Registration Dossier

Administrative data

Endpoint:
respiratory sensitisation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: no GLP

Data source

Reference
Reference Type:
publication
Title:
Induction of type I hypersensitivity in guinea pigs after inhalation of phthalic anhydride
Author:
Sarlo K, Clark ED, Ferguson J, Zeiss CR, Hatoum N
Year:
1994
Bibliographic source:
J. Allergy Clin. Immunol. 94, 747- 756.

Materials and methods

Principles of method if other than guideline:
guinea pigs were exposed through inhalation to phthalic anhydride (PA) dust at 0.5, 1.0, and 5.0 mg/m³, 3 hours/day for 5 consecutive days. Inhalation challenge with aerosolized pthalic anhydride-guinea pig serum albumin (PA-GPSA) was performed
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
guinea pig
Strain:
Hartley
Sex:
female

Test system

Route of induction exposure:
inhalation
Route of challenge exposure:
inhalation
Vehicle:
unchanged (no vehicle)
Concentration:
0.5, 1.0, and 5.0 mg/m³
No. of animals per dose:
8 animals were exposed to 0.5 or 1.0 mg/m³
16 animals were exposed to 5.0 mg/m³

Results and discussion

Results:
Inhalation challenge with phthalic anhydride dust. Changes in respiratory rate were not significantly greater than the changes in
respiratory rate measured in air control animals challenged with phthalic anhydride dust.
The decrease noted in plethysmograph pressure changes was not different from those measurements taken from air control animals exposed to the same concentration of phthalic anhydride dust.
Inhalation challenge with PA-GPSA conjugate One animal in the 0.5 mg/m3 group and four animals in the 5 mg/m3 group experienced significant and sustained increases in respiratory rate on challenge, as compared with the air control animals. The same animal in the 0.5 mg/m3 group, one animal in the 1 mg/m3 group, and three animals (two with significant increases in rate) in the 5.0 mg/m3 group experienced sustained respiratory reactions that resulted in significant increases in plethysmograph pressure, as compared with the air control animals.
ELISA Linear regression analysis showed a highly significant dose-response relationship (p < 0.001) for IgG antibody. Phthalic anhydride dust exposure level: Mean O.D. (±SE) at 1/100 serum dilution Air contr: 0.048 ± 0.008 0.5 mg/m3: 0.230 ± 0.071 1.0 mg/m3: 0.298 ± 0.024 5.0 mg/m3: 0.692 ± 0.1061 PCA Animals with IgG1a and IgE antibody to PA-GPSA 0.5 mg/m3: 3/8; 0/8 1.0 mg/m3: 1/8; 0/8 5.0 mg/m3: 5/8; 0/8 5.0 mg/m3: (challenged with phthalic anhydride) 1/8ND Thirty-eight percent (3 of 8) of the animals in the 0.5 mg/m3 group had measurable circulating IgG1a antibody in serum. Of these three animals, one had a significant respiratory reaction on inhalation challenge with conjugate. One of eight animals (13%) in the 1.0 mg/m3 exposure group had IgG1a antibody; this same animal had significant respiratory reactivity on conjugate challenge. Sixty-three percent (5 of 8) of the animals in the 5.0 mg/m3 exposure group had allergic antibody. All five animals experienced respiratory reactivity on conjugate challenge. None of the study animals had detectable IgE antibody to PA-GPSA. Histopathology and antibody titers Foci were observed in 8 of 8 animals in the PA dust-exposed and challenged group, with 3 of 8 having 189 foci or more (individual scores: 11, 6, 1, 365, 14, 2, 331, 189, mean value 15; mean value control group: 1). One or two lung foci were noted in 5 of 8 filtered air control/PA dust-challenged guinea pigs. No indication of hemorrhage or inflammation was noted. Alveolar hemorrhage, with accumulation of red blood cells, and a few alveolar macrophages were observed. Minimal type II cell hyperplasia was also noted.

Any other information on results incl. tables

Characterization of phthalic anhydride dust
phthalic anhydride dust exposure level: Mean analytical concentration (mg/m3); MMAD (µm)
0.5 mg/m3: 0.55; 3.12 +/- 2.02
1.0 mg/m3: 1.27; 3.26 +/- 2.02
5.0 mg/m3: 5.57; 3.91 +/- 2.

Applicant's summary and conclusion

Interpretation of results:
sensitising
Executive summary:

guinea pigs were exposed through inhalation to phthalic anhydride (PA) dust

at 0.5, 1.0, and 5.0 mg/m³, 3 hours/day for 5 consecutive days. Inhalation

challenge with aerosolized phthalic anhydride-guinea pig serum albumin (PA-GPSA)

was performed

Animals exposed to and challenged with 5.0 mg/m3 PA dust had significant numbers of hemorrhagic lung foci. Those animals with the greatest numberof foci had high IgG antibody activity to PA, measured by ELISA.