Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-05-05 to 1986-02-01
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Similar to OECD Guideline 413 with the following deviations: (1) Only one concentration was tested rather than 3: (2) 8 animals/sex/dose were evaluated rather than 10/sex/dose; (3) ophthalmological and clinical chemistry evaluations were not conducted; (4) histopathology did not include bone marrow evaluation.

Data source

Referenceopen allclose all

Reference Type:
grey literature
Title:
Unnamed
Year:
1986
Report Date:
1986
Reference Type:
publication
Title:
SIDS Initial Assessment Report for SIAM 21 for Tungsten Carbide (12070-12-1), Washington DC,18-20 October, 2005
Author:
OECD-SIDS
Year:
2005
Bibliographic source:
UNEP Publications
Report Date:
2005

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
(1) Only one concentration was tested rather than 3: (2) 8 animals/sex/dose were evaluated rather than 10(3) ophthalmological and clinical chemistry evaluations were not conducted; (4) histopathology did not include bone marrow evaluation.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): tungsten carbide
- Purity: >99.4%

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 9-11 weeks
- Housing: individually in stainless steel, wire-mesh cages
- Diet: ad libitum (except during exposure periods)
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1983-05-09 to 1983-06-09 To: 1983-08-02 to 1983-09-02

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: MMAD = 4.2 um with a GSD = 1.86
Details on inhalation exposure:
- The tungsten particles were aerosolized using model 9310 generators. The automatic feed systems of the generators were not employed because the physical consistency of these powders rendered the feed mechanisms ineffective. Instead, each powder was mixed with bronze beads from the respective generator by vigorously shaking in a plastic container. During the mixing process, the bronze beads were coated with dust particles. To disperse the particles, dry, filtered air was introduced through the microporous stainless steel support screen at the bottom of the bed. he air caused the beads to Collide with one another, striping the particles from the beads and carrying the resultant aerosol to the outlet of the generator. The delivery line from each generator leading to the air intake line of the exposure chambers was equipped with a 60 mCi 85Kr neutralizing source to bring the electrical charge of the particles to Boltzman equilibrium.
- Separate generators were used to aerosolize the WC dust in each chamber.
- Exposures were carried out in 5.0 m Hinners type chambers constructed of stainless steel and Lucite. Airflow through the chambers was 11 chamber volumes per hour. Exhaust air from the chambers was passed through electrostatic precipitators, a prefilter and a HEPA filter before being discharged. Temperature in each chamber was monitored continuously by computer and the average temperature during each 0 .5 hr interval recorded. The average temperature during the exposure of these animals was 20 .5 degree C . The mean average daily temperature ranged from 19 .2 to 22 .7 degree C and the minimum and maximum 0 .5 hr averages were 18 .6 and 23 .9 degree C, respectively .
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On-line monitoring of the aerosol mass in the exposure chambers was accomplished using RAM-1 mass monitors and strip chart recorders. During each daily exposure period, at least one but more frequently 2, filter samples were drawn from each exposure chamber. The total dust concentrationsin the WC chambers were determined gravimetrically. The concentration of WC was determined by difference .
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
15 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
14.97 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
8 mice/sex were designated for observation of body weight changes, organ weights, hematology, and pathology. Another 10 male mice were designated for cytogenetic and sperm abnormality studies.
Control animals:
yes, sham-exposed
Details on study design:
Post-exposure period: 6 days
Positive control:
none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily prior to exposure, when the food troughs were removed and clean catch pans were provided, and again following the exposure period when the food troughs were replaced.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On the days that the animals were weighed.

BODY WEIGHT: Yes
- Time schedule for examinations: Each animal was weighed in the morning of its initial exposure and then weekly on Mondays and Wednesdays and on the morning following their final exposure and on the day of the endpoint assessment.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At sacrifice
- Anaesthetic used for blood collection: Yes
- Animals fasted: No data
- How many animals: No data
- Parameters that were examined: white and red blood cell counts, hemoglobin, hematocrits, mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, 8 animals/sex/dose
HISTOPATHOLOGY: Yes, Brain, pituitary, adrenals, trachea, esophagus, thyroid, parathyroids, thymus, heart, pancreas, spleen, kidneys, liver, preputial glands, gall bladder, larynx, peribronchial lymph node, lungs, uterus, testis, prostate, epididymis, urinary bladder, stomach, duodenum, jejunum, ileum cecum, colon, salivary gland, skin, mammary gland, mesenteric lymph node, nasal turbinate, sternum, rib junction, skeletal muscle, peripheral nerve, eyes, diaphragm, and penis
Other examinations:
Cytogenetic and sperm abnormality studies.
Statistics:
Growth of male and female exposure groups were analyzed separately. Variation in body weights was examined by analysis of covariance with repeated measures, in which the exposure groups represented the treatment factors, weekly weights were the repeated measures, and initial weights were considered the covariants. Differences in growth rates among the exposure groups were investigated by finding least squares linear regression equations that expressed the mean weekly adjusted weight for each group as a function of exposure time. To statistically assess the differences of means of a single variable between any 2 groups the Student's-t test was employed. However, one way analysis of variance (ANOVA) was used to compare the means of single variables across exposure groups. When ANOVA indicated a significant difference among group means, Duncan's multiple range method of multiple comparisons was used to investigate the source of the differences (p = 0 .05). In addition to ANOVA, quasi-static compliance data and flow-volume data were each analyzed as sets of variables. These sets were compared among exposure groups by a multi-variate analysis of variance (MANOVA). To investigate differences among exposure groups based on histopathologic data, the values were non-parametrically ranked and were then analyzed by the Kruskal-Wallis non-parametric test. When a significant difference was indicated among the groups, non-parametric multiple comparisons were performed according to the Mann-Whitney Simultaneous Test Procedure to identify the source of the differences.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
The incidence of chronic runny nose (rhinitis) in female mice was 0/8 controls and 4/8 of the WC group. Other changes in the tissues of the female exposure groups appeared to be incidental. No significant effects on hematological parameters were reported.

No effects were seen in males.

Bone marrow was not evaluated as part of the general histopathology evaluation, but subsets of rats were exposed and bone marrow was removed from the femurs and slides were prepared for a genetic toxicity evaluation. However, the slides prepared were not reviewed.

Effect levels

open allclose all
Dose descriptor:
LOEL
Effect level:
15 mg/m³ air (nominal)
Sex:
female
Basis for effect level:
other: Chronic rhinitis in females
Dose descriptor:
NOAEL
Effect level:
>= 15 mg/m³ air (nominal)
Sex:
male
Basis for effect level:
other: no apparent effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The LOAEL for females was 15 mg/m3 based on chronic rhinitis. No effects were seen in males exposed at this dose level therefore the NOAEL for males was determined to be >=15 mg/m3.