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Description of key information

Oral


There are three reliable key studies available. The first in a type A zeolite has a NOAEL of c. 102.9 mg/kg bw/d and a LOAEL of c. 412.4 mg/kg bw/d. Both values are above the GHS threshold levels. The second, also in a type A zeolite, is the most critical with a NOAEL of c. 75.1 mg/kg bw/d and a LOAEL of c. 1250.8 mg/kg bw/d. Although the former value is within the classification limits of GHS, the last is high above them. As the GHS classification system is based on the lowest value at which actual adverse effects are recognised, there is no need for classification, because this value is somewhere between 75.1 and 1250.8 mg/kg bw/d. The low NOAEL derived in this study is probably simply due to the fact that no intermediate dose levels were tested. This is also in accordance with the results of the third key study, again in a type A zeolite, with a NOAEL of c. 292 mg/kg bw/d and a LOAEL 577 mg/kg bw/d. In summary, it can be assumed that the actual LOAEL of zeolites is greater than 292 and less than 412 mg/kg bw/d. Also, a NOAEL of 292 mg/kg bw/d can be used for classification, because in no study any adverse effects were observed below this level and in one this value was established as a NOAEL.


 


Inhalation


There are two reliable studies available in a type A zeolite. In both studies, in hamsters and rats, a NOAEL of equal or greater than 20 mg/m³ was assessed. There was no evidence of fibrotic disease or silicotic changes of or carcinogenic effects to the internal organs after inhalation of the type A zeolite.


It was also examined whether that substance got into the lower respiratory system of the experimental animals. According to this study, the presence of silicium in the lungs of rats after inhalation could be considered as evident. But macroscopically no changes in the internal organs nor deviations from the controls were observed. 


 


Dermal


There is no study in repeated dermal toxicity available, but an expert's weight-of-evidence approach concludes that dermal exposure to conventional zeolites did not raise safety concerns with regard to systemic toxicity, and new animal testing was not supported both from an animal welfare perspective and from the fact that there would be no new knowledge gain from such experiment. 

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

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
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
Specific details on test material used for the study:
UDL-1078 (A Zeolite)
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
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
Dose / conc.:
0.125 other: % of diet (w/w)
Remarks:
group II (c. 75.1 mg/kg bw/d)
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
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.
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
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
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
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

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.

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.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
experimental phase: Sep. 12, 1975 - Mar. 2, 1976; report: May 24, 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
administered for 24weeks in the diet, 3 dose levels
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
Test Material: UDL-1077 (A Zeolite)
Description: Fine white powder
Storage: Room temperature
Species:
rat
Strain:
Long-Evans
Details on species / strain selection:
Supplier: Blue Spruce Farns, Altarnont, New York, USA
Sex:
male/female
Details on test animals or test system and environmental conditions:
Age When Received: 4-5 weeks
Weight: 77-137 (males), 67-127 (females)
Housjng: Individually in elevated stainless steel wire mesh cages
Food: Standard laboratory diet ad libitum. Fresh food presented weekly.
Water: ad libitum
Teeth Care: cut as needed
Light Cycle: 12 hours on, 12 hours off
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Appropriate amounts of compound were mixed with standard laboratory diet weekly. Random samples from each dietary level were saved monthly for anaiysis by sponsor. Compound Consumption: Calculated from food consumption data.
Duration of treatment / exposure:
24 weeks, but half of the rats were necropsied after week 13
Frequency of treatment:
continuously in the diet
Dose / conc.:
0.125 other: percent of total diet
Remarks:
c. 102.9 mg/kg bw/d
Dose / conc.:
0.5 other: percent of total diet
Remarks:
c. 412.4 mg/kg bw/d
Dose / conc.:
2 other: percent of total diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
Daily for physical appearance, signs of local or systemic toxicity, pharmacologic effects or mortality.
Body Weight: Twice pretest, weekly during treatment, and terminally (after fasting).
Food Consumption: Weekly, beginning one week prior to treatment
Laboratory Studies: Urinalysis at weeks 13 and 24 (Term.), pH values of urine measured at weeks 7, 10, 13, 18 and 24
Sacrifice and pathology:
complete gross and histopatholigical examination after 13 or 24 weeks of treatment
Statistics:
Body weight, food consumption, feed efficiency, organ weights, organ/body weight ratios, urine volumes, specific gravity values, and pH values were analyzed. All dose groups were compared to control at each time interval.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Signs noted during physical observations were comparable for all groups and did not indicate an effect of the test material.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight decrease in body weights, as compared to control, was noted in the high-dose males for all weeks. This decrease was usually statistically significant (p <= 0.05) between weeks 6 and 15. Differences seen ihereafter were not statisticaliy significant. Body weights of the low and mid-dose males were usually slightly lower than control but not statistically different throughout the study.
Although the body weights of the high-dose females were consistently lower than controls for the first 16 weeks of study, these differences were considered minimal and were not statistically significant. From week 17 through 24, body weights of the control and high-dose females were considered comparable. Body weights of low and mid-dose females were either comparable to or slightly higher than control.
Terminal body weiqhts (fasted) of all compound-treated groups of males were slightly lower than control at three rnonths and at termination; this difference was statistically significant in the high-dose males at three months. Terminal body weights of the females were comparable to control at both time intervals.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
effects observed, non-treatment-related
Description (incidence and severity):
Values representing efficiency of feed utilization were generally comparable among all groups during the first seven weeks of the study. Thereafter values varied with scattered statistically significant differences ; however, no dose-related pattern was noted.
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):
Alterations noted in high-dose animals of both sexes included: (1) reduced specific gravity values for 24-hour urine samples collected at 13 weeks and for 24-hour and 6-hour (concentration test) sarnples collected at 24 weeks; and (2) increased 24-hour and 6-hour volumes at 24 weeks. The majority of these differences from control were statistically significant. 24-hour urine volumes at 13 weeks were unremarkable. No consistent pattern of differences between control and low and mid-dose animals was apparent in urine volume or specific gravity data.
Data generated during the 4-hour urine dilution test were unremarkable except for the absence of one-hour urine samples in all high-dose females. Specific gravity values and total 4-hour volumes were comparable among control and compound-treated groups.
Microscopic analysis revealed a lower incidence of urinary crystals in the high-dose group as compared to control in both sexes at 13 weeks and in the males only at 24 weeks. A slightly higher incidence of leukocytes in the urine was also noted in the hiqh-dose males as compared to control at week13 only. No other remarkable differences were noted in the microscopic urinalyses.
pH values measured at 7, 10, 13, 18 and 24 weeks did not indicate differences from control considered to be related to treatment with UDL-1077.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Scattered differences, sometimes statistically signif icant, were evident between Organ weights 2nd organ/body weight ratios of control and compound-treated groups. These differences were considered to ref l ect lower terminal body weights (in the males) or to represent normal biological variation. No toxicological significance was attributed to these variations.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Examination after 13 weeks:
The kidneys and urinary bladders from male and fernale rats receiving UDL-1077 in their diet at the rate of 0.125%, 0.5% and 2.0% of the diet for a period of three months were examined microscopically.
The kidneys and urinary bladders from male and female rats maintained on laboratory chow for three months were also exaniined and served as
Compound-related microscopic alterations were seen in the kidneys from all of the male and female rats receiving a diet containing 2.0% of UDL-1077. Five of 10 male rats and three of 10 female rats receiving a diet containing 0.5% UDL-1077 also possessed compound-related rnicroscopic alterations. No compound-related microscopic alterations were seen in the kidneys from either male or fernale rats receiving 0.125% UDL-1077 in their diet.
The microscopic alterations seen in the kidneys from the rats receiving 0.5% and 2.0% UDL-1077 in their diet were characterized by a purulent nephriti which generally involved the tubules in the middle cortex of the kidney, but occasionally extended into the inner cortex and medulla. The interstitium of the cortex and the proximal convoluted tubules were infiltrated with polymorphonuclear granulocytes. The tubules in the affected areas were undergoing degeneration, and there were varying degrees of regenerative epithelium in the proximal convoluted tubulcs. Fibrosis of the interstitium was also a prominent feature of the lesions as were dilated tubules, many of which contained proteinaceous material. The surface of the kidney was pitted in the areas of nephritis. The severity of the nephritis in the animals receiving 2.0% UDL71077 in their diet generally ranged from moderate to severe; whereas, in the rats receiving 0.5% UDL-1077, the degree of nephritis was generally slight.
No compound-related microscopic alterations were seen in the urinary bladders from any of the treated rats. Calculi were seen in the lumen of the urinary bladders from both control and treated male rats.

Examination after 24 weeks (Group I was designated as the controls, Group II the low level, Group III the intermediate level , and Group IV the high level.):
Compound related microscopic alterations were seen in the kidneys from the male and female rats in Groups III and IV. Compound related microscopic alterations were not seen in the kidneys from the male and female rats in Group II. The severity of the microscopic alterations was somewhat greater in the males than in the females in Group III; however, in Group IV there were no meaningful differences in severity between the male and female rats. The compound related microscopic alterations seen in the kidneys were characterized by varying degrees of interstitial nephritis, regenerative epithelium, tubular degeneration and necrosis, purulent pyelnephritis, pelvic epithelial hyperplasia and the presence of crystalline material in the tubules or lumen of the pelvis. The interstitial nephritis was characterized by an infiltration of lymphocytes and mononuclear macrophages into the interstitium of the cortex, corticomedullary and medulla. Varying degrees of fibrosis accompanied this cellular infiltrate. The glomeruli and tubules in the areas of fibrosis and inflammation were degenerate or necrotic. The severity of these microscopic alterations in the kidneys from the male and female rats in Group IV ranged from moderate to moderately severe; whereas, in the females from Group III, the severity ranged from slight to moderate.
No compound related microscopic alterations were seen in the ureters or urinary bladders from any of the treated rats. Similarly, the histologic appearance of the kidneys from the male and female rats in Group II was comparable to that seen in the Group I controls.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
LOAEL
Effect level:
0.5 other: % of total diet
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: c. 412.4 mg/kg bw/d
Key result
Dose descriptor:
NOAEL
Effect level:
0.125 other: % of total diet
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Remarks on result:
other: c. 102.9 mg/kg bw/d
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
0.5 other: % of total diet
System:
haematopoietic
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
In conclusion, the results of this study indicate that the dietry administration of UDL-1077 at 0.5% and 2.0% of the diet for a period of 13 or 24 weeks resulted in the development of a purulent nephritis with degeneration of the epithelium in the proximal convoluted tubules. The administration of 0.125% UDL-1077 in the diet for 13 or 24 weeks did not result in any compound-related microscopic changes.
Executive summary:

This study, conducted for The Procter & Gamble Company, was designed to assess the toxicity of UDL-1077 when administered in the diet to rats for twenty-four weeks at dose levels of 0.125, 0.5 and 2.0 percent of total diet.

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
sub-chronic toxicty study, substance administered orally in the diet, 3 test groups plus control, 12 weeks of treatment
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
Sasil (A Zeolite)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Wistar rat of the MuRa SPF 67 strain, c. 144 (males) and c. 151 (females) days old on section day (after 12 weeks of treatment)
Average weight at study's beginning: 158 (males) and 140 (females) grams
Acclimatisation time: 8 days
Temperature: 21 */- 2 °C
Relative humidity: 50 +/- 5 %
Light/dark: 12/12 h
Diet: Altromin #1324 (ad libitum)
Route of administration:
oral: feed
Duration of treatment / exposure:
12 weeks
Frequency of treatment:
Substance was added to the feed, which was available ad libitum.
Dose / conc.:
1 000 ppm
Remarks:
Group 1
Dose / conc.:
5 000 ppm
Remarks:
Group 2
Dose / conc.:
10 000 ppm
Remarks:
Group 3
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
The first examination of the rats for their state of health were made after introduction and sorting. Then daily observations through the viewing window, detailed 4 times a week when moving the animals. Food and water consumption were measured once a week. Test animals were weighed once a week, on the same day at the same hour, using the Messtec animal scales.
Sacrifice and pathology:
After the end of the experiment, all rats were bled and dissected while inebriation. Internal organs were examined macroscopically. The most important organs were removed and the absolute wet weights determined.
The amount of copper in the liver was also determined, as well as the amount of silicon in the food, in the organs and in the water, plus the amount of tin and aluminum in the kidney.
A histopathological examinatio of the following organs was performed:
Other examinations:
The examinations of the urine and the composition of the urine sediment were carried out on all rats at the beginning and at the end of the experiment. Subsequent in vitro parameters were determined: amount of urine, pH, protein, glucose, urobilinogen, ketone bodies, specific weight, blood, epithelia (bladder), renal epithelia, leukocytes, erythrocytes, bacteria, urates, calcium oxalate, triple phosphate and other foreign bodies.
At the beginning and at the end of the experiment, the blood was taken from the tail vein for hematological investigations in all animals. The following was determined: hemoglobin, red blood cell count, white blood cell count, and blood sugar.
The blood for these investigations was obtained at the beginning and at the end of the experiment by cardiac puncture while the animals were intoxicated. The following parameters were determined in the serum: alkaline phosphatase, glutamate oxaloacetate transaminase, glutamate pyruvate transaminase (GPT), urea and total protein.
Statistics:
The mean values, standard deviations, the upper and lower confidence limits were determined with the computer.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In comparison with controls, the test animals showed no changes in their behavior during the application period. From week 6 onwards, well-defined, local alopecia on the lower neck area and on the flanks was found in 3 female animals of group 3 (10,000 ppm). The same finding was observed in 3 male animals in group 1 (1,000 ppm) and in 2 male control animals from the 8th week of the experiment. This finding is known in the rats that are used in groups and cannot be related to the test substance.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There were considerable fluctuations in food and water consumption during the experiment, which, according to the authors' experience, was normal for rats. In addition, one had to take into account the sometimes considerable losses of feed and water that were caused by keeping the animals. However, the tables and figures showed that the two parameters run more or less parallel in all animal groups.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
cf. above: Food consumption and compound intake
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no haematological findings in all 4 groups.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No abnormal findings, no differences between the test groups and the control.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
In test groups 1 and 2 (1,000 ppm and 5,000 ppm) there were no findings that differed significantly from the controls. The traces of protein or values around 100 are a frequent occurrence in the rat urine and are due to the activity of the accessory gonads (seminal vesicles, prostate), especially in male animals.

A certain deviation in the urine picture between the experimental animals and controls could be observed when looking at the individual values of male 10,000 ppm rats as follows:
- Decreased urine output
- Blood in the urine of 3 experimental animals
- An increased excretion of the ketone bodies

With regard to faeces, between the test groups and thr control no essential differences were noted.
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At the dose of 10,000 ppm, stones were found in the urinary bladder in 12 of the 20 male rats, which had a diameter of 0.5-5 mm. The number of stones was 1 to 20, depending on the size. The main component of the stones was silicon, but traces of sulfur, chlorine and potassium were also found.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The lymphocyte infiltrates in the submucosa of the urinary bladder in 2 male and 2 female animals of the 5000 ppm dose group, as well as the liver changes in the test and control animals, were assessed as an expression of a non-specific defense against latent antigens that could not be further defined.
The renal changes in a single rat from the highest dose group were found to be focal tubular nephrosis. In this context it was an incidental finding. No further changes were detectable.
Histopathological findings: neoplastic:
no effects observed
Details on results:
In summary, it was found that the dose of 5,000 ppm in the rats did not lead to any changes which could be attributed to a cumulative toxic effect of the test substance.
Dose descriptor:
NOAEL
Effect level:
>= 10 000 ppm
Sex:
female
Remarks on result:
other: 10000 ppm = ~ 706 mg/kg bw/d
Dose descriptor:
NOAEL
Effect level:
5 000 ppm
Sex:
male
Remarks on result:
other: 5000 ppm = ~ 292 mg/kg bw/d
Key result
Dose descriptor:
LOAEL
Effect level:
10 000 ppm
Sex:
male
Basis for effect level:
gross pathology
Remarks on result:
other: 10000 ppm = ~ 577 mg/kg bw/d
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 000 ppm
System:
gastrointestinal tract
Organ:
bladder
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
At the dose of 5,000 ppm (c. 292 mg/kg bw/d), no findings were made that could be attributed to the cumulative toxic effect of the test substance. The dose of 5,000 ppm was therefore the no effect level for rats.

The diet of 10,000 ppm (c. 577 mg/kg bw/d) resulted in the formation of stones in the urinary bladder in male rats. The stones of different sizes contained mainly silicon and traces of S, CL and K.
Executive summary:

In a sub-chronic toxicty study Sasil was administered orally in the diet to rats for 12 weeks. Adverse effects were only discovered in males of the highest dose group of 10,000 ppm.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
292 mg/kg bw/day
Study duration:
subchronic
Experimental exposure time per week (hours/week):
168
Species:
rat
Quality of whole database:
reiliability 1
System:
haematopoietic
Organ:
kidney

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
silicone content in lungs
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline followed
Principles of method if other than guideline:
examination whether silicone got into the lower respiratory system of experimental animals: 1 dose and 1 control group, 3 whole body inhalations per week, total of 13 applications
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder with a middle particle diameter of 11.1 µm.
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
- adult SPF Wistar rats with an average body weight of 250 g (tretated group) and 251 g (control animals) at the start of the experiment
- keeping of the rats: conventionally under daylight
- feed: ALTROMIN 1324 and water ad libitim. During inhalations food and water were withdrawn from the animals.
- inhalation chambers: 24°C; relative humidity 55%; in wire cages; 2 test animals or 2 control animals per cage, separated by a perforated sheet metal wall.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 days of application
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
24 (males only) in treatment and control groups
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
daily observation
weighted once per week
Sacrifice and pathology:
After the last application all rats were killed and an individual silicon determinations of the lungs performed.
Other examinations:
The lungs were dried at 130° C for 16 hours. After weighing they were pulverised in a micromill with a steel mortar and steel balls.
Clinical signs:
no effects observed
Description (incidence and severity):
All rats survived the experiment without any apparent symptoms.
Mortality:
no mortality observed
Description (incidence):
All rats survived the experiment without any apparent symptoms.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
SASIL
1 / 2 / 3 week: 250 / 294 / 320 g

Control
1 / 2 / 3 week: 251 / 290 / 313 g
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopically no changes in the internal organs or no deviations from the controls.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Silicon content in lungs after 13 applications
Sasil: 0.0822 +/- 0.0294 mg/cm³
Control: 0.0493 +/- 0.0213 mg/cm³
Critical effects observed:
no
System:
respiratory system: lower respiratory tract
Organ:
lungs
Conclusions:
According to these results, the presence of silicium in the lungs of rats after inhalation can be considered as evident. But macroscopically no changes in the internal organs nor deviations from the controls were observed.
Executive summary:

Based on their long-term inhalation experiments with rats the authors examined whether SASIL got into the lower respiratory system of the experimental animals.

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Feb. 28, 1976 - Feb. 8, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
But the results of this study have to be considered with some caution due to chronic pneumonia that affected almost all animals.
Qualifier:
no guideline followed
Principles of method if other than guideline:
chronic inhalation study in rats: 1 dose and 1 control group (and one additional dose and one additional control group after 14 months), 3 whole body inhalations per week.
Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed after 22 months.
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder, particle size to over 80% between 1 and 6 µm.
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- HAN 67 SPF Wistar rats with an average body weight of 139-154 g (main group) and 125-130 g (additional group) at the start of the experiment
- keeping: conventionally under daylight
- feed: ALTROMIN 1324 and water ad libitim. During inhalations food and water were withdrawn from the animals.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gravimetric measurements of the amount of dust and dose
Duration of treatment / exposure:
main groups: 22 months
additional groups: 8 months
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
15 in treatment and control groups (main groups for 22 months)
15 males and 10 females in treatment and control groups (additional groups for 8 months)
Control animals:
yes, concurrent vehicle
Details on study design:
inhalation chambers: 24°C; relative humidity 55%; in wire cages; 5 test animals or 5 control animals per cage.
Observations and examinations performed and frequency:
daily observation
weighted once per week until week 23, thereafter every fortnight, and beginning with the 32nd week of the experiment once per month
Sacrifice and pathology:
All rats were dissected at the end of the experiment and the internal organs, especially the target organs, histologically examined. 2 male controls were also microbiologically examined due to infectious disease of airways of all rats.
Due to chronic pneumonia that attacked about the 20th month of the experiment almost all animals, the final sacrifice was performed already after 22 months.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
10 months after the start of the experiment, the first cases of respiratory diseases were observed. The affected rats began to sneeze briefly,
there were convulsions of coughing with whistling sounds in the expirium. The animals lost weight and sat apathetically in a crouching position in the cages. After occurrence of the marked dyspnea some rats developed a reddish discharge from the nose. These observations concerned both the test animals and the controls evenly. Reinforced hygiene measures did not help. The chronic pneumonia attacked about the 20th month of the experiment almost all animals
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality occured in treated and control animals.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The average body weights of the two groups of animals were more or less parallel during the experiment, and taking the age of the animals into account
it was without any special features. The slight deviations from the 11th month onward were not significant and did not occur substance-specific, but rather due to the moribund state of some rats.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
The animals calmed down quickly after onset of inhalation and lay isolated, rarely in small groups, with normal breathing frequency, in the cages. The rats did not show aggressiveness. There were no abnormalities with regard to excrement or urine output. The experimental animals cleaned themselves more often than the controls and closed their eyes during the inhalation time and also in the in the activity phase more often (avoidance of conjunctival foreign body reactions due to SASIL).
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The rats showed macroscopically almost without exception bronchiectasis, purulent slimy exudates in the trachea and in the large
bronchial branches. Some of the lungs were atelectatic bloated, the individual gray-red lung lobes partially to completely hepatized. The mediastinal lymph nodes were mostly enlarged and dark to black.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
All animals examined, i.e. controls and experimental animals showed bronchopneumonia in various stages corresponding to the picture of chronic murine pneumonia.
But there were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Different kinds of tumors were observed in five treated and in five control animals.
There were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.
Description (incidence and severity):
The test substance ws deposited in alveolar epihelias near the alveolar septum, in alveolar macrophages or alveolar epithelia in the alveoli, or in macrophages in the perivascular or peribronchial lymph sheaths. In the further consequence the substance was also deposited in the paracortical area
of the mediastinal lymph node.
Details on results:
A histopathological examination of some rats came to the following conclusion:
"The findings suggest a soluble dust, the initially clear fibrotic reaction of which was in regression.
In the periportal and mediastinal lymph nodes, individual and groups of macrophages were found that contained the material (SASIL). The dust centers showed no fibrotic tendency after the test period. They were fitted into the local network of reticular fibers. An increase in reticular and collagen fibers could certainly be ruled out. Thus, the material behaved like inert dust in the lymph nodes.

Another histopathological examination of 6 Sasil-treated and 4 control rats concluded that after 22 months of administration the inhaled Sasil did not cause tumors in the six experimental animals of the treated group and did not produce fibrosis in the lungs and regional mediastinal lymph nodes.
Dose descriptor:
NOAEL
Effect level:
>= 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
20 mg/m³ air (nominal)
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
no

The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed. The quality of those tumors observed and their temporal occurrence gave no indications of a carcinogenic activity of the test substance.

Conclusions:
The experiment had to be interrupted after 22 months of inhalation, since the rats developed chronic murine pneumonia.
But the findings suggested that SASIL neither produces fibrogenic nor carcinogenic effects.
Executive summary:

The aim of this investigation was to determine whether SASIL produces fibrotic or silicotic changes after repeated inhalation, and if it might produce tumors. For this purpose main groups of 15 male and 15 female Wistar rats were exposed to an aerosol of zeolite A at an average concentration of 20 mg/m³ for five hours a day, three days a week for a schedulded time period of 24 months. The control group received pure air. One additional dose group was dosed beginning after the 14th month of the experiment. Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed already after 22 months for the main groups (i.e. 8 months of administration for the additional group).


The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed.

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
experimental phase: Feb. 1976 - Mar. 1977; histopathological examination on Mar. 22, 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Inhalation of SISAL dust at a rate of 20 mg / m³, 3 x weekly (Mondays, Wednesdays, Fridays) 5 hours each for over one year
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder, particle size to over 80% between 1 - 6 µm
Species:
hamster, Syrian
Strain:
other: golden hamsters
Sex:
male/female
Details on test animals or test system and environmental conditions:
initial body weight:70 - 77 g
feed: Altromin 7020 (ad libitum) and everdy third day a fresh carrot
Water: tap water (ad libitum)
relative humidity: 45 -55 %
temperature: 19-23 °C
light/dark: 10:14 hours
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
1 year
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
daily observation
weighing once per week
Other examinations:
At the end of the experiment, all surviving hamsters were dissected and in particular the target organs (lungs) histologically examined.
In additiom, for external histological evaluation of the lungs, 3 step sections were made from the 4 main lobes of the lungs (lobus sinister, lobus dexter apicalis, - cardiacus, - diaphragmaticus) of 3 female and 2 male bamsters of the test group as well as 1 section each from the 4 main lobes of the lung of 5 females and 4 males from the control group.
Clinical signs:
no effects observed
Description (incidence and severity):
During the application time the hamsters showed no abnormalities. After the initial exploration phase, they slept with normal respiratory rates most of the inhalation time in typical positions.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Beginning the 9th month of the experiment, the animals became spontaneously and in increasing rate sick with generalized amyloidosis and renal insufficiency. The mortality rates of the controls were slightly higher than that of the treated groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The male and female experimental animals gained slightly more weight than the controls
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The main findings, both in treated and control animals, were infections, pneumonic foci, amyloidosis, preferably of the kidneys and bile duct proliferation.
In an additional external examination, the lungs of 4 Syrian golden hamsters (2 females and 2 males) were well ventilated and showed no pathological changes. The other organs were equally without any pathological finding.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No findings that pointed to silicotic, fibrotic or carcinogenic effects were made in the main study.

In the additional external examination, all animals of the test group showed focal purulent pneumonia different only in degree. The changes regularly concentrated in the lung area around bronchioli terminales and ductuli alveolares. The bronchi themselves remained free. The pneumonia foci consisted of macrophages with fine to coarse granular inclusions in the cytoplasm and accumulations of large ulocytes. Less common lympho-histiocytic cells occured.
With regard to controls, in one case, a subacute to chronic bronchitis and peribronchitis was observed, in another case a focal and diffuse purulent pneumonia was seen. In almost all animals existed in the area of the bronchioli terminales and puctuli alveolares small foci of makrophages with fine to coarse-grained, dusty pigmant inclusions as well as different strong granulocyte infiltrates.
The changes in the test and control animals, especially the processes in the area of the terminal bronchioles, showed a similar picture and differed considerably only in the degree of their development. From the nature of the changes, it could be concluded that there was an acute to subacute disease process that might have affected the animals only in the late stage of the experiments. The considerably different strengths of the reactions in the control and test animals could be caused by the different exposure levels in the experiment.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no connective tissue reactions, neither foreign body nasty cells in treated or control animals.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
clinical signs
gross pathology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
Key result
Dose descriptor:
NOEL
Effect level:
< 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain
histopathology: non-neoplastic
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
20 mg/m³ air (nominal)
System:
respiratory system: lower respiratory tract
Organ:
lungs

In the lungs, as the target organs, more pronounced purulent pneumonia was detected. These changes were also made in the controls, but somewhat less pronounced. There was no evidence of fibrotic disease or silicotic changes of the internal organs after inhalation of SASIL.

Conclusions:
In the lungs, as the target organs, more pronounced purulent pneumonia was detected. These changes were also made in the controls, but somewhat less pronounced. There was no evidence of fibrotic disease or silicotic changes of or carcinogenic effects to the internal organs after inhalation of SASIL.
Executive summary:

The aim of the experiment was to determine whether SASIL leads to fibrotic and silicotic changes after repeated inhalation. There were no findings that point to silicotic, fibrotic or carcinogenic effects.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Experimental exposure time per week (hours/week):
15
Species:
other: rat, hamster
Quality of whole database:
reliability 2

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Remarks:
silicone content in lungs
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose for cross-reference:
read-across source
Qualifier:
no guideline followed
Principles of method if other than guideline:
examination whether silicone got into the lower respiratory system of experimental animals: 1 dose and 1 control group, 3 whole body inhalations per week, total of 13 applications
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder with a middle particle diameter of 11.1 µm.
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
- adult SPF Wistar rats with an average body weight of 250 g (tretated group) and 251 g (control animals) at the start of the experiment
- keeping of the rats: conventionally under daylight
- feed: ALTROMIN 1324 and water ad libitim. During inhalations food and water were withdrawn from the animals.
- inhalation chambers: 24°C; relative humidity 55%; in wire cages; 2 test animals or 2 control animals per cage, separated by a perforated sheet metal wall.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
13 days of application
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
24 (males only) in treatment and control groups
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
daily observation
weighted once per week
Sacrifice and pathology:
After the last application all rats were killed and an individual silicon determinations of the lungs performed.
Other examinations:
The lungs were dried at 130° C for 16 hours. After weighing they were pulverised in a micromill with a steel mortar and steel balls.
Clinical signs:
no effects observed
Description (incidence and severity):
All rats survived the experiment without any apparent symptoms.
Mortality:
no mortality observed
Description (incidence):
All rats survived the experiment without any apparent symptoms.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
SASIL
1 / 2 / 3 week: 250 / 294 / 320 g

Control
1 / 2 / 3 week: 251 / 290 / 313 g
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopically no changes in the internal organs or no deviations from the controls.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Silicon content in lungs after 13 applications
Sasil: 0.0822 +/- 0.0294 mg/cm³
Control: 0.0493 +/- 0.0213 mg/cm³
Critical effects observed:
no
System:
respiratory system: lower respiratory tract
Organ:
lungs
Conclusions:
According to these results, the presence of silicium in the lungs of rats after inhalation can be considered as evident. But macroscopically no changes in the internal organs nor deviations from the controls were observed.
Executive summary:

Based on their long-term inhalation experiments with rats the authors examined whether SASIL got into the lower respiratory system of the experimental animals.

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Feb. 28, 1976 - Feb. 8, 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
But the results of this study have to be considered with some caution due to chronic pneumonia that affected almost all animals.
Qualifier:
no guideline followed
Principles of method if other than guideline:
chronic inhalation study in rats: 1 dose and 1 control group (and one additional dose and one additional control group after 14 months), 3 whole body inhalations per week.
Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed after 22 months.
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder, particle size to over 80% between 1 and 6 µm.
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- HAN 67 SPF Wistar rats with an average body weight of 139-154 g (main group) and 125-130 g (additional group) at the start of the experiment
- keeping: conventionally under daylight
- feed: ALTROMIN 1324 and water ad libitim. During inhalations food and water were withdrawn from the animals.
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
gravimetric measurements of the amount of dust and dose
Duration of treatment / exposure:
main groups: 22 months
additional groups: 8 months
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
15 in treatment and control groups (main groups for 22 months)
15 males and 10 females in treatment and control groups (additional groups for 8 months)
Control animals:
yes, concurrent vehicle
Details on study design:
inhalation chambers: 24°C; relative humidity 55%; in wire cages; 5 test animals or 5 control animals per cage.
Observations and examinations performed and frequency:
daily observation
weighted once per week until week 23, thereafter every fortnight, and beginning with the 32nd week of the experiment once per month
Sacrifice and pathology:
All rats were dissected at the end of the experiment and the internal organs, especially the target organs, histologically examined. 2 male controls were also microbiologically examined due to infectious disease of airways of all rats.
Due to chronic pneumonia that attacked about the 20th month of the experiment almost all animals, the final sacrifice was performed already after 22 months.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
10 months after the start of the experiment, the first cases of respiratory diseases were observed. The affected rats began to sneeze briefly,
there were convulsions of coughing with whistling sounds in the expirium. The animals lost weight and sat apathetically in a crouching position in the cages. After occurrence of the marked dyspnea some rats developed a reddish discharge from the nose. These observations concerned both the test animals and the controls evenly. Reinforced hygiene measures did not help. The chronic pneumonia attacked about the 20th month of the experiment almost all animals
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality occured in treated and control animals.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The average body weights of the two groups of animals were more or less parallel during the experiment, and taking the age of the animals into account
it was without any special features. The slight deviations from the 11th month onward were not significant and did not occur substance-specific, but rather due to the moribund state of some rats.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
After taking the animals out of the chambers and they were transferred to their stay cages, the feed consumption and water consumption increased for about 2 hours, obsered both in the experimental and control animals.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
The animals calmed down quickly after onset of inhalation and lay isolated, rarely in small groups, with normal breathing frequency, in the cages. The rats did not show aggressiveness. There were no abnormalities with regard to excrement or urine output. The experimental animals cleaned themselves more often than the controls and closed their eyes during the inhalation time and also in the in the activity phase more often (avoidance of conjunctival foreign body reactions due to SASIL).
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The rats showed macroscopically almost without exception bronchiectasis, purulent slimy exudates in the trachea and in the large
bronchial branches. Some of the lungs were atelectatic bloated, the individual gray-red lung lobes partially to completely hepatized. The mediastinal lymph nodes were mostly enlarged and dark to black.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
All animals examined, i.e. controls and experimental animals showed bronchopneumonia in various stages corresponding to the picture of chronic murine pneumonia.
But there were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Different kinds of tumors were observed in five treated and in five control animals.
There were no histological indications either for fibrogenic, silicogenic or carcinogenic effects provoked by SASIL.
Description (incidence and severity):
The test substance ws deposited in alveolar epihelias near the alveolar septum, in alveolar macrophages or alveolar epithelia in the alveoli, or in macrophages in the perivascular or peribronchial lymph sheaths. In the further consequence the substance was also deposited in the paracortical area
of the mediastinal lymph node.
Details on results:
A histopathological examination of some rats came to the following conclusion:
"The findings suggest a soluble dust, the initially clear fibrotic reaction of which was in regression.
In the periportal and mediastinal lymph nodes, individual and groups of macrophages were found that contained the material (SASIL). The dust centers showed no fibrotic tendency after the test period. They were fitted into the local network of reticular fibers. An increase in reticular and collagen fibers could certainly be ruled out. Thus, the material behaved like inert dust in the lymph nodes.

Another histopathological examination of 6 Sasil-treated and 4 control rats concluded that after 22 months of administration the inhaled Sasil did not cause tumors in the six experimental animals of the treated group and did not produce fibrosis in the lungs and regional mediastinal lymph nodes.
Dose descriptor:
NOAEL
Effect level:
>= 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
histopathology: non-neoplastic
Critical effects observed:
yes
Lowest effective dose / conc.:
20 mg/m³ air (nominal)
System:
respiratory system: lower respiratory tract
Organ:
lungs
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
no

The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed. The quality of those tumors observed and their temporal occurrence gave no indications of a carcinogenic activity of the test substance.

Conclusions:
The experiment had to be interrupted after 22 months of inhalation, since the rats developed chronic murine pneumonia.
But the findings suggested that SASIL neither produces fibrogenic nor carcinogenic effects.
Executive summary:

The aim of this investigation was to determine whether SASIL produces fibrotic or silicotic changes after repeated inhalation, and if it might produce tumors. For this purpose main groups of 15 male and 15 female Wistar rats were exposed to an aerosol of zeolite A at an average concentration of 20 mg/m³ for five hours a day, three days a week for a schedulded time period of 24 months. The control group received pure air. One additional dose group was dosed beginning after the 14th month of the experiment. Due to chronic pneumonia that affected almost all animals about the 20th month of the experiment, the final sacrifice was performed already after 22 months for the main groups (i.e. 8 months of administration for the additional group).


The results of this inhalation experiment allowed to conclude that the test substance after chronic inhalation in the lungs was neither silicogenic nor fibrogenic. No tumorous changes were found pathologically or histologically in the respiratory tract or in other associated locations observed.

Endpoint:
chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
experimental phase: Feb. 1976 - Mar. 1977; histopathological examination on Mar. 22, 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Inhalation of SISAL dust at a rate of 20 mg / m³, 3 x weekly (Mondays, Wednesdays, Fridays) 5 hours each for over one year
GLP compliance:
no
Limit test:
yes
Specific details on test material used for the study:
SASIL (A Zeolite)
charge F-325, fine white powder, particle size to over 80% between 1 - 6 µm
Species:
hamster, Syrian
Strain:
other: golden hamsters
Sex:
male/female
Details on test animals or test system and environmental conditions:
initial body weight:70 - 77 g
feed: Altromin 7020 (ad libitum) and everdy third day a fresh carrot
Water: tap water (ad libitum)
relative humidity: 45 -55 %
temperature: 19-23 °C
light/dark: 10:14 hours
Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Remarks:
inhalation chamber
Vehicle:
air
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
1 year
Frequency of treatment:
on Mondays, Wednesdays and Fridays for 5 hours each
Dose / conc.:
20 mg/m³ air (nominal)
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
daily observation
weighing once per week
Other examinations:
At the end of the experiment, all surviving hamsters were dissected and in particular the target organs (lungs) histologically examined.
In additiom, for external histological evaluation of the lungs, 3 step sections were made from the 4 main lobes of the lungs (lobus sinister, lobus dexter apicalis, - cardiacus, - diaphragmaticus) of 3 female and 2 male bamsters of the test group as well as 1 section each from the 4 main lobes of the lung of 5 females and 4 males from the control group.
Clinical signs:
no effects observed
Description (incidence and severity):
During the application time the hamsters showed no abnormalities. After the initial exploration phase, they slept with normal respiratory rates most of the inhalation time in typical positions.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Beginning the 9th month of the experiment, the animals became spontaneously and in increasing rate sick with generalized amyloidosis and renal insufficiency. The mortality rates of the controls were slightly higher than that of the treated groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The male and female experimental animals gained slightly more weight than the controls
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The main findings, both in treated and control animals, were infections, pneumonic foci, amyloidosis, preferably of the kidneys and bile duct proliferation.
In an additional external examination, the lungs of 4 Syrian golden hamsters (2 females and 2 males) were well ventilated and showed no pathological changes. The other organs were equally without any pathological finding.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No findings that pointed to silicotic, fibrotic or carcinogenic effects were made in the main study.

In the additional external examination, all animals of the test group showed focal purulent pneumonia different only in degree. The changes regularly concentrated in the lung area around bronchioli terminales and ductuli alveolares. The bronchi themselves remained free. The pneumonia foci consisted of macrophages with fine to coarse granular inclusions in the cytoplasm and accumulations of large ulocytes. Less common lympho-histiocytic cells occured.
With regard to controls, in one case, a subacute to chronic bronchitis and peribronchitis was observed, in another case a focal and diffuse purulent pneumonia was seen. In almost all animals existed in the area of the bronchioli terminales and puctuli alveolares small foci of makrophages with fine to coarse-grained, dusty pigmant inclusions as well as different strong granulocyte infiltrates.
The changes in the test and control animals, especially the processes in the area of the terminal bronchioles, showed a similar picture and differed considerably only in the degree of their development. From the nature of the changes, it could be concluded that there was an acute to subacute disease process that might have affected the animals only in the late stage of the experiments. The considerably different strengths of the reactions in the control and test animals could be caused by the different exposure levels in the experiment.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no connective tissue reactions, neither foreign body nasty cells in treated or control animals.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
clinical signs
gross pathology
histopathology: neoplastic
histopathology: non-neoplastic
mortality
Key result
Dose descriptor:
NOEL
Effect level:
< 20 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
body weight and weight gain
histopathology: non-neoplastic
Key result
Critical effects observed:
no
Lowest effective dose / conc.:
20 mg/m³ air (nominal)
System:
respiratory system: lower respiratory tract
Organ:
lungs

In the lungs, as the target organs, more pronounced purulent pneumonia was detected. These changes were also made in the controls, but somewhat less pronounced. There was no evidence of fibrotic disease or silicotic changes of the internal organs after inhalation of SASIL.

Conclusions:
In the lungs, as the target organs, more pronounced purulent pneumonia was detected. These changes were also made in the controls, but somewhat less pronounced. There was no evidence of fibrotic disease or silicotic changes of or carcinogenic effects to the internal organs after inhalation of SASIL.
Executive summary:

The aim of the experiment was to determine whether SASIL leads to fibrotic and silicotic changes after repeated inhalation. There were no findings that point to silicotic, fibrotic or carcinogenic effects.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
other: rat, hamster
Quality of whole database:
reliability 2

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In the 2010 edition of this dossier the study in monkeys was used as a key one for inhalation. However, a re-evaluation has shown that it should be entirely disregarded as no NOAEL effect level can reliably be derived from it: Pre-existing kaolin (from treatment against diarrhea) or widespread mite lesions appeared to have increased the severity of the effect of inhalation of the test compound. Therefore, all observed effects, at least partially, might have been provoked by these factors. This is stated by the authors of the studies themselves on page 101 of the study report: "inflammatory reactions [...] were primarily in lobes of the lungs where there was residual damage from Pneumonyssus sp. (mites) or from kaolin."

Justification for classification or non-classification

As the studies via the inhalation route did not provoke harmful effects and the observed results of those via the oral route are above the threshold level of GHS, there is no need for classification. The weight-of-evidence also does not suggest any harmful dermal effects.