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Toxicity to reproduction

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toxicity to reproduction
other: 28-day repeat dose inhalation toxicity study
Type of information:
experimental study
Adequacy of study:
supporting study
4 (not assignable)
Rationale for reliability incl. deficiencies:
documentation insufficient for assessment
28-day inhalation toxicity study on tungsten Blue oxide (TBO). For purposes of evaluation of reproductive toxicity, only reproductive organs were evaluated. Due to higher water solubility and greater in vitro bioaccessibility in synthetic alveolar, lysosomal, and interstitial fluids simulating inhalation exposure for the source substance (TBO) as compared to the target substance (tungsten metal) and lack of toxicity from acute toxicity studies for the target and source substances, toxicity data on the target substance is expected to represent a worse case, so read-across is appropriate between these substances. In addition, read-across is appropriate for this endpoint because the classification and labelling for human health toxicity endpoints is the same for the source and target substances, the PBT/vPvB profile is the same, and the dose descriptors are, or are expected to be, sufficiently similar or more conservative for the target substance. For more details, refer to the attached description of the read-across approach.

Data source

Reference Type:
study report

Materials and methods

Test guideline
according to
other: OECD 428
GLP compliance:
Limit test:

Test material

Details on test material:
- Name of test material (as cited in study report): Tungsten blue oxide (TBO)
- Physical state: dark blue heavy powder
- Analytical purity: 99.7-100%
- Storage condition of test material: stored at room temperature (approximately 15-30 degree C) in its original container

Test animals

Details on test animals and environmental conditions:
- Source: Charles River Laboratories, (St. Constant, Canada)
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: One day following receipt, body weight ranges of the first shipment of rats 226 to 279 g (males) and 146 to 173 g (females). One day following receipt, body weight range of the second shipment of male rats was 207 to 234 g.
- Fasting period before study: no food or water was provided during exposures.
- Housing: At the start of food consumption measurements, the rats were individually housed in clear polycarbonate rodent cages (Allentown Caging Equipment Co., Allentown, NJ).
-Diet: Certified Rodent Chow 5002 meal (PMI Nutrition International, Inc., Brentwood, MO) was provided ad libitum, except during inhalation exposures and scheduled fasting periods. Diet analysis reports received from the supplier are maintained with facility records. The diet contained no known contaminants at levels that would be expected to interfere with the test substance or the animals or confound interpretation of the study.
- Water (e.g. ad libitum): Each rodent cage was provided with an automatic watering system (Edstrom Industries, Inc., Waterford, WI) supplying fresh city of Chicago water without additional treatment ad libitum, except during inhalation exposures.
- Acclimation period: The animals were quarantined for 2 weeks; To condition the animals for placement and restraint in the nose-only exposure tubes, and reduce stress during the exposure phase, the animals were acclimated to the restraining tubes during a three-day acclimation period. Animals were restrained for 1/4 (1.5 hours), 1/2 (3 hours), and 3/4 (4.5 hours) of the daily exposure duration (6 hours) on three non-holiday weekdays before the animals were exposed.

- Temperature (°C): 18.6 to 23.0 degree C
- Humidity (%): 25.1-64.6%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): automatic 12-hour light/dark cycle was maintained in the exposure and housing chamber laboratories.

IN-LIFE DATES: From: 2010-09-09 To: 2010-10-21

Administration / exposure

Route of administration:
inhalation: dust
Type of inhalation exposure (if applicable):
nose only
Details on exposure:
- Exposure apparatus: The nose-only chamber employed for test substance exposure was contained in an acrylic enclosure to isolate the exposure chamber and protect laboratory personnel. The dilution air to the atmosphere generator was of breathable quality and was filtered with a compressed air filter and a carbon absorber. The exhaust from the exposure chamber was moved through a particulate filter by a ring compressor and exhausted outside the building. Inlet and exhaust flows to and from the chamber were continuously monitored by rotameters.
- Method of holding animals in test chamber: During the inhalation exposures, the rats were restrained in nose-only exposure animal holding tubes (CH Technologies, Westwood, NJ). Animal tube loading and unloading, and tube insertion and removal from the exposure chamber were performed
according to standard procedures designed to minimize stress to study rats. At all times that rats were restrained in holders, they were observed
frequently and when necessary, action was taken to avoid injury, death, or improper exposure. Prior to the start of the exposure, rats were transferred from their housing cages to the nose-only holding tubes. Following confirmation of correct animal number, the animals in the holders were inserted into the ports of the exposure chambers. Following the exposure, the holders were removed. The rats were removed from the holders and returned to their home cages. Chamber port rotation occurred weekly.
- System of generating particulates/aerosols: Test atmospheres in the exposure chambers were generated by aerosolizing the test substance using a compressed air-operated Wright Dust Aerosol Generation System positioned over the chamber. Each inhalation exposure system was equipped with a separate aerosol generation system. The test substance was weighed out and packed into a dust reservoir daily. A constant speed rotating scraper separated a thin film of the test substance at the surface of the cake and delivered it into a dispersing unit, drawn in by aspiration and dispersed by a high velocity air jet. The resulting test atmosphere entered a mixing plenum where it was diluted with breathable quality compressed air to the target concentration prior to introduction to the nose-only inhalation exposure chamber.
- Air flow rate: The total airflow was set to produce an airflow range of approximately 0.5 to 1.0 L/min/exposure port.
- Method of particle size determination: The aerosol particle size distribution was monitored twice per week during the exposure phase of the study by an Aerodynamic Particle Sizer (APS) 3321 with Aerosol Diluter 3302A (both manufactured by TSI Inc., Shoreview, MN). The APS sizes particles in the range from 0.5 to 20 um using a time-of-flight technique that measures aerodynamic diameter in real time.

- Brief description of analytical method used: The test atmosphere mass concentration was monitored gravimetrically by collecting gravimetric samples on pre-weighed glass fiber filters placed in closed-face filter holders. Samples were collected at a constant flow rate equal to the port flow of the delivery tube, and the total volume of air sampled was measured by a dry gas meter. Test atmosphere samples were collected at least three times during the exposure (generally, once during the first two hours, once during the middle two hours and once during the last two hours). The filter-collected samples were weighed and one filter per group per day (including the control to confirm the absence of test substance in the test atmosphere) was analyzed chemically to confirm the mass of TBO collected; percent recovery (chemical analysis concentration vs. gravimetric concentration) was calculated for each filter analyzed. Chemical analysis was conducted by means of ICP-mass spectrometry. In addition, the test atmosphere aerosol concentration in each chamber was monitored with a real-time aerosol sensor (model # pDR-1000AN, MIE, Inc. Bedford, MA). The sensors were employed only as a real-time indicator of short-term changes in aerosol concentration and were used in guiding laboratory personnel if concentration excursions were encountered.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
28 days with 14 day recovery period
Frequency of treatment:
6 hours/day, 7 days/week
Doses / concentrationsopen allclose all
Doses / Concentrations:
0.08, 0.325 and 0.65 mg/L Air
other: target concentration
Doses / Concentrations:
14.8, 60.2, and 118.8 mg/kg/day
other: mean inhaled calculated
No. of animals per sex per dose:
Control animals:
yes, sham-exposed


Parental animals: Observations and examinations:
Gross and histopathology included evaluation of the ovaries, seminal vesicles, testes, and uterus.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Details on results (P0)

No effects were observed on the reproductive organs of male and female rats following repeat exposure via inhalation to TBO at doses up to 0.65 mg/L air for 28 days.

Effect levels (P0)

Dose descriptor:
other: NOAEL for Reproductive Organs
Effect level:
0.65 mg/L air
Based on:
other: target concentration
Basis for effect level:
other: No effects were observed on any of the reproductive organs in either males or females at the highest dose tested.
Remarks on result:
other: Generation: male/female rats exposed in a 28-day inhalation toxicity study (migrated information)

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

No effects were observed on the reproductive organs of male and female rats following repeat exposure via inhalation to TBO at doses up to 0.65 mg/L air for 28 days. Therefore, the NOAEL for reproductive organ effects was deemed to be 0.65 mg/L.