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Appendix 3 Cyclohexylamine Acute Exposure Guideline Levels
Pages 92-144

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From page 92...
... Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels.
From page 93...
... With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
From page 94...
... At 54.2 ppm, rats developed labored breathing, partially closed eyes, and red nasal discharge. Rats exposed to the two higher concentrations also exhibited rales, gasping, dried red facial material, tremors, body weight loss, and ocular lesions (corneal opacity, ulceration)
From page 95...
... . A total uncertainty factor of 30 was used: 10 for interspecies variability because, although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study failed to delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited.
From page 96...
... mg/m3) effects and ocular irritation; NOAEL for irreversible ocular lesions (Bio/dynamics, Inc.
From page 97...
... Acute exposure of animals resulted in extreme mucous membrane irritation, gasping, lung hemorrhage, opaque corneas, tremors, restlessness and clonic spasm of the trunk and paw muscles, hemolysis, and vascular lesions. The primary fate of cyclohexylamine in the atmosphere is reaction with hydroxyl radicals, with a half-life of approximately 1.82 days (EPA 1987)
From page 98...
... Odor Threshold/Odor Awareness The odor detection threshold for cyclohexylamine was reported to be 2.6 ppm by Amoore and Hautala (1983)
From page 99...
... ) had cyclohexylamine concentrations below detectable limits (~0.08 ppm)
From page 100...
... found that exposure during an unspecified fraction of a workday to 4-10 ppm cyclohexylamine "caused no symptoms of any kind," but there was no indication whether the workers were able to detect the characteristic odor. Widely varying odor detection thresholds were reported for cyclohexylamine in two secondary sources (2.6 ppm and 26-110 ppm)
From page 101...
... 3. ANIMAL TOXICITY DATA Only a small number of animal studies were located; these used rats, mice, guinea pigs, and rabbits.
From page 102...
... 0/10 Lacrimation, red nasal discharge (see Table 3) Corneal lesions, 4h 567 (none)
From page 103...
... 1,200 7h 4/5b Extreme irritation, lung hemorrhage, opaque corneas, death (Watrous and Schulz 1950) Guinea pig 7 h/d x 10 d 150 ≤10 day 0/2?
From page 104...
... Of the rats exposed to 800 ppm, "five survived 24 h of exposure;" it was not stated how many animals died after 24 h of exposure. Of the rats exposed to 150 ppm cyclohexylamine, 4/5 survived 70 h of exposure.
From page 105...
... inside the chamber 3 1 0 0 -- -- -- Dried brown material on face 1 4 0 0 -- -- -- Labored breathing Few Most Most 10 2 1 1 Gasping 7 0 0 1 -- -- -- Rales: moist or dry 6 4 5 5 -- -- -- Eyes closed All All All 0 0 0 0 Coarse tremors 6 0 0 0 -- -- -- Corneal opacity 2 7 8 7 -- -- -- Corneal irregularity or ulceration 9 1 0 8 -- -- -- Yellow ano-genital stains 2 2 2 0 -- -- -- Alopecia 0 0 1 2 -- -- -- Decreased activity 10 0 0 0 -- -- -- GROUP II (567 ppm) Observations n=10 n=10 n=10 n=10 Excessive lacrimation Few Few Few could not be 5 0 0 0 -- Chromodacryorrhea made due to 0 0 0 0 -- -- -- -- Mucoid nasal discharge Few Few Few residual build- 0 0 0 0 -- up inside the chamber (Continued)
From page 106...
... n=10 n=10 n=10 All sacriExcessive lacrimation 1 0 0 ficed on -- -- -- -- -- -- Chromodacryorrhea 0 0 0 day 15 -- -- -- -- -- -- Mucoid nasal discharge 0 0 0 -- -- -- -- -- -- Red nasal discharge (wet or dried) Few Few Few 0 1 0 -- -- -- Dried brown/red material on face 9 1 0 -- -- -- -- -- -- Labored breathing Few Some Most Most All All 0 0 0 Eyes partially closed Most All All 0 0 0 -- -- -- a The animals (5/sex)
From page 107...
... 3.1.4. Guinea Pigs Guinea pigs were exposed to 150, 800, or 1,200 ppm cyclohexylamine for 7 h/day, 5 days/week (Watrous and Schulz 1950)
From page 108...
... found mucous membrane irritation, CNS excitability, decreased body weight, increased blood methemoglobin, hemolysis (not at 24.6 ppm) , vascular lesions, and/or organ weight changes, but no mortality in groups of albino rats exposed once to 443 ppm (duration unknown)
From page 109...
... . The lower value of the RD50 compared to the RD50TC indicates that the respiratory toxicity of cyclohexylamine is primarily related to its upper airway irritant effects.
From page 110...
... Lomonova (1965) reported that the lowest single exposure concentration that altered the CNS capacity for summation of subthreshold impulses in mice was 2.5 ppm and that 12.3 ppm was the "maximum tolerated" dose (see Section 3.1.1.
From page 111...
... Parental toxicity was not evaluated, although it was noted that treated mice had significantly lower body weight but a better survival rate than controls.
From page 112...
... 3.7. Summary Cyclohexylamine acute lethality inhalation studies were located for rats, mice, guinea pigs, and rabbits.
From page 113...
... Rats appeared less sensitive to cyclohexylamine than mice, guinea pigs, or rabbits with respect to lethality in two studies. The data, however, were inadequate to define the most sensitive species.
From page 114...
... found in rats, guinea pigs, and rabbits exposed to ≥542 ppm cyclohexylamine (Watrous and Schulz 1950; Bio/dynamics, Inc.
From page 115...
... also examined the inhalation toxicity of dicyclohexylamine (DCHA)
From page 116...
... To obtain protective AEGL-2 and AEGL-3 values for 30, 60, and 480 min, scaling across time was performed using n = 3 to extrapolate to shorter exposure times and n = 1 to extrapolate to longer exposure times, to provide AEGL values that would be protective of human health (NRC 2001) (the AEGL-1 was not scaled)
From page 117...
... An uncertainty factor of 3 was applied for interspecies variability, and 3 was applied for sensitive humans (yielding 1.8 ppm for 10 min to 8 h) , because mild sensory irritation from an alkaline irritant gas is not likely to vary greatly among humans or animals, and both human and additional animal data indicate that a greater UF is not needed.
From page 118...
... 6.2. Summary of Animal Data Relevant to AEGL-2 The Bio/dynamics, Inc.
From page 119...
... . To obtain protective AEGL-2 values, scaling across time was performed using n = 3 to extrapolate to exposure times <4 h (exposure duration in the key study)
From page 120...
... (1990) study, in which rats were exposed for 4 h to 54.2 ppm had labored breathing, partially closed eyes, and red nasal discharge, and rats exposed to 567 ppm or to a vapor/aerosol combination containing 542 ppm vapor and ~612 mg/m3 aerosol additionally had rales, gasping, dried red facial material, tremors, weight loss, irreversible ocular lesions, and two rats exposed to the aerosol-containing atmosphere died; (2)
From page 121...
... A total uncertainty factor of 30 was used: 10 for interspecies variability because, although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study did not precisely delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited. An intraspecies uncertainty factor of 3 was applied because tissue destruction caused by a severely corrosive agent is not expected to vary greatly among humans; a greater uncertainty factor is not warranted because it yields concentrations comparable to AEGL-2 values.
From page 122...
... . Data were not available to determine the concentrationtime relationship for cyclohexylamine toxicity and scaling across time was performed using the equation Cn × t = k, using the exponent n = 3 to extrapolate to exposure times <4 h (exposure duration in the key study)
From page 123...
... A total uncertainty factor of 30 was used: 10 for interspecies variability because, although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study failed to delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited. An intraspecies uncertainty factor of 3 was applied because tissue destruction caused by a severely corrosive agent is not expected to vary greatly among humans; a greater uncertainty factor is not warranted because it yields concentrations comparable to AEGL-2 values in Table 3-8.
From page 124...
... i a NIOSH REL-TWA (National Institute of Occupational Safety and Health, Recommended Exposure Limits - Time Weighted Average)
From page 125...
... h LLV (Level Limit Value) Swedish Occupational Exposure Limits.
From page 126...
... Data Quality and Research Needs The data set used to derive cyclohexylamine AEGL values was limited and would be improved by the availability of (1) additional studies with end points within the scope of AEGL-2, since in the key study there was a 10-fold difference in the lowest test concentration, which was used for AEGL-2 derivation, and the next higher test concentration, which was used for AEGL-3 derivation, (2)
From page 127...
... 1983. Odor as an aid to chemical safety: odor thresholds compared with threshold limit values and volatil ities for 214 industrial chemicals in air and water dilution.
From page 128...
... Cyclohexylamine. MEDLARS Online Information Retrieval System, National Li brary of Medicine (http://toxnet.nlm.nih.gov; retrieved 7/2005)
From page 129...
... 2001. Standing Operating Proce dures for Developing Acute Exposure Guideline Levels for Haz ardous Chemicals.
From page 130...
... 2000. Swedish Occupational Exposure Limits: LLV (Level Limit Val ues)
From page 131...
... 1950. Cyclohexylamine, p chloronitrobenzene, 2-aminopyridine: Toxic effects in industrial use.
From page 132...
... expected to cause mild sensory irritation. At the two higher doses, rats also displayed rales, gasp ing, dried red material on the facial area, trem ors, weight loss, ocular irritation, and irreversi ble ocular lesions; 2/10 rats exposed to the aero sol/vapor mix died (had nasal, lung, and uro genital lesions)
From page 133...
... At the two higher doses, rats also displayed rales, gasp ing, dried red material on the facial area, trem ors, weight loss, ocular irritation, and irreversi ble ocular lesions; 2/10 rats exposed to the aero sol/vapor mix died (had nasal, lung, and uro genital lesions)
From page 134...
... = k = 21.7 ppm-h UF 10 C1 × 8 h = 21.7 ppm-h 8 h AEGL-2 8 h AEGL-2 = 2.7 ppm [11 mg/m3] Derivation of AEGL-3 Key study: Bio/dynamics, Inc.
From page 135...
... . Uncertainty factors: Total Uncertainty Factors: 30 Interspecies: 10 -- Although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study did not precisely delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited.
From page 136...
... 136 Acute Exposure Guideline Levels 30 min AEGL-3 = 38 ppm [150 mg/m3]
From page 137...
... of distinct odor detection (I=3) is derived using the Fechner function: I = kw × log C /OT50)
From page 138...
... Based on the current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4/3 = 1.33.
From page 139...
... Effects: At 54.2 ppm, rats had labored breathing, red nasal discharge, and partly closed eyes primarily during the 4-h exposure. Rats exposed to 567 ppm or the vapor/aerosol combination had severe respiratory effects and irreversible ocular lesions; 2/10 rats exposed to the aerosolcontaining atmosphere died.
From page 140...
... Effects: At 54.2 ppm, rats had labored breathing, red nasal discharge, and partly closed eyes primarily during the 4-h exposure. Rats exposed to 567 ppm or the vapor/aerosol combination had severe respiratory effects and irreversible ocular lesions; 2/10 rats exposed to the aerosolcontaining atmosphere died.
From page 141...
... Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 10 -- Although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study did not precisely delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited. (Continued)
From page 142...
... . Data Adequacy: The data set was small but the key study was wellconducted (GLP guidelines used)
From page 143...
... APPENDIX D Category Plot for Cyclohexylamine
From page 144...
... Chemical Toxicity - TSD All Data 144 Cyclohexylamine 100000.0 Human - No Effect Human - Discomfort 10000.0 Human - Disabling Animal - No Effect 1000.0 Animal - Discomfort ppm 100.0 Animal - Disabling AEGL-3 Animal - Some Lethality 10.0 AEGL-2 Animal - Lethal AEGL-1 AEGL 1.0 0 60 120 180 240 300 360 420 480 Minutes FIGURE D-1 Chemical toxicity -- TSD all data, cyclohexylamine. Note that multiple-exposure studies were input as single exposures.


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