Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants Volume 5 (2008) / Chapter Skim
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13 Limonene
13 Limonene
Pages 250-274
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13 Limonene Chiu-wing Lam, Ph.D., D.A.B.T. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Synonym: 1-Methyl-4-(1-methylethenyl)
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. Consumption of d-limonene has been estimated to be 0.2 to 2 mg/kg body weight per day (or 14 to 140 mg/70 kg/d)
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This document has been drafted to set the airborne exposure limits of dlimonene on the ISS and should also provide the data needed for deciding whether to increase d-limonene uses as a degreaser or cleaner associated with space mission operations. TOXICOKINETICS AND METABOLISM Absorption, Distribution, and Excretion d-Limonene, a small lipophilic compound, has high blood/air, oil/water, and oil/blood partition coefficients (λblood/air = 42, λoil/water = 3,167, λoil/blood = 140)
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. In the two human test subjects, about 30% of the administered dose was found in the urine as d-limonene-8,9diol and its glucuronide; about 10% was identified as perillic acid (M-III; Figure 1)
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Acute and Short-Term Toxicity Studies Human Exposures In a study to investigate the pulmonary uptake of inhaled d-limonene in humans (mentioned above) , eight test subjects were exposed for 2 h on three occasions at concentrations of approximately 10, 225, and 450 mg/m³ (about 2, 40, or 80 ppm)
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X X X* X X M-V p-Mentha-1,8-dien-10-yl-β-D-glucopyranosiduronic X X X X X X acid M-VI 8-Hydroxy-p-menth-1-en-9-yl-β-D- X X*
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. TABLE 13-2 Incidence of Kidney Lesions, Including Cancer, in Male Rats Dosed Orally with d-Limonene for 2 Yearsa Lesions 0 mg/kg/d 75 mg/kg/d 150 mg/kg/d Papilla mineralization 7/50 43/50 48/50 Papilla epithelial 0/50 35/50 43/50 hyperplasia Tubular cell hyperplasia 0/50 4/50 7/50 Tubular cell adenoma 0/50 4/50 8/50 Tubular cell 0/50 4/50 3/50 adenocarcinoma a d-Limonene in corn oil was administered by gavage 5 days per week.
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TABLE 13-4 Oral Toxicity of d-Limonene in Rodents Dosage, Exposure mg/kg/d Durationa Speciesb Effects 6,000 16 d 10 rats, 10 mice 10/10 rats died, 10/20 mice died 3,000 16 d 10 rats, 10 mice 2/10 rats died, 1/20 mice died 1,650 16 d 10 rats, 10 mice No deaths; decrease in body weight gain 825 16 d 10 rats, 10 mice No observable effects (no histologic exam) 413 16 d 10 rats, 10 mice No observable effects (no histologic exam)
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No effects 150 2y 50 rats (M) 5% less body weight gain, decrease in survival, renal lesions and tumorsc,d 75 2y 50 rats (M)
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1990 (5 M, 5 F) kidney lesions 2,363 Gestation 15 mice ↓ maternal body weight Kodama et al.
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In the 2,400-mg/kg groups, 14 rats died; in the 2,000-mg/kg groups, 3 mice died. Body weight gain decreased in a dose-related fashion in the male rats starting at 600 mg/kg/d; in male mice, the decrease was observed in the 1,000and 2,000-mg/kg groups.
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and B6C3F1 mice gavaged with d-limonene. Doses as high as 500 mg/kg/d in female rats and 1,000 mg/kg/d in male and female mice did not increase cancer incidences in these rodents.
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The accumulated protein complex caused tubular cell degeneration and necrosis with some degree of cell regeneration (Saito et al.
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but not to other lipocalin proteins found in other species, including human-derived α1-acid glycoprotein and human protein 1. The International Agency for Research on Cancer Working Group concluded that d-limonene produces renal tubular tumors in male rats by a nonDNA-reactive mechanism, through an α2u-globulin-associated response.
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. The high dose caused a significant decrease in maternal body weight; it also caused a significant increase in the number of fetuses with skeletal abnormalities, including lumbar ribs, fused ribs, and delayed ossification of several bones in the paws.
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This human therapeutic dosage is 2,368 times higher than the mouse LD50 reported by Evan et al. In an NTP study involving large numbers of mice, no deaths or other sign of toxicity, other than decreased body weight gain, were observed in B6C3F1 mice exposed to d-limonene at 1,600 mg/kg/d for 16 days (NTP 1990)
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Therefore, the results for male rats would not be considered in setting exposure limits. Spacecraft maximum allowable concentrations (SMACs)
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b TWA for 15 min. TABLE 13-7 Spacecraft Maximum Allowable Concentrations for Limonenea Duration ppm mg/m3 Target Toxicity 1h 80 450 Eye and pulmonary irritation 24 h 80 450 Eye and pulmonary irritation 7d 20 115 Eye and pulmonary irritation 30 d 20 115 Eye and pulmonary irritation 180 d 20 115 Eye and pulmonary irritation 1,000 d 20 115 Eye and pulmonary irritation a Chosen from the lowest AC at each time point summarized in Table 13-8.
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dosed at 500 and 600 mg/kg/d for toxicity studyb 13 wk showed no clinical signs or histopathology. The dose of 500 mg/kg/d is equivalent to an acceptable daily inhalation concentration of ~40 ppm for humans.
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× 70 kg = 3,500 mg/d. In order to use this 13-wk NTP gavage study data to extrapolate equivalent risk of inhalation exposure, two assumptions are made.
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After week 28 of the study, the high-dose group of female mice had 5% to 15% lower mean body weights than the control group. In male mice, the incidence of multi
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Applying a rodent-to-human extrapolation factor of 10 would provide an acceptable human oral exposure dose of 25 mg/kg/d (1,750 mg/70kg/d)
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male rats fail to de velop renal disease following exposure to agents that induce alpha2u-globulin nephropathy. Fundam.
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1982. Sensory irritation, pulmonary irritation, and respira tory stimulation by airborne benzene and alkylbenzenes: Prediction of safe indus trial exposure levels and correlation with their thermodynamic properties.
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1992. Guidelines for Developing Spacecraft Maxi mum Allowable Concentrations for Space Station Contaminants.
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