%, Si: 15.52 - 68.64% (general composition); additionally, depending on the water quality: Ca, Mg and K might be present below 6%

IUPAC Name:

Zeolite, cuboidal, crystalline, synthetic, non-fibrous

Test material form:

solid: particulate/powder

Remarks:

no surface treatment

Specific details on test material used for the study:

UDL-1078 (A Zeolite)

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Remarks:

COX-SD

Sex:

male

Details on test animals or test system and environmental conditions:

housed individually, 72-78 °, c. 45% relative humidity, 12 h day/light intervals, feed and water ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The basal laboratory diet (ad libitum) consisted of Purina Laboratory Chow . There was no supplementation of the diet during the study.

Duration of treatment / exposure:

up to 200 days, but half the rats were sacrified after 160 days of administration

Frequency of treatment:

feed was administered ad libitum

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0.125 other: % of diet (w/w)

Remarks:

group II (c. 75.1 mg/kg bw/d)

Doses / concentrations 2

Dose / conc.:

2 other: % of diet (w/w)

Remarks:

group III (c. 1250.8 mg/kg bw/d)

No. of animals per sex per dose:

40 (males only)

Control animals:

yes, plain diet

Positive control:

none

Examinations

Observations and examinations performed and frequency:

A daily examination of physical appearance, gross signs of systemic toxicity and/or pharmacological effects, behavior and mortality, was maintained for all animals
(Test and Control Groups) throughout the entire study (7 days a week).
Body weight and feed consumption values were recorded weekly for al animals (Test and Control Groupsl throughout the study.

Sacrifice and pathology:

One-half of the surviving animals of the Control Group and the Test Low Group and the Test High Group were sacrificed on the 160th day of the study. The remalning animals from the Control Group, Test Low Group and Test High Group were sacrificed at 200 days of the study.
Pathology: Gross pathology of all organs, with special attention paid to kidneys and bladders

Other examinations:

On Day 155 of the study, a complete urinalysis,consisting of volume of the 8-hour collection, urobilin, urobilinogen, albumin, acetone, bilirubin, color, occult blood, glucose, specific gravity, pH, appearance, RBC, IBC, casts, crystals, spermatozoa, and epithelial cells, was conducted on the urine of each surviving animal of the Test and Control Groups.
In addition, on Day 158, a urine concentration test utilizing the specific gravity as the measured Parameter, was conducted on each surviving animal of the Test and Control Groups.
Urine was collected from ten animals, randomly selected, from each group, for pH determination a t 55, 76, 97, 118, 145, 181, and 196 days. The urine collected on Day 13 and Day 196 had the additional determination of specific gravity.

At 0, 45, and 90 days of the study, urine was obtained from all animals of the Control Group and the two Test Groups. This urine was collected in sterile tubes and evaluated microbiologically for evidence of urinary tract infection.

At Day 90 of the study, all surviving animals were anesthetized by controlled inhalation of metofans and a whole body x-ray was made of each of the anesthetized rats. The x-rays performed were of the dorsal ventral plain and were designed to evaluate the genital urinary system.

Results and discussion

Results of examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

No gross signs of adverse systemic effect due to the ingestion of the test material, UDL-1078, through the dietary redime, were observed in any of the animals of Group II or III during the study. Occasional minor incidental abnormalities were noted in the animals of each group during the study. These phenomena are generally associated with natural occurring disease processes commonly found within the laboratory rat.

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Bodyweights for the control and test groups (Groups I, II, and III) were within expected limits throughout the study. No effect of adding the test material, UDL-1078, to the feed was observed at any time throughout the study.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Animals of the Control Group, Test Low Group and Test High Group (Groups I, II, and III) disylayed normal appetite md consumed normal amounts of feed within limits of expectation throughout the stydy. The feed consumption values (absolute and relative) and the feed efficiency ratios for the Test Groups (Groups II and III) were comparable to the Control Group values.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

The results of the urine analysis for all surviving animals under all test conditions at 158 days, were generally within the normal range of urine values for laboratory rats. The results obtained for the Control Group (Group I) was comparable to the results obtained for the low and high Test Groups (Groups II and III).
The urine concentration test performed at 158 days showed no evidence of kidney disfunction in the Test Low or Test High, as compared with the specific gravity values obtained on the Control animals.
Specific gravity and pH evaluation of the urine of randomly selected rats in the Control Group (Group I) and Test Low and Test High Groups (Groups II and III) formed at 55, 76, 97, 118, 145, 181, and 196 days, showed no evidence of alteration due to the administration of the test rnaterial at either level . A comparison of the Test Groups with the Control Groups showed the results to be comparable and within expected limits for laboratory rats.
It was noted at each of the urine collections, that in the Test Low and Test High a white crystalline material was visible in the urine of the rats. This gave the appearance of a dose-response situation since the crystalline material appeared to be in greater quantities in the Test High than in the Test Low.
Other than the appearance of the crystalline material, there was no evidence of an alteration of urine pariimeters or kidney function due to the oral administration of the test material, UDL-1078.
Microbiological evaluation of the urine of test and control animals at 0, 54, and 90 days, showed a general tendency for an ecological change from the E. coli- Enterococcus group to the proteus-pseudomonas group. The general bacterial level and the general type of bacteria was comparable in the Control and Test Low and Test High Groups. There was no evidence of urinary infection in the microbiological test data.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Gross necropsy of the three Control animals which succumbed during the study, and the three anirnals which were sacrificed (non-scheduled
sacrifices) showed the usual picture of animals with diseases contracted in the laboratory. Three of these slx animals showed no gross pathological indication of disease. One of the sacrificed animals showed a thickened and distended bladder and one showed a distended bladder. Of those which succumbed during the study, one showed enlarged testes but no bladder gross pathology was observed.
The gross necropsy of fifteen animals sacrificed at the 160-day interval, showed twelve to be grossly not remarkable and one animal had a single renal calculi and with thickened and inflamed bladder walls.
Gross necropsy of the eighteen Control animals sacrificed at the 200-day terminal sacrifice, showed sixteen of the animals to be not remarkable. The other two had grossly observed congestion of the lungs.
Gross necropsy of five Test Low animals, four of which were sacrificed (unscheduled sacrifices) and one of which succumbed during the study, showed no lesions which were attributable to the administration of the test material. The lesions found were those to be expected from diseases contracted in lahoratory conditions. Gross necropsy of the seventeen animals of the Test Low Group sacrificed on Day 160, showed eleven to be not remarkable and the others to have gross pathological conditions, not related to the administration of the test material. 0ne animal showed a single renal calculi with no kidney or bladder involvement.
Gross necropsy of eighteen animals of the Test Low Group sacrificed termirially at 200 days, showed thirteen to be grossly not remarkable
and the remaining animals to have no gross lesions whiich could be related to the administration of the test material. All gross lesions found were those which would be expected in animals under test conditions.
Gross necropsy of the two Test High animals sacrificed during the study (unscheduled sacrifice) and the three Test High animals which
succumbed during the study, showed one animal with a distended bladder, one animal with crystals visible in the urine and one animal with stones in the bladder, Only one animal was found to be not remarkable of the five sacrificed or which succumbed during the study. Other lesions found in these animals were those which are consistent with laboratory conditions.
Gross necropsy of the eighteen Test High animals, sacrificed at 160 days, showed eight to be not remarkable, two with kidneys which were either congested or roughened, and five with urinary bladde stones.
Gross necropsy of the seventeen Test High animals sacrificed terminally at 200 days, showed two to be not remarkable, eleven had urinary bladder stones, and five had kidney stones.
Other lesions found in the Test High Group sacrificed at 160 i and 200 days,were those which would be expected to be found in laboratory animals and not related to the administration of the test material.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Radiographs made of all animals at 90 days, showed no evidence of urinary bladder stones in the Control Group or the Test low or Test High Groups. There was no evidence of radiographic change due to the administration of the test material, UDL-1078.

Histopathological findings: neoplastic:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

0.125 other: % of diet (w/w)

Sex:

male

Basis for effect level:

gross pathology

Remarks on result:

other: c. 75.1 mg/kg bw/d

2

Key result

Dose descriptor:

LOAEL

Effect level:

2 other: % of diet (w/w)

Sex:

male

Basis for effect level:

gross pathology

Remarks on result:

other: c. 1250.8 mg/kg bw/d

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2 other: % of diet (w/w)

System:

urinary

Organ:

bladder

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

The Parameters investigated in this study showed a low toxicity for the material, UDL-1078. The only toxic manifestation which was significant was the appearance of accretation of material into kidney and bladder stones at the Test High Level. This occurred mainly between the 160th day and 200th day of the study. An ancillary interesting phenomena, which was observed, was the almost dose-response of the appearance of crystalline material in the urine of the Test Low and Test High Groups, during the midpart of the study.

To point out the significance of the stones in the kidneys and bladders of the Test High Level, one only has to realize that, in the Control animals, one kidney stone was observed at the 160-day interval sacrifice; in the Test Low Group, one kidney stone was observed at the 160-day interval sacrifice, and at the Test High Level, five animals were observed to have bladder stoaes at the 160-day interval sacrifice, and at the 200-day sacrifice, eleven animals were found to have bladder stones, and five to have kidney stones.

Applicant's summary and conclusion

Conclusions:

The only toxic manifestation which was significant was the appearance of accretation of material into kidney and bladder stones at the Test High Level.
LOAEL: 2% (w/w) in the diet (c. 1250.8 mg/kg bw/d)
NOAEL: 0.125 % (w/w) in the diet (c. 75.1 mg/kg bw/d)

Executive summary:

The purpose of this study was to evaluate and characterize any potential urinary bladder or renal toxicological effect of the material coded, UDL-1078. This material was orally administered as an admixture to the basal diet of male albino rats for a period of 200 days.