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Toxicological information

Acute Toxicity: other routes

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Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: publication without full reporting of all underlying data

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Ground metallic beryllium or alloy of beryllium (2 %) and copper (98 %) in physiological saline were instilled into the trachea of mice .
Interim sacrifices were performed after 1 hour, 1, 7 14 and 28 days.
Right lungs were used for the determination of lung burden/clearance, the left lobe were fixed and used for histological assessment. Haematocrit, liver and lung pathology was also investigated.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material I (as cited in study report): metallic beryllium
- Name of test material II: beryllium-copper alloy (2 % Be, 98 % Cu), obtained from Brush-Wellman, Co., Elmore, OH, USA
- Substance types: metal
- Physical state: solid
- Analytical purity: not reported
- Impurities (identity and concentrations): not reported
- Composition of test material, percentage of components: metallic beryllium, beryllium-copper alloy (2 % Be, 98 % Cu)
- Lot/batch No.: not reported
- Stability under test conditions: assumed to be stable

Test animals

Species:
mouse
Strain:
other: C3H/HeJ
Sex:
female
Details on test animals and environmental conditions:
Female C3H/HeJ mice, appr. 7 weeks old /20 g weight, supplier Charles River Laboratories Wilmington.
Houised in polycarbonate cages with hardwood chip bedding and filter tops, 20 - 22 °C, 20 - 50 % rel humidity, 12h light cycle
Feed (Harlan Teklad certified rodent diet) and water ad libitum.

Administration / exposure

Route of administration:
other: intratracheal infusion
Vehicle:
water
Details on exposure:
The BeCu alloy nuggets were initially ground to a coarse powder using a disk and puck mill and then passed trough a jet mill and size fractioned using a cyclone train. Particles with a mass median aerodynamic diameter in the 1 - 3 micrometer range were pooled. The metal powders were suspended in saline (0.9 % NaCl) containing 0.2 % Tween 80. The application volume was 0.1 ml and was made under anaesthesia via a transoral intratracheal catheter.
Doses:
Saline control
2 µg Be/mouse
8 µg Be/mouse
12.5 µg BeCu alloy/mouse
50 µg BeCu alloy/mouse
100 µg BeCu alloy/mouse
No. of animals per sex per dose:
24 controls (for 3 time points)
40 for each treatment group (5 time points) except for the 100mcg Be group, which was 40 for the 28 day timepoint.
Control animals:
yes
Details on study design:
For experimental design see below.
Statistics:
Weight data were evaluated with the ToxPath software using Dunnett's t test at a significanc level of p < 0.05.
The lung clearing rates were evaluated using one or two component negative exponential equations.

Results and discussion

Any other information on results incl. tables

Mortality: Ten mice (25 %) dosed with 100 mcg BeCu died/were sacrificed within 24 hours. Three mice dosed 25 µg BeCu died between days 2 and 6.

Body and organ weights: The treatment had no influence on body weights. The Be administration did not influence lung weights, whereas the BeCu dosed animals showed increases reaching sometimes statistical significance. Liver weights were not affected by the treatment.

Haematocrit: No effect of treatment

Histopathology: See supporting document (attached)

Lung clearance: See supporting document (attached)

Applicant's summary and conclusion

Conclusions:
BeCu alloy is more acutely toxic to lung than Be metal.
The Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure.
Executive summary:

The pulmonary toxicity and clearance of BeCu alloy (2 % Be; 98 % Cu) was investigated in mice. Groups of 40 female C3H/HeJ mice were administered 12.5, 25, and 100 μg BeCu alloy or 2 and 8 μg Be metal by intratracheal instillation. Mice were sacrificed at 1 h and 1, 7, 14, and 28 days postinstillation. Left lungs were evaluated for histopathological change. Right lungs were analyzed for Be and Cu content. 25 % of the high-dose BeCu mice and 7.5 % of the mid-dose BeCu mice died within 24 h of dosing. Acute pulmonary lesions included acute alveolitis and interstitial inflammation. Type II epithelial cell hyperplasia and centriacinar fibrosis were present by 7 days after dosing. Lesions persisted through 28 days after instillation. No lesions attributable to alloy exposure were present in liver or kidney. Be metal instillation caused no deaths and minimal pulmonary changes over the time studied, indicating that the pulmonary lesions were due to Cu rather than Be. Cu cleared the lung with a half-time of 0.5–2 days. Be cleared with a half-time of several weeks or longer. Results of this study suggest that exposure to BeCu alloy is more acutely toxic to lung than Be metal. The results of tissue analyses also indicate that, while the Cu component of the alloy clears the lung rapidly, Be is retained and may accumulate upon repeated exposure.