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EC number: 232-077-3
CAS number: 7785-26-4
ATMOSPHERE ANALYSIS AND ESTIMATION OF ACHIEVED DOSE
To be completed when available
Table 7.5.2/2: Test Item-Related Effects in Organ Weight Parameters –Terminal Sacrifice
Absolute Weight (g)
Table 7.5.2/3: Incidence of Test Item-Related Macroscopic Findings – Terminal Sacrifice
Table 7.5.2/4: Incidence and Severity of Test Item-Related Microscopic Findings –Terminal Sacrifice
Target exposure level (mg/L)
Accumulation, Hyaline Droplets, Epithelial, Tubular
Basophilia, Epithelial, Tubular
Casts, Granular, Tubular
Table 7.5.2/5: Incidence and Severity of Test Item-Related Microscopic Findings – Recovery
Table 7.5.2/6: Incidence and Severity of Microscopic Findings of Uncertain Relationship to Exposure– Terminal Sacrifice
Lungs and Bronchi
Alveolar Macrophages, Foamy
Eosinophilic Crystals with Associated Inflammatory Cell Infiltrate, Alveoli
Table 7.5.2/7: Incidence and Severity of Microscopic Findings of Uncertain Relationship to Exposure– Recovery
In a repeated dose toxicity study conducted according to OECD Guideline 413 and in compliance with GLP, (-)-alpha-pinene was administered by inhalation-aerosol to groups of Sprague Dawley rats (10 rats/sex/group) by whole-body inhalation exposure at target exposure levels of 0.15, 0.3 and 0.9 mg/L for 6 hours per day, 5 days per week for 13 weeks. Control animals received air only. Recovery animals were similarly treated for 13 weeks followed by a 4 week off dose period. During the study, clinical condition, body weight, food consumption, ophthalmoscopy, haematology (peripheral blood), blood chemistry, organ weight, broncho-alveolar lavage examinations, macropathology and histopathology investigations were undertaken.
There were no treatment related clinical signs or effects on food consumption, blood chemistry, ophthalmoscopy, urinalysis, organ weights or broncho-alveolar lavage examinations.
There were two unscheduled female deaths during the exposure phase of the study in the group exposed to 0.9 mg/L. Following microscopic examination, no histopathological cause for either death was established.
In the kidneys of exposure phase males, test item-related accumulation of hyaline droplets in the cortical tubular epithelium and basophilia of the cortical tubular epithelium was seen in all males exposed to (-)-alpha-pinene and demonstrated a relationship to concentration in terms of severity. Immunohistochemical (IHC) staining for alpha‑2µ-globulin in the kidneys of representative exposure phase animals confirmed the presence of this protein in the epithelial hyaline droplets. Tubular granular casts in the outer medulla was seen in the majority of males exposed to 0.3 or 0.9 mg/L and a few males exposed to 0.15 mg/L and cortical tubular degeneration was also seen in two males of each test exposure group. The association of hyaline droplets with basophilic tubules and granular casts, known as alpha‑2µ-globulin nephropathy, is considered to be adverse in the animals affected. These findings accounted for the irregular renal surface seen at necropsy in two males exposed to 0.9 mg/L and for the higher than control mean body weight adjusted kidney weights for males exposed to 0.9 mg/L. These test item-related findings were confined to males.
In the kidneys of recovery phase males, accumulation of hyaline droplets in the cortical tubular epithelium was seen in one male of each group previously exposed to (‑)‑alpha‑pinene. Basophilia of the cortical tubular epithelium was seen in all males previously exposed to (-)-alpha-pinene and in two control males, and tubular granular casts in the outer medulla was seen in a few males previously exposed to 0.15, 0.3 or 0.9 mg/L. Cortical scars, which were considered the result of previous tubular degeneration, were seen in one male and three males previously exposed to 0.3 or 0.9 mg/L, respectively. Therefore, accumulation of hyaline droplets and tubular granular casts both exhibited partial recovery in terms of severity and relative incidence, however, basophilia of the cortical tubular epithelium did not demonstrate recovery.
In the lungs and bronchi of exposure phase animals, findings of an uncertain relationship to the test item were seen in males. Foamy alveolar macrophages were seen at a higher incidence in males exposed to 0.9 mg/L than in control males and alveolar eosinophilic crystals with associated inflammatory cell infiltrate (generally mixed cell) were seen at a clearly higher incidence in males exposed to 0.9 mg/L than in male controls. The foamy macrophages generally accounted for the pale areas seen at necropsy.
In the lungs and bronchi of recovery phase animals, foamy alveolar macrophages were seen at, or lower than, the control incidence in males and females previously exposed to (‑)‑alpha‑pinene and alveolar eosinophilic crystals with associated inflammatory cell infiltrate (mixed cell) were seen in one male previously exposed to 0.15 mg/L. In consequence, these two findings were considered to be within the background level in these previously exposed male and female animals, and thus the foamy alveolar macrophages was considered to show full recovery.
Clinical signs after exposure noted at 0.9 mg/L tended to be more noticeable on days when the chamber aerosol concentrations were higher than target, and resulted in two deaths in female animals that were considered test item related. These signs were thus considered adverse. A few signs noted at 0.15 or 0.3 mg/L were considered due to the incidence and frequency to be not adverse.
The slight, transient, lower food consumption in females in Week 1 and 2 was not accompanied by any change in body weight and as such the food consumption change is considered not adverse.
There was no pathological correlates seen in the liver to account for the slightly higher weight in animals exposed to 0.9 mg/L; hence this change was considered not adverse and of no toxicological significance.
Therefore, the No Observed Adverse Effect Concentration (NOAEC) was considered to be 0.3 mg/L, based on the two females decedents at the concentration level of 0.9 mg/L due to general poor clinical condition.
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