Spacecraft Water Exposure Guidelines for Selected Contaminants Volume 1 (2004) / Chapter Skim
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Appendix 3: Di-n-butyl Phthalate
Appendix 3: Di-n-butyl Phthalate
Pages 88-120
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From page 88... ...
Johnson Space Center Meclical Sciences Division Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Di-n-butyl phthalate (DBP) is a colorless to faint yellow viscous liquid with a slight aromatic odor and a strong bitter taste (see Table 3-1)
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From page 89... ...
1.047 at 20°C (WHO 1997) drinking water from various countries, the maximum concentration of DBP reported was 5 ~g/L (WHO 1997~.
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From page 90... ...
(1998) reported the tissue distribution of radioactivity following a single oral dose of ~4C-labeled DBP at 500 mg/kg or 1,500 mg/kg to pregnant rats on gestation day 14.
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From page 91... ...
1977~. In rats, the hydrolysis seems to continue, because o-phthalic acid has been reported in the urine of rats given an oral dose of DBP (ACGIH 1991~.
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From page 92... ...
1978~. All of the metabolites shown in Figure 3-1 were found in rat urine except the keto compound; MBP was the predominate metabolite in urine.
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From page 93... ...
or o-phthalic acid. The 4-d NOAEL for testicular effects in young rats was 500 mg/kg/d by bolus oral dose.
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From page 94... ...
When 3- to 4-wk-old male rats were given DBP at 2,000 mg/kg in corn oil by gavage for 14 4, the relative liver weights of the exposed rats progressively exceeded the relative liver weights of the controls (Cater et al 1977~. The fraction by which the exposed rat livers exceeded control rat livers was as follows: after 3 4, WHO; after 7 4, 10%; after 10 4, 11%; and after 14 4, 14%.
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From page 95... ...
The findings in rats can be summarized as follows: reduced final body weights in male rats receiving 10,000 ppm or higher and in female rats receiving 20,000 ppm or higher; hepatomegaly in male rats at or above 5,000 ppm and in female rats at or above 10,000 ppm; reduced testicular weight in male rats at 20,000 and 40,000 ppm; slight anemia in male rats at or above 5,000 ppm; reduced cholesterol in male and female rats receiving 10,000 ppm or more; reduced triglycerides in all DBP-exposed male rats and in female rats receiving 10,000 ppm or more; elevated peroxisome enzymes in male and female rats ingesting 5,000 ppm or more; and depletion of the germinal epithelium and zinc in testes of male rats given 20,000 ppm or more. If the hypocholesterolemia is not considered an adverse effect, then the NOAEL was 2,500 ppm for F-344 rats.
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From page 96... ...
Kidney weights were increased end were clearlyrelatedto DBP exposure; however, despite extensive histopathology, there were no kidney changes noted, so this change was not confirmed as adverse. BMD analyses were conducted on the two indices of testicular injury and on the reduced RBC counts (Table 3-4, Figures 3-2 and 3-3~.
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From page 97... ...
97 -i O ~ 0 0 ~ O o o o ° o o o V ^ ~ on ~ o ~ ~ ~ o ~ ~ ~ ~ =_' ~ ~ or or or or Ct V]
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From page 98... ...
In a complementary study, rats were given the two lowest doses for 21 mo, and the high-dose group was given the DBP-enriched diet for 15 mot The French study concluded that under the test conditions there were no harmful effects of DBP and that the three doses were equivalent to a 70-kg, moderately active human ingesting 60, 180, and 300 mg of DBP per day, respectively. Even though these tests were not conducted according to modern protocols, they seem to suggest that the chronic oral toxicity of DBP is low.
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From page 99... ...
. , ~ 0 200 400 600 800 1000 1200 1400 1600 Dose FIGURE 3-2 BMD analysis ofthe incidence of germinal epithelial atrophy in male rats ingesting DBP for 13 wk (BMDLol = 1 1 1 mg/kg/d)
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From page 100... ...
Neither SCEs nor chromosomal aberrations were induced in Chinese hamster ovary (CHO) cells exposed at concentrations up to 27.8 mg/mL (Abe and Sasaki 1977~.
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From page 101... ...
Based on the NOAELs from the BMD analysis, the reduction in acid phosphatase is a more sensitive end point than the reduction in testicular weights. The question is whether enzymatic changes in the testes are an adverse or adaptive response to DBP exposure.
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From page 102... ...
Hence, the reduced sperm counts, not the reduced acid phosphatase activity (which could be considered a marker of testicular effects) , will be considered the adverse effect.
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From page 103... ...
5 in o4 Q in tY 3 a) ~ 1 o 103 Polynomial Model with 0.95 Confidence Level JET > \ \ \ \ < i, \ \ \ \ Polynomial \ - BMDL BMD I I I 0 200 400 600 800 1 000 Dose FIGURE 3-4 BMD analysis of sperm counts in rats given DBP by Savage for 15 d (BMDLo~ = 70 mg/kg/d)
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From page 104... ...
During the latter two periods, reproductive function was measured as the number of litters per breeding pair, number of live pups per litter, pup weight, and pup survival. Even though the body weights ofthe 1.0% males were less than the control body weights, there was not a statistically significant difference in the weights of the testes, epididymis, prostate, or seminal vesicles among the groups (Lamb et al.
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From page 105... ...
2000~. In another developmental toxicity study, CD rats were given oral doses of DBP at 0,100,250, and 500 mg/kg/d from gestation day 12 to gestation day 21.
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From page 107... ...
107 Do Cq, Do ~ as ~ ¢ A ¢ .
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From page 108... ...
108 an so ad ~= ~ A, ad r c, r r 3 AL, c) so, ~ O u, ~ r ~ tilt ~ Al c., ~ ~O 5 S #o ED o At U
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From page 109... ...
; only a factor of 10 for interspecies differences was used to estimate the SWEG. There was no intraspecies factor used in the SWEG because the astronaut population consists of healthy adults, so protection of very young persons or ill persons is not required.
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From page 110... ...
on the reproductive toxicity of DBP in rats. A BRIDLE of 70 mg/kg/d was estimated for reduced sperm counts using doses from 250 to 1,000 mg/kg/d for 15 d and a polynomial fit of the data (Table 3-5)
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From page 111... ...
Factors of 10 for species differences and 3 for possible susceptibility to reduced red cell mass were included. There is no EPA limit that can be compared directly to this SWEG.
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From page 112... ...
A further note is that rats seem to be much more susceptible than primates to the toxic effects of DBP and other phthalates; however, the species extrapolation factor of 10 will be retained for conservatism and because there are few studies involving human subjects. Developmental toxicity was not considered because pregnant astronauts are not expected to fly in the foreseeable future.
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From page 115... ...
Reproductive Toxicity Reproductive toxicity in males was evaluated according to the BMDLo~ calculations shown in Tables 3-3 and 3-4. The BMDLo~ for atrophy ofthe germinal epithelium in rats exposed to DBP in their food for 13 wk was found to be 111 mg/kg/d.
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From page 116... ...
is to compensate for the exposure time in the study being less than the AC exposure time. This can be rounded to 100 mg/L for reproductive effects; however, an additional factor of 3 was applied for possible interactions between spaceflight effects and hematotoxicity, which was assumed from the hematotoxic findings in the 90-d study (NTP 1995~.
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From page 117... ...
1977. Chromosome aberrations and sister chromatic exchanges in Chinese hamster ovary cells exposed to various chemicals.
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From page 118... ...
1992. Drinking Water Criteria Document for Phthalic Acid Esters (Revised Final Report)
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From page 119... ...
2000. Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di~n-butyl)
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From page 120... ...
Reproductive Toxicity of Di-n-butylphthalate in a Continuous Breeding Protocol in Sprague-Dawley Rats. Environ.
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