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Acute Toxicity: inhalation

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Administrative data

Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study similar/equivalent to OECD 403 with acceptable deviations. Exposure duration of 1 hour used, particle size distribution was not presented, and limited details on test substance preparation were included.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
: Exposure duration of 1 hour used and particle size distribution was not presented.
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): Unformulated pure Red Phosphorus smoke

Test animals

Species:
other: rat, mouse, rabbit and guinea pig
Strain:
other: Porton strain rats and mice, New Zealnd white rabbits, and Dunkin-Hartley Guinea pigs
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum




Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: smoke chamber
- Exposure chamber volume: 10 cubic meter
- Source and rate of air: copper tube at 5 L/min
- System of generating particulates/aerosols: Solid red phosphorus was spread evenly over the bottom of an elongated tray that had an electrical resistance wire running up the axis of the tray. Placed about 2 inches above the tray, and running its length, a copper tube was positioned with a row of holes facing the tray. An air blower connected to one end of the tube, forced air through the copper tube. Combustion of the red phosphorus was started by electrically heating the resistance wire. A fan was used to completely distribute smoke through the chamber.
- Treatment of exhaust air: complete oxidation of the combusted air was ensured by blowing air through the copper tube
- Temperature, humidity, pressure in air chamber: no data


TEST ATMOSPHERE
- Brief description of analytical method used: In a preliminary smoke distribution study, without animals in the chamber, samples of the atmosphere were collected periodically over a 1-h interval from sampling tubes placed near the top, middle, and bottom of the chamber. The atmosphere was sampled at 5-min intervals, by drawing air at 5 liters/min through Whatman No. 1 filter papers. Phosphorus in the papers was measured based on its conversion to ammonium phosphorus-molybdate, then reduced in the presence of acid to give a blue coloration that was measured spectrophotometrically.


Analytical verification of test atmosphere concentrations:
yes
Remarks:
in preliminary test, but not during test with animals
Duration of exposure:
1 h
Concentrations:
Rats and rabbits were tested at doses of 450, 870, 1600 and 2130 mg phosphorus/cubic meter (form not identified based on analytical methodology), when this value was expressed as orthophosphoric acid (OPA) equivalents the concentrations in the smoke were 1422, 2749, 5056, and 6731 mg of OPA/m3.
Mice were tested at doses of 111, 136, 220, 450 and 870 mg phosphorus/cubic meter (form not identified based on analytical methodology), when this value was expressed as orthophosphoric acid (OPA) equivalents the concentrations in the smoke were 351, 430, 695, 1422, and 2749 mg of OPA/m3.
Guinea pigs were evaluated at doses of 36, 52, 111 and 450 mg phosphorus/cubic meter (form not identified based on analytical methodology) were tested in rats, when this value was expressed as orthophosphoric acid (OPA) equivalents the concentrations in the smoke were 114, 164, 351 and 1422 mg of OPA/m3.
No. of animals per sex per dose:
Rats: 9-12 males/dose group
Mice: 20-50 males per dose group
Rabbits: 10 males per dose group
Guinea pigs: 10-20 males per dose group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: histopathology of larynx, trachea, lungs, liver, and kidneys
Statistics:
LC50 and L(CT)50 (LC50 X 60 min) values were calculated.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LC50
Effect level:
1 217 other: mg/m3, concentration expressed as phosphorus
95% CL:
970 - 1 489
Exp. duration:
1 h
Remarks on result:
other: Rat
Sex:
male
Dose descriptor:
LC50
Effect level:
271 other: mg/m3, concentration expressed as phosphorus
95% CL:
196 - 670
Exp. duration:
1 h
Remarks on result:
other: Mouse
Sex:
male
Dose descriptor:
LC50
Effect level:
1 689 other: mg/m3, concentration expressed as phosphorus
95% CL:
1 200 - 3 586
Exp. duration:
1 h
Remarks on result:
other: Rabbit
Sex:
male
Dose descriptor:
LC50
Effect level:
61 other: mg/m3, concentration expressed as phosphorus
95% CL:
52 - 80
Exp. duration:
1 h
Remarks on result:
other: Guinea Pig
Sex:
male
Dose descriptor:
LC50
Effect level:
3 846 other: mg/m3, expressed as ortho-phosphate acid equivalents
95% CL:
3 065 - 4 705
Exp. duration:
1 h
Remarks on result:
other: Rat
Sex:
male
Dose descriptor:
LC50
Effect level:
856 other: mg/m3 expressed as ortho-phosphate acid equivalents
95% CL:
691 - 2 117
Exp. duration:
1 h
Remarks on result:
other: Mouse
Sex:
male
Dose descriptor:
LC50
Effect level:
5 337 other: mg/m3, expressed as ortho-phosphate acid equivalents
95% CL:
3 792 - 11 332
Exp. duration:
1 h
Remarks on result:
other: Rabbit
Sex:
male
Dose descriptor:
LC50
Effect level:
193 other: mg/m3, expressed as ortho-phosphate acid equivalents
95% CL:
164 - 253
Exp. duration:
1 h
Remarks on result:
other: Guinea Pig
Mortality:
Rats:
- 2130 mg phosphorus/cubic meter = 12/12 died
- 1600 mg phosphorus/cubic meter = 6/9 died
- 870 mg phosphorus/cubic meter = 2/10 died
- 450 mg phosphorus/cubic meter = 0/12 died

Mouse:
- 870 mg phosphorus/cubic meter = 20/20 died
- 450 mg phosphorus/cubic meter = 15/20 died
- 220 mg phosphorus/cubic meter = 22/50 died
- 136 mg phosphorus/cubic meter = 1/50 died
- 111 mg phosphorus/cubic meter = 0/12 died

Rabbit:
- 2130 mg phosphorus/cubic meter = 8/10 died
- 1600 mg phosphorus/cubic meter = 3/10 died
- 870 mg phosphorus/cubic meter = 1/10 died
- 450 mg phosphorus/cubic meter = 0/10 died

Guinea pigs:
- 870 mg phosphorus/cubic meter = 10/10 died
- 111 mg phosphorus/cubic meter = 9/10 died
- 52 mg phosphorus/cubic meter = 9/20 died
- 36 mg phosphorus/cubic meter = 0/20 died

Rats and rabbits did not differ significantly in lethal toxicity and were the least sensitive species. Red phosphorus smoke was significantly more toxic to the mouse and even more toxic to the guinea pig, which appeared highly susceptible to the smoke. Most animals died during exposure, although a small portion survived a few hours or days post exposure.
Other findings:
- Histopathology: Minimal findings in survivors from potential lethal exposure concentrations were observed, indicating that reversibility and healing occur.

- Rats: There was generalized and epithelial necrosis in both the larynx and trachea, with inflammatory cell infiltration and fibrinous and hemorrhagic exudates in the lumen. Lungs showed moderately severe congestion and alveolar hemorrhages; about half of them had pulmonary edema. Polymorphonuclear cell infiltration of the alveoli was present, with macrophage aggregates in the alveoli and bronchioles. The liver, although not the kidney, showed congestion. There was one instance of mild renal cortical tubular necrosis in a rat that died following exposure to 1600 mg/cubic meter. Most sacrificed survivors had normal respiratory tract histology, although a few showed residual laryngotracheal epithelial necrosis and inflammatory cell infiltration.

- Rabbits: Rabbits dying following exposure to the higher concentrations of red phosphorus smoke (2130 and 1600 mg/m3) showed moderate to severe laryngotracheal injury. Necrosis was widespread in many animals with injury to subepithelial tissues, but restricted to the epithelium in only a few. There was frequently an overlying fibrinous or hemorrhagic exudate in the laryngeal or tracheal lumen. Moderate-to-marked infl ammatory cell infiltration was present in the larynx and trachea, principally polymorphonuclear cells but also some lymphocytic in infiltration. Decedents from the higher two concentrations also showed severe lung changes, in particular congestion, alveolar hemorrhages, and edema. Polymorphonuclear cell infiltrates were seen in the alveolar walls, and bronchiolar aggregates of macrophages were present. At the lower concentrations (870 and 450 mg/m3), effects were minimal in the larynx, but the trachea showed epithelial necrosis and acute inflammatory cell infiltration. Lungs from the 870 mg/m3 dose group showed congestion and hemorrhage but not edema or significant inflammatory cell infilltration. Livers and kidneys, from the higher two
concentrations, showed only congestion.
Survivors, sacrificed at 14 days, showed residual inflammatory cell infiltration and epithelial necrosis in a few instances, but lungs from survivors of the lower two concentrations were generally normal.


- Mice: As with rabbits and rats, mice that died had severe necrotic and inflammatory lesions in the larynx and trachea. However, the lung effects were more variable and in general less marked. Although congestion was present, alveolar hemorrhages were less frequently seen. Also, edema was not as marked as with the rat and rabbit. Acute inflammatory cell infiltration of the lungs was not a feature in mice that died from exposure to smokes of red phosphorus. Liver and kidney congestion was seen, and renal cortical tubular necrosis was present in 7 of 22 animals that died from exposure to 220 mg/m3.
A few survivors showed residual necrotic and inflammatory changes in the larynx and trachea. Other than congestion, the lungs of survivors were normal.

- Guinea pigs: Histopathological effects in guinea pigs that died were few, and when present were mild. Minor laryngeal and tracheal epithelial necrosis and inflammatory cell infiltration were only seen at the lowest lethal concentration (52 mg/m 3). Pulmonary effects were limited to mild-to-moderate congestion. Minor-to-moderate hepatorenal congestion was seen, but no other pathology in these organs. Survivors of the lower concentrations had mild epithelial necrosis and inflammatory cell infiltration of the larynx and trachea, with occasional pulmonary congestion, edema, and inflammatory infiltration.


Any other information on results incl. tables

The data ( LC50 and histopathology) suggest that the mechanism of lethal inhalation toxicity of red phosphorus smoke is different for the rabbit and rat when compared to the mouse and the guinea pig.

No particle sizing was included in the report.

Applicant's summary and conclusion

Interpretation of results:
other: The 1 hr male rat LC50 was determined to be 3846 mg/m³ (concentration expressed as Orthophosphoric acid) for red phosphorus smoke. The LC50's for male rabbits, mice and guinea pigs were determined to be 5337, 856 and 193 mg/m³ (concentration expressed as
Remarks:
Criteria used for interpretation of results: not specified
Conclusions:
The 1 hr male rat LC50 was determined to be 3846 mg/m³ (concentration expressed as Orthophosphoric acid) for red phosphorus smoke. The LC50's for male rabbits, mice and guinea pigs were determined to be 5337, 856 and 193 mg/m³ (concentration expressed as Orthophosphoric acid) for red phosphorus smoke. The data ( LC50 and histopathology) suggest that the mechanism of lethal inhalation toxicity of red phosphorus smoke is different for the rabbit and rat when compared to the mouse and the guinea pig.

The minimal findings in survivors from potential lethal exposure concentrations indicate that reversibility and healing occur.