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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Septmber 24 1991 - December 30 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to GLP and internationally accepted OECD guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Kieselguhr, soda ash flux-calcined
EC Number:
272-489-0
EC Name:
Kieselguhr, soda ash flux-calcined
Cas Number:
68855-54-9
Molecular formula:
SiO2
IUPAC Name:
Kieselguhr, soda ash flux-calcined
Details on test material:
- Name of test material (as cited in study report): Natural Diatomaceous Earth and Flux Calcined Diatomaceous Earth
-Source: Supplied by Manville Corporation
- Lot/batch No.: Natural Diatomaceous Earth (5%) - 10418.0, Flux Calcined Diatomaceous earth 1% - 10419.0 and Flux Calcined Diatomaceous Earth 5% - 10420.0
- Storage condition of test material: Under refrigeration

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: 6 weeks
- Weight at study initiation: 163 - 220 g for males and 136 - 171 g for females
- Housing: Stainless steel, hanging wire-mesh cages
- Diet: Pelleted Purina Certified Rodent Chow #5002 available ad libitum during acclimation period
- Water: Tapwater via an automatic watering system was available ad libitum during both acclimation and study periods
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature: 72 ± 6°F
- Humidity: 50 ± 20%
- Photoperiod: 12hrs dark / 12 hrs light:


Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test materials were formulated into pellets with a single lot of Purina Certified Rodent Chow #5002. Purina Certified Rodent Chow #5002 was also formulated into pellets to serve as the control material
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The total silica and crystalline silica (quartz and cristobalite) were determined in the feed mixtures priorto the study and in the pellets at weeks 1, 7 and 13. The percent total silica in the 5% feed mixtures and pellets of Natural Diatomaceous Earth was 4.8% with 0.44% quartz and no cristobalite. The percent total silica in the 1% feed mixtures and pellets of Flux Calcined Diatomaceous Earth was 1.2% with 0.24% quartz and 0.26& cristobalite. The percent total silica in the 5% feed mixtures and pellets of Flux Calcined Diatomaceous Earth was 5.1% with 0.43% quartz and 1.70% cristobalite.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Natural Diatomaceous Earth 5% (average of 3765.5 mg/kg/day)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Flux Calcined Diatomaceous Earth 1% ( average of 698.3 mg/kg/day)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Flux Calcined Diatomaceous Earth 5% ( average of 3737.9 mg/kg/day)
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, plain diet

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Time schedule: Twice daily for mortality and moribundity

DETAILED CLINICAL OBSERVATIONS: Yes
Time schedule: Once daily


BODY WEIGHT: Yes
Time schedule for examinations: Measured and recorded at randomization, prior to treatment and weekly, thereafter

WATER CONSUMPTION: No


FOOD CONSUMPTION AND COMPOUND INTAKE (: Yes
Time schedule for examinations: Measured and recorded weekly for weeks 1-13

HAEMATOLOGY: Yes
Time schedule for collection of blood: During week 13 of the study
Animals fasted: Yes
How many animals: first ten animals/sex/group
Parameters checked: cell morphology, corrected leukocyte count (COR WBC), erythrocyte count (RBC), haematocrit (HCT), haemoglobin(HGB), leukocyte count (WBC), leukocyte differential, platelet count

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: During week 13 of the study
Animals fasted: Yes
How many animals: first ten animals/sex/group
Parameters checked: alanine aminotransferase (ALT), albumin, aspartate aminotransferase (AST), blood urea nitrogen (BUN), calcium, chloride, creatine , gamma glutamyltransferase (GGT), glucose, inorganic phosphorous (IN PHOS), potassium, sodium, total bilirubin (T BILI), total protein (T PROT), creatinine, total protein (T PROT),

URINALYSIS: Yes
Time schedule for collection of blood: During week 13 of the study
Animals fasted: Yes
How many animals: last five animals/sex/group
Parameters checked: Urine samples were analyzed for total silica content

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: An indirect opthalmoscopic examination was performed on each animal prior to treatment and on all group 1 and 4 animals during week 13

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY:
Performed on all animals. The necropsy included: adrenals, aorta, brain, cervical spinal cord, colon, cecum, rectum, duodenum, jejunum,ileum, esophagus, eyes, heart, kidneys, lesions, liver, lumbar spinal cord, lung, mammary gland, mesenteric lymph node, mid-thoracic spinal cord, ovaries, pancreas, pituitary, prostat, sciatic nerve, spleen, salivary glands, sternum with bone marrow, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus with vagina and cervix.

HISTOPATHOLOGY:
Histopathology performed on all preserved tissue from groups 1, 2 and 4

ORAN WEIGHTS:
Adrenals, kidneys, liver, testes with epididymides

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All animals survived to study termination. Alopecia and sores were the clinical signs most frequenly observed but occurred sporadically at a low frequency and were not considered related to treatment.


BODY WEIGHT AND WEIGHT GAIN
During the study there were no statistically significant differences noted in the mean body weight or mean body weight change data between the treated and control groups of either sex

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
mean food consumption for the group 3 males was significantly less than the respective control value for weeks 1-4, 1-8, and 1-13. No other statistically significant differences were noted in food consumption data for either sex at the intervals analyzed. Mean overall compound consumption (mg/kg/day) for weeks 1-13 was 3533.3, 655.3 and 3543.4 for the group 2, 3 and 4 males, respectively, and 3997.8, 740.7, and 3932.3 for the group 2, 3 and 4 females, respectively.

FOOD EFFICIENCY
In the males, mean overall food efficiency (%) for weeks 1-13 was 14.3, 14.6, 15.5 and 14.8 for groups 1 through 4, respectively, and in females was 9.1, 8.8, 9.3 and 9.0 forgroups 1 through 4 respectively.


OPHTHALMOSCOPIC EXAMINATION
During the 13 week ophthalmic examinations, a group 4 female exhibited chromodacryorrhea of the right eye. This finding was not considered treatment related. No other ophthalmic lesions were observed at the week 13 examinations.

HAEMATOLOGY
There were no significant findings in the hematology data

CLINICAL CHEMISTRY
There were no significant findings in the serum chemistry data

URINALYSIS
Refer to table 2 for data

ORGAN WEIGHTS
Statistical analysis of mean organ weight data revealed no significant differences between treated and control groups.


GROSS PATHOLOGY
There were few gross pathology findings at terminal scarifice and the findings were of the type routinely observed in rats. None were considered treatment related.

HISTOPATHOLOGY: NON-NEOPLASTIC
No compound related histomorphological findings were observed after 13 weeks of treatment. Similar frequency and severity of commonly seen spontaneous disease lesions and incidental findings were noted in control and experimental rats of both sexes.

Effect levels

Dose descriptor:
NOAEL
Remarks:
Flux Calcined DE
Effect level:
3 737.9 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No treatment related effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 2: Mean total silica content in urine ( µg/g)

Group

Week 1

Week 7

Week 13

Male

Female

Male

Female

Male

Female

1

31

28

29

34

28

58

2

36

40

48

52

42

91

3

34

24

23

30

37

43

4

35

45

30

46

32

49

Results were obtained from 5 animals/group/sex

Within one standard deviation the silica content in the urine of both males and females fed the control diet, the 5% natural DE pellets and the 1% flux calcined pellets or the 5% flux calcined pellets did not changed between 1 and 13 weeks during the study. Within one standard deviation, the silica content in the urine of the males and females ded the 5% natural DE pellets, the 1% flux calcined pellets or the 5% flux calcined pellets did not differ from the silica content in males and females fed the control diet.

Applicant's summary and conclusion

Conclusions:
In conclusion, administration of Natural DE at a dose level of 5% (average of 3765.6 mg/kg/day) or Flux Calcined DE at dose levels of 1% (average of 698.3 mg/kg/day) and 5% (average of 3737.9 mg/kg/day) did not produce any treatment related effects.