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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented study with clear scope. Tailor-made for the purpose. Non-GLP, not following guideline.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Single exposure of rats during 50 minutes to Berylliummetal followed by investigation period over 171 days.
GLP compliance:
not specified
Test type:
other:
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Beryllium metal
- Substance type: metal
- Physical state: solid
- Analytical purity: not repored
- Lot/batch No.: from stock batch of metal particles (Type I-400) prepared by Brush-Wellman Co. (Elmore, OH)
- Expiration date of the lot/batch: not reported
- Stability under test conditions: assumed to be stable
- Storage condition of test material: not reported

Test animals

Species:
rat
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Lovelace Inhalation Toxicology Research Institute Breeding colony
- Age at study initiation: 11 - 13 weeks
- Fasting period before study: none
- Housing: filter topped polycarbonate cages lined with hardwood chip bedding
- Diet : not reported, assumed ad libitum
- Water :not reported, assumed ad libitum
- Acclimation period: not reported


ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported


IN-LIFE DATES: not reported

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: "Lovelace 96-port nose only chamber"
- Exposure chamber volume: not reported
- Method of holding animals in test chamber: single
- Source and rate of air: 24 l/min
- Method of conditioning air: not reported
- System of generating particulates/aerosols: ball milled metal paricles were passed into a dry powder mill, then passed through single stage cyclone to remove larg particle fraction
- Method of particle size determination: cascade impactor
- Treatment of exhaust air: not reported
- Temperature, humidity, pressure in air chamber: not reported


TEST ATMOSPHERE
- Brief description of analytical method used: continuous air monitor (PCAM; ppm, Inc., Knoxville TN), filterpaper weighing
- Samples taken from breathing zone: yes (assumed)



TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: (50 % effective cutoff diameter of cyclone = 1.7 micrometer)
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.4 +/- 0.1 µm/ 1.9 +/- 0.1 µm

Analytical verification of test atmosphere concentrations:
yes
Remarks:
assumed, not reported in publication
Duration of exposure:
50 min
Concentrations:
800 mg/cubicmeter, resulting in 625 µg Be metal per rat
No. of animals per sex per dose:
Total of 74 male rats, divided into groups of 6 per sacrifice time point
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 171 days
- Frequency of observations and weighing: days 3, 7, 10, 14, 31, 59, 115, 171
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, lung weights, macropathology, histopathology, other: Broncho-alveolar lavage (differntial cells, total protein, beta-glucuronidase, LDH, Beryllium burden
Statistics:
Treated animals vs. controls: two-way analysis of variance (Neter 1985)
Each endpoint and contrast (8 time-point) F distribution at p= 0.05 and p= 0.01

Results and discussion

Effect levels
Dose descriptor:
LC50
Remarks on result:
not determinable
Mortality:
20 animals died spontaneously between days 12 and 15 post exposure.
Clinical signs:
All exposed animals were lethargic and had increased respiratory rates from day 3 to 14 post exposure. After day 31, all appeared clinically normal.
Body weight:
Not reported
Gross pathology:
Lungs after 3 days: diffusely tan to grey, collaps poorly.
Lungs after 7, 10, 14 days: increasingly dark brown, mottled with bright red areas. At 14 d wet & heavy, do not collaps.
Lungs after 31 days: only mildly mottled and grey, collaps well.
Lungs after 59 days: Multiple pales, small soft raised foci scattered throughout parenchyma and pleural surface.
Lungs after 115 days: foci increased in size,
Lungs after 1717 days: Foci large and confluent, lungs firm.
Tracheobroncial lymph nodes: mildly enlarged after 10 days, markedly enlarged and dark grey from day 59 to 171.

Control animals had no macroscopic changes at any time point.

Any other information on results incl. tables

For

  • Lung weight development
  • Microscopical lesions
  • Differential cell counts
  • Total protein, LDH and beta-glucuronidase
  • Beryllium clearance from lung

see attached document.

Applicant's summary and conclusion

Conclusions:
In rats the lesions induced by beryllium inhalation appear to be due to direct chemical toxicity and foreign-body type reactions.
Executive summary:

Rats were exposed to an aerosol of metallic Beryllium once during 50 minutes at a concentration of 800 mg/m3, (= 625 mg/rat) and followed up for 171 days. At the sacrifices after 3, 7, 10, 14, 31, 59, 115 and 171 days the investgated parameters were weight, macro- and micropathology of lungs, bronchoalveolar lavage (BAL) for cytology and enzymes and Be contents and clearance.

The treatment induced an increase in lung weight, acute necrotizing, haemorrhagic, exudative pneuminitis and intraalveolar fibrosis that peaked after 14 days. After 31 days, the inflammatory lesions had regressed to be replaced by minimal interstitial and intraalveolar fibrosis. Necrotizing inflammation reappeared after 59 days and progressed to chronic active inflammation after 115 days and worsened progressively, as did alveolar macrophage and epithelial hyperplasia, being severe after 171 days. Few diffusely distributed lymphocytes were present, but not associated with granulomas. In the BAL cells were elevated, mainly due to neutrophils. Lymphocytes were not increased. LDH, beta-glucuronidase and total protein levels were elevated up to day 14, and normal again at day 31. Only LDH was substantially increased again at day 59 and later. The Be-clearance was estimated to have a half life of about 240 days.

The results indicate that inhalation of beryllium metal by rats result in severe, acute chemical pneumonitis that is followed by a quiescent period of minimal inflammation and mild fibrosis. Progressive, chronic-active, fibrosing pneumonitis is observed later. The lesions appear to be due to direct chemical toxicity and foreign-body type reactions.