B7

Polydimethylcyclosiloxanes

John T. James, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Name:

Hexamethylcyclo

trisiloxane (HMCTS) D3

Octamethylcyclo

tetrasiloxane (OMCTS) D4

Decamethylcyclo

pentasiloxane (DMCPS) D5

Formula:

((CH3)2SiO)3

((CH3)2SiO)4

((CH3)2SiO)5

Form:

white solid

oily liquid

oily liquid

CAS no.:

541-05-9

556-67-2

541-02-6

Molecular weight:

222.46

296.64

370.80

Boiling point:

135°C

175°C

210°C

Melting point:

65°C

17.5°C

7.5°C

Spec. Gravity:

1.10

0.954 at 25°C

0.959 at 25°C

Vapor pressure:

8 mmHg at 20°C

1 mmHg at 22°C

0.2 mmHg at 25°C

Solubility

insoluble

0.05 mg/L at 25°C

0.24 mg/L at 25°C

Conversion factors:

1 ppm = 9.1 mg/M3

12.0 mg/M3

15.1 mg/M3

 

1 mg/M3 = 0.110 ppm

0.0835 ppm

0.0662 ppm

OCCURRENCE AND USE

Because siloxane fluids are thought to be relatively nontoxic and are water repellent, they have found widespread use in cosmetics, creams, and antiperspirants. Concentrations of OMCTS in the sub-parts-per-billion range have been reported in indoor air (Shah and Singh 1988). During the 6 min after use of



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B7 Polydimethylcyclosiloxanes John T. James, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Name: Hexamethylcyclo trisiloxane (HMCTS) D3 Octamethylcyclo tetrasiloxane (OMCTS) D4 Decamethylcyclo pentasiloxane (DMCPS) D5 Formula: ((CH3)2SiO)3 ((CH3)2SiO)4 ((CH3)2SiO)5 Form: white solid oily liquid oily liquid CAS no.: 541-05-9 556-67-2 541-02-6 Molecular weight: 222.46 296.64 370.80 Boiling point: 135°C 175°C 210°C Melting point: 65°C 17.5°C 7.5°C Spec. Gravity: 1.10 0.954 at 25°C 0.959 at 25°C Vapor pressure: 8 mmHg at 20°C 1 mmHg at 22°C 0.2 mmHg at 25°C Solubility insoluble 0.05 mg/L at 25°C 0.24 mg/L at 25°C Conversion factors: 1 ppm = 9.1 mg/M3 12.0 mg/M3 15.1 mg/M3   1 mg/M3 = 0.110 ppm 0.0835 ppm 0.0662 ppm OCCURRENCE AND USE Because siloxane fluids are thought to be relatively nontoxic and are water repellent, they have found widespread use in cosmetics, creams, and antiperspirants. Concentrations of OMCTS in the sub-parts-per-billion range have been reported in indoor air (Shah and Singh 1988). During the 6 min after use of

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 antiperspirants the combined concentration of polydimethylcyclosiloxanes in the breathing zone of a person wearing the antiperspirant ranged from 0.3 to 2.9 ppm (Dow Corning Corporation 1989). One or more of the polydimethylcyclosiloxanes is found in most samples of space shuttle air. The combined concentrations are typically in the 0.1 to 1 mg/M3 range; however, occasionally the concentration exceeds 1 mg/M3 (James et al. 1994). TOXICOKINETICS AND METABOLISM Absorption No data could be found on the absorption of any of the three specific siloxanes under review. In testing of three other silicone oils on five human subjects, Hobbs et al. (1972) found that dermal application of 50 mg/kg/d for 10 d did not significantly increase the blood or urinary silicon concentrations. The detection limit was 5 µg/mL. Distribution No data were found on the distribution of these siloxanes after administration by any route of administration. Elimination The elimination of OMCTS metabolites from male and female Fischer 344 (F344) rats exposed by nose-only inhalation at 700 ppm (8.4 mg/L) was reported in an abstract (Plotzke et al. 1996). Rats were exposed for 14 d (presumably 6 h/d) to the siloxane and then given a 14C-OMCTS exposure on the 15th day. Immediately after exposure, the animals were placed in metabolism cages and excreta collected for 168 h. The radioactivity was recovered as follows: urine, 38%; expired volatiles, 36% (non-CO2); feces, 18%; and CO2, 4.5%. There was no apparent difference between the sexes of rat. Data on HMCTS and DMCPS were not found. Metabolism There were no peer-reviewed studies found on the metabolism of the three siloxanes under consideration; however, minimal information was found on

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 structurally related siloxanes. Apparently, liver enzymes can be induced in mice by oral administration of phenylheptamethylcyclotetrasiloxane (PHMCTS), suggesting that the compound might be metabolized there. Mice given PHMCTS at 100 mg/kg for 4 d showed a hexabarbital sleep time of only 8 min on d 5, compared with 34 min in controls (Bennett et al. 1972). Rats given the same dosage of PHMCTS did not show the reduced sleep time after administration of hexabarbital. Recent investigations reported in abstract form have begun to address the metabolism of OMCTS and DMCPS. In particular, there seems to be much interest in the ability of these siloxanes to induce various enzymes in the liver as an explanation of the hepatomegaly which is seen after prolonged exposure. F344 rats exposed for 28 d (6 h/d, 5 d/w) to 8.4 mg/L OMCTS showed 14% to 20% increases in liver mass and 43% to 54% increases in total cytochrome P-450 activity (McKim et al. 1995). The activity of ethoxycoumarin-O-deethylase increased by over 100% in the same animals. A later abstract indicated that the types of cytochrome P-450 induced were the 2B1 and 1A1 forms (Salyers et al. 1996). That report also indicated that six metabolites of OMCTS were found in urine samples. Similarly, an abstract report described the induction of hepatic cytochrome P-450 2B1 and 1A1 in female F344 rats inhaling DMCPS for 28 d at a concentration of 160 ppm (2.4 mg/L) (McKim et al. 1996). TOXICITY SUMMARY The toxicity data base consists mostly of studies conducted on OMCTS because it is used often in cosmetics and other products that contact human skin. The data base demonstrates that this siloxane is of low toxicity by inhalation and other routes of administration. Data on HMCTS and DMCPS were not available in peer-reviewed reports; however, available information from abstract reports and summary documents will be given. Acute and Short-Term Exposures Hexamethylcyclotrisiloxane A "toxicity profile" and a summary of a 4-w inhalation study were available for review (GE Silicones and LPT Report No. 6529/91 (Summary) provided by K. West, General Electric, unpublished information, August 8, 1996).1 Accord- 1    Referred to as LPT Report throughout Chapter B7.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 ing to these documents, HMCTS has been studied by the oral and inhalation routes. Gavage studies of rats given up to 1600 mg/kg/d for 28 d showed increased liver weights at concentrations as low as 400 mg/kg/d; however, none of the rats showed histopathological lesions associated with the hepatomegaly. In the LPT inhalation study, Sprague-Dawley rats of both sexes were exposed to actual concentrations of 0.08, 0.94, and 9.0 mg/L (nominal concentrations were 1.1, 6.9, and 34.7 mg/L), 6 h/d (7 d/w?) for 4 w. The concentrations were generated by heating HMCTS to about 85°C before mixing with air entering the nose-only chambers. The large differences in analytical and nominal concentrations were not explained in the abstract report. Between test days 13 and 16, 3/10 males and 1/10 females in the high-concentration group (9.0 mg/L) were found dead. These animals showed congestion of the kidneys, liver, and lungs (with perivascular edema). Rats in the high-concentration group showed slight inflammatory changes in the nasal cavity (microscopically) and exhibited slight narcosis after exposure. The pulmonary effects were not fully reversible during a 4-w recovery period. None of the animals showed changes in body-weight gain, clinical laboratory values, organ weights, and histopathology (adrenals, heart, kidneys, lacriminal gland, liver, pharynx, and spleen). The only effect noted in the intermediate group was slight red encrustation around the nares; however, the authors concluded that the no-effect concentration was the lowest concentration (0.08 mg/L). Octamethylcyclotetrasiloxane The acute effects of OMCTS have been studied by the dermal, oral, and inhalation routes of exposure. In 200 test subjects, 0.9 mL of OMCTS was applied to the upper arm on a disc for 24 h with occluded dressing. After removal of the dressing, the application site was examined, rested for 24 h (or 48 h on weekends), and then OMCTS was reapplied for a total of 15 applications (Shelanski 1974). Two of the 200 subjects showed skin changes signifying injury during applications 2 to 15. After a 2-w rest, the material was again applied to test for sensitization. There was no evidence of sensitization in the test population. Albino rats given 64 mL/kg by stomach tube showed sluggishness and labored breathing but did not die as a result of the dosage (Weil 1972). Mild growth retardation was induced in female rats given OMCTS at 2 g/kg/d for 28 d by oral gavage; however, there was no clear effect on growth in males (Manston 1988). Neither sex showed treatment-related effects during gross necropsy. The results of several acute inhalation tests are shown in the toxicity summary table. The tests consist mostly of screening tests conducted by labo-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 ratories supporting companies with a commercial interest in OMCTS. One human study has been reported by abstract. Twelve subjects were exposed for 1 h to OMCTS at 10 ppm (0.12 mg/L) and evaluated for immune function using a variety of end points (Looney et al. 1996). These initial studies indicated that exposure to OMCTS did not adversely affect the human immune system. In a screening test, concentrations near saturation were required to kill two of six rats during exposures of 8 h (Weil 1972). The two rats died 6 and 7 h into the exposure and showed breathing difficulties and spasms before dying. Exposures to OMCTS at near-saturation concentrations for 6 h failed to kill any of the 10 test rats, and gross pathology showed ''nothing remarkable" (Myers et al. 1982). Exposures of 8 h to 42 mg/L did not cause death in any of the six test animals; however, loss of coordination and slow, irregular breathing were noted 7 h into the exposure (Clayton 1974). Although those tests are useful for screening purposes, they lack the detailed assessment of toxic effects and dose-response information necessary to facilitate their use in setting human exposure limits. A 4-w inhalation study using Wistar rats revealed that repeated exposures to OMCTS cause few, if any, adverse effects even at high concentrations (Appleman et al. 1984). Male and female rats (10 each per group) were exposed at 0, 0.2, 1.0, and 5.1 mg/L, 6 h/d, 5 d/w for 4 w. The control and high-concentration groups were supplemented with five rats per group and sex to assess the reversibility of any adverse effects. The animals were killed 14 d after exposure ended. Observations included clinical signs, body weights, food consumption, clinical chemistry, hematology, urinalysis, gross pathology, and histopathology. The statistically significant findings were as follows: 5.1 mg/L in females: 3% reduction in weight gain after 28 d (reversible)   16% increase in relative liver weights after 28 d 5.1 mg/L in males: 7% increase in relative liver weight after 28 d In addition, there was a "very slight" increase in mitotic figures in the liver across several of the exposure groups as shown in Table 7-1. After the 14-d recovery period, the increase in mitotic figures had disappeared. The authors concluded that the test material, under the conditions of the study, caused slight, reversible effects on the liver. In our opinion, the reported effects do not fit the criteria for adverse effects. A recent abstract suggests liver-weight increases in rats exposed to OMCTS (6 h/d, 5 d/w, 28 d) can occur at concentrations as low as 0.84 mg/L (McKim et al. 1995). A second inhalation study, in which male and female mice, guinea pigs, rabbits, and hamsters were exposed to OMCTS at 8.3 mg/L, 6 h/d for 28 consecutive days has been reported (Siddiqui et al. 1989a). There were 10

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 7-1 Incidence of "Very Slight" Increases in Hepatocyte Mitotic Figures Group Incidence in Males Incidence in Females Control 0/10 0/10 0.2 mg/L 2/10 0/10 1.0 mg/L 3/10 3/10 5.1 mg/L 4/10 2/10 animals per group and sex, except rabbits, where only 5 animals were used for each sex and group. The observations included body weights, food consumption, clinical signs, gross pathology, selected organ weights, and selected histopathology. Clinical chemistry and hematology were not reported and the chamber temperatures reported (26-27°C) were somewhat high for some species involved. The only change linked to OMCTS exposure was hepatomegaly. Relative liver weights were statistically increased as follows: male mice, 16%; female mice, 30%; and female hamsters, 16%. There were no statistically increased liver weights in the other exposure groups, nor could any histopathological changes be correlated with those groups that showed the hepatomegaly. In our opinion, the reported changes do not reflect adverse effects. Decamethylcyclopentasiloxane The acute inhalation toxicity has been evaluated in F344 rats (five males and five females per group) exposed for 4 h to DMCPS at 4.6, 6.7, 9.8, and 15.4 mg/L (aerosol and vapor) and held for 15 d after exposure. No animals died at the lowest concentration, but four of five animals of each sex died in the upper-intermediate group, and all animals died in the highest-concentration group. The summary report is not clear about how many animals died in the lower-intermediate group. The description indicates that four of five died in each sex in the group, but the LC50 (lethal concentration for 50% of the animals) could not be 8.7 mg/L (as reported) if that were the case (Dow Corning 1995a). An inhalation study of F344 rats exposed 6 h/d, 5 d/w, by nose only to DMCPS at 0.44, 0.65, 1.50, and 3.06 mg/L has been reported by abstract (Kelly et al. 1995). Animals in the two highest-concentration groups had increased mean corpuscular volumes (MCVs) and triglycerides. Females in the highest-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 concentration group showed increased liver weights, and morphological evidence of irritation in their nasal cavities. In another study reported in abstract form, F344 rats were exposed whole body, 6 h/d, 7 d/w for 28 d to DMCPS at concentrations of 10, 25, 75, or 160 ppm (0.15, 0.38, 1.1, and 2.4 mg/L, respectively) (Burns et al., 1996). A satellite group was held for 14 d after exposures ended to assess reversibility of effects. Animals were evaluated for clinical signs, body weights, organ weights, gross pathology, histopathology, and clinical laboratory (including immune function) changes. At the end of exposures, the only effects reported were in the high-concentration group, and these included the following: slight anemia in females, increases in liver weight (both sexes), and increased thymus weight (males only). All of these were reversible after 14 d. Subchronic and Chronic Exposures Hexamethylcyclotrisiloxane No inhalation studies longer than 4 w could be found on this compound; however, dietary administration of HMCTS to rats for 1 y at 1% did not produce evidence of adverse effects using standard end points (toxicity profile document 1965-10065-1179-01 from GE Silicones, provided by K. West, unpublished information, July 17, 1996). Octamethylcyclotetrasiloxane A subchronic inhalation toxicity study of OMCTS has been reported in Sprague-Dawley rats exposed to vapor concentrations of 0, 0.61, 3.6, and 8.4 mg/L, 6 h/d for 90 d (Siddiqui et al. 1989b). There were 10 rats per sex and exposure concentration as well as satellite groups (control and high concentration). The satellite groups were killed 28 d after the end of exposures to assess the reversibility of any lesions present immediately after exposures ended. Observations included the following: clinical signs, body weights, food consumption, hematology, clinical chemistry, urinalysis, gross pathology, organ weights, and histopathology. At the terminal sacrifice, females in the 8.4-mg/L group showed statistically increased red-blood-cell (RBC) count, hematocrit, and hemoglobin compared with controls. The magnitude of the increase was 4-6% and had disappeared when the satellite females were evaluated 28 d after the end of exposure. The changes were not considered biologically significant

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 by the authors. At the terminal sacrifice, all groups of exposed males showed statistically increased relative liver weights (9-22%), but there was no apparent dose-response relationship. Relative liver weights were also increased in the two highest-exposure female groups at sacrifice; the increase was 30% in the highest-exposure group. The hepatomegaly had disappeared in satellite males and was reduced to 10% in satellite females. Ovarian weights were statistically decreased (28%) in the satellite group. The authors felt that that was not a direct effect of OMCTS exposure; however, structurally related compounds are known to interfere with female reproduction (see below). There were no histopathological changes associated with exposure to OMCTS. The effects in Sprague-Dawley rats of 13 w of exposure to OMCTS vapor at concentrations of 0, 0.06, 0.12, and 3.6 mg/L have been reported (Ulrich 1991). The exposure groups consisted of 10 rats per sex and concentration, with additional animals in the control and high-concentration groups for recovery studies. The end points included in this study were as follows: clinical signs, body weights, food consumption, ophthalmological examination, clinical chemistry, hematology, urinalysis, gross pathology, organ weights, and histopathology. There were a number of statistically significant differences between controls and exposed groups; however, the differences typically did not show a dose-response relationship, occurred randomly throughout the exposed groups, and had disappeared in the 4-w recovery group. The authors concluded that the apparent differences were not toxicologically significant and were within expected normal ranges for animals of the age and strain used. Only a 21% increase in liver weights in females at the terminal sacrifice was attributed to the test compound. This conclusion was partly based on results of previous studies. In contrast to the results above, ovarian weights at terminal sacrifice were increased relative to controls. Significant histopathological changes were not reported in the exposed animals. In a study reported by abstract, F344 rats were exposed nose-only for 90 d to 0.3, 1.2, 5.0, and 12.0 mg/L OMCTS for 6 h/d, 5 d/w (Mast et al. 1996). A satellite group was retained for 28 d after the last exposure to assess reversibility of lesions. Animals were evaluated for body weight changes, clinical signs, clinical laboratory parameters, gross pathology, organ weights, and histopathology. The major findings were as follows: high dose: reduced weight gain, moderate increase in serum gammaglutamyl transferase, minimal goblet cell proliferation in nasopharyngeal duct, ovarian atrophy, and vaginal mucification second dose: minimal goblet cell proliferation in nasopharyngeal duct, ovarian atrophy.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 In addition, there was a dose-dependent, reversible increase in liver weights; the concentration at which this effect disappeared was not specified. During the recovery period, essentially all the histopathological changes disappeared. Decamethylcyclopentasiloxane Two 13-w inhalation studies were available in summary form (Dow Corning 1995a). Since the second of these studies involved more test animals and a more thorough assessment of end points, it will be summarized here. Five groups of F344 rats were exposed 6 h/d, 5 d/w for 13 w to concentrations of 0, 0.44, 0.75, 1.33, and 3.5 mg/L. Each group consisted of at least 20 rats per sex. There were no clinical signs of toxicity during the exposures in any group. Liver weights were decreased in male rats (group 5) and female rats (groups 3,4 and 5) after exposures. There was a dose-related increase in serum gammaglutamyltransferase in females and lung weights remained elevated in female group 5 even after the 28-d recovery period. The NOAEL was 0.44 mg/L for both sexes. Carcinogenicity No studies were found on the carcinogenicity potential of any of the siloxanes. Genotoxicity The dimethylcyclosiloxanes have generally shown little genotoxicity when evaluated in batteries of in vitro and in vivo tests. All three siloxanes were negative in the following tests with and without S9 activation: Salmonella typhimurium and Saccharomyces cerevisiae reverse mutation assays, E. coli repair test for DNA damage, and the mouse lymphoma cell mutation test. There was an increase in the sister chromatid exchanges in mouse lymphoma cells when HMCTS was tested with and without the S9 fraction present (Isquith et al. 1988a). In vivo testing of HMCTS in the bone marrow cytogenic assay and rat dominant lethal test indicated no clastogenic activity (Isquith et al. 1988b). OMCTS was tested in cultured mouse lymphoma cells for induction of SCEs, point mutations, chromosomal aberrations, and primary DNA damage, with and without microsomal activation (Dow Corning 1995b). All results were negative except that with the activation system the indices of SCE frequency were increased. A dominant lethal assay in Sprague-Dawley rats given OMCTS by

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 gavage up to 1000 mg/kg/d, 5 d/w, for 8 w was negative for chromosomal damage in germinal cells of males, and for fertility, number of implants, number of dead implants in females mated to dosed males (Dow Corning 1995b). Reproductive Toxicology Few studies of the reproductive toxicity of dimethylcyclosiloxanes could be found; however, structurally related organosiloxanes produce adverse reproductive effects on male and female rats. Bennett et al. (1972) found that 7 d of oral administration of PHMCTC was "quite active" in producing adverse effects on the male reproductive systems of rats. The effect seemed to be specific to the route of administration because subcutaneous and intraperitoneal administrations caused much reduced effects on the male rats. In a study of the effects of 32 organosiloxanes on the weight of uteri from ovariectomized immature rats, PHMCTS was found to be the most estrogenic (+4) (Hayden and Barlow 1972). Three days of oral administration of this compound resulted in a 300% increase in uterine weight compared to controls. In the same study, OMCTS was found to have slight (+1) estrogenic activity and phenylpentamethylcyclotrisiloxane had moderate (+2) activity. Developmental Toxicity No developmental toxicity data could be found on the specific siloxanes of interest here; however, some data were found on structurally related compounds. PHMCTS administered at a dose of 220 mg/kg/d on gestational days 16 to 21 did not cause urogenital malformations in female rat pups; however, diphenylhexamethylcyclotetrasiloxane did elicit such malformations (Le Fevre et al. 1972). Neither compound caused abnormalities in male pups; however, either compound administered earlier in gestation caused adverse effects on the pregnancy. Interactions with Other Chemicals None of these siloxanes have been evaluated for their ability to alter the toxicity of other compounds; however, they have been shown to induce a number of hepatic enzymes (see "Metabolism" section). A summary of the toxicity data on the polydimethylcyclosiloxanes are presented in Table 7-2.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 7-2 Toxicity Summary Concentration or Dosage Exposure Duration Species Effects Reference 0.12 mg/L OMCTS 1 h, inhalation Human No immunological effects Looney et al. 1996 0.9 mL OMCTS Skin patch, 15 applications Human (n = 200) 2/200 showed skin reaction, no sensitization found 2 w after end of regular applications Shelanski 1974 0.06, 0.12, 3.6 mg/L OMCTS 6 h/d, 5 d/w, 13 w, inhalation Rat (M, F) 28% increased liver weight in high exposure females (reversible), no other effects Ulrich 1991 0.44, 0.75, 1.3, 3.5 mg/L DMCPS 6 h/d, 5 d/w, 13 w, inhalation Rat (M, F) Increased liver weight at 0.75 mg/L and above (F), dose related increase in GGT; high group had increased lung weights and possible histological effects on ovaries and testis; NOAEL for all effects was 0.44 mg/L Dow Corning 1995a 0.08, 0.94 mg/L HMCTS 6 h/d, 7 d/w (?), 4 w, inhalation Rat (M, F) NOAEL for all end points measured, higher dose rats showed some blood encrustation of nares LPT Report 0.2, 1.0, 5.1 mg/L OMCTS 6 h/d, 5 d/w, 4 w, inhalation Rat (M, F) Slight growth retardation in high exposure females, increase in relative liver weights (high exposure, both sexes, reversible) Appleton et al. 1984 0.3, 1.2 mg/L OMCTS 6 h/d, 5 d/w, 13 w, inhalation Rat (M, F) NOAEL for histopathology Mast et al. 1996 0.84, 8.4 mg/L OMCTS 6 h/d, 5 d/w, 28 d, inhalation Rat (M, F) Increased liver size McKim et al. 1995 1.1 mg/L DMCPS 6 h/d, 7 d/w, 28 d, inhalation Rat (M, F) NOAEL clinical pathology, immunotoxicity, organ weights Burns et al. 1996 2.4 mg/L DMCPS 6 h/d, 7 d/w, 28 d, inhalation Rat (F) 17% increase in liver weight (reversible) McKim et al. 1996

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration or Dosage Exposure Duration Species Effects Reference 52 mg/L OMCTS 8 h, aerosol inhalation Rat 5/6 died Clayton 1974 2 g/kg/d OMCTS 28 d, oral gavage Rat (M, F) Up to 7% growth retardation in females, no treatment effects by gross necropsy Manston 1988 >16 mL/kg OMCTS Skin patch Rabbit No deaths, erythema at site Weil 1972 >64 mL/kg OMCTS Oral gavage Rat No deaths, animals sluggish Weil 1972

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 No exposure limits have been set by other organizations. RATIONALE FOR ACCEPTABLE CONCENTRATIONS The toxicological data base, much of it not peer reviewed, on these three siloxanes suggests that they are relatively nontoxic compounds. Clinical signs indicating CNS depression have been noted in high-concentration exposures and only hepatomegaly, without histopathological change, respiratory irritation, and possibly injury to the ovaries or testis have been noted after prolonged exposures to high concentrations. With some studies showing decreased RBC measurements and others showing increased RBC measurements, the findings on anemia are inconsistent. The guidelines developed by the Committee on Toxicology have been used to derive SMACs (NRC 1992). Although the compounds have toxicological similarities, significant differences in the toxicological data bases of the compounds led the NRC to recommend that each compound be treated individually, rather than as members of a group with similar structural and toxicological properties. The most serious limitation of the toxicological data bases is the lack of good acute data. Most acute toxicity studies focus on lethality as an end point, so it is difficult to know if injury to organ systems has occurred as a result of a brief exposure. Fortunately, there is no need for short-term SMACs for these compounds because there is no known mechanism by which large amounts could be released into the cabin. For that reason, short-term SMACs were not set. To the extent possible, SMACs were based on studies that have been reported in detail, rather than by abstract. In addition, toxic effects that were superficially reported (e.g., ovarian effects and CNS depression) for two or more of the compounds were considered for purposes of setting SMACs. Possible Liver Injury Several studies indicate that both OMCTS and DMCPS induce a reversible hepatomegaly in rats. OMCPS concentrations as low as 0.84 mg/L have been shown to induce increased liver weight during 4-w exposures (McKim et al., 1995). A reversible increase in hepatocyte mitotic figures was noted in rats exposed to OMCTS at 1.0 or 5.1 mg/L for 4 w (Appleton et al., 1984). DMCPS exposures of 1.1 mg/L did not induce hepatomegaly in rats in 4 w; however, 2.4 mg/L induced a 17% weight increase in the livers of female rats (McKim et al. 1996). In contrast, HMCTS was not reported to induce hepatomegaly in rats exposed at 9.0 mg/L for 4 w (LPT Report). Reversible hepatomegaly without

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 histological evidence of injury is considered an adaptive rather than an adverse effect. Hexamethylcyclotrisiloxane The best data available on the inhalation toxicity of this compound come from rats exposed to analytical concentrations of 0.08. 0.94, and 9.0 mg/L (9,100, and 1000 ppm) 6 h/d, 7 d/w, for 4 w (LPT Report). The summary report describes microscopically observed inflammatory changes in the nasal cavities and an increased incidence of pulmonary perivascular infiltration in the high-exposure rats. The NOAEL for respiratory system injury was 100 ppm for a cumulative exposure of 168 h. Applying a species factor of 10, the 7-d AC to protect from respiratory-system injury was calculated to be 10 ppm (Table 7-3). That AC was extended to 30 d by dividing by a factor of 2 (30-d AC = 5 ppm), because 4-w and 13-w data on the other two siloxanes suggest that a factor of 2 (or less) is appropriate (see Tables 7-4 and 7-5). Because no data beyond 13 w were available, the default approach (Haber's rule) was used to extrapolate from the 30-d AC to the 180-d AC. The 180-d AC was set at 1 ppm. In the LPT Report, signs of slight temporary sedation were noted in the highest-exposure rats immediately after exposure. Because no signs of CNS depression were reported in the 100-ppm (middle) group, that concentration was selected as the NOAEL. Applying a species factor of 10 and no time factor gave long-term SMACs of 10 ppm. A time factor was not applied because CNS depression of this sort is a threshold-type effect. Octamethylcyclotetrasiloxane There was minimal evidence of respiratory-system effects caused by exposure to OMCTS; however, ACs were set for this possible effect. The evidence consisted of minimal goblet-cell proliferation in the nasopharyngeal duct and minor influx of alveolar macrophages in the lungs of rats exposed to concentrations as low as 5 mg/L for 6 h/d, 5 d/w, for 13 w (Mast et al. 1996). NOAELs for this effect came from a 4-w study in which rats were exposed to OMCTS at 5.1 mg/L (425 ppm), 6 h/d, 5 d/w (Appleman et al. 1984), and a 13-w study in which rats were exposed to OMCTS at 3.6 mg/L (300 ppm), 6 h/d, 5 d/w for 13 w (Ulrich et al. 1991). The 7-d AC was calculated from the 4-w data as follows: 7-d AC = 425 ppm × 120 h/168 h × 1/10 (species) = 32 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Similarly, the 30-d AC was calculated as follows: 30-d AC = 300 ppm × 390 h/720 h × 1/10 (species) = 16 ppm. In rats, the ACs only differ by a factor of 2, even though the exposure times are more than 4-fold different. With no data beyond 13 w, the default approach (Haber's rule) was used to extrapolate from the 30-d AC to the 180-d AC. The 180-d AC was set at 3 ppm. Indications of CNS effects were reported in rats exposed to OMCTS for 6 h/d, 5 d/w for 4 w (Dow Corning 1995b). Abnormal gait was reported in rats exposed at 5.1 mg/L and above, but 2.8 mg/L (230 ppm) was a NOAEL for all clinical signs. Applying a species factor of 10 gave ACs for protection from CNS effects of 23 ppm. Ovarian atrophy was reported in rats exposed to OMCTS at 5.0 mg/L by nose only for 6 h/d, 5 d/w for 13 w but not to in the next lower group exposed at 1.2 mg/L (100 ppm) (Mast et al. 1996). The atrophy was apparently observed microscopically but disappeared during the 28-d recovery period. The 30-d AC was calculated as follows: 30-d AC = 100 ppm × 390 h/ 720 h × 1/10 (species) = 5 ppm. The 180-d AC was calculated using Haber's rule to give 1 ppm. The 7-d AC for ovarian effects was calculated to be 32 ppm from the 4-w NOAEL of 425 ppm (Appleton et al. 1984). Decamethylcyclopentasiloxane Rats exposed to DMCPS at 2.3 to 3.1 mg/L (200 ppm), 6 h/d, 5 d/w (120 h total) for 4 w showed morphological changes in their nasal cavities as a result of irritation and slight inflammation in the lung paranchyma (Kelly et al. 1995, Dow Corning 1995a); however, the next lower group, 1.5 mg/L (100 ppm), did not show these changes. The 7-d AC was calculated as follows: 7-d AC = 100 ppm × 120 h/168 h × 1/10 (species) = 7 ppm. Increased lung weights were reported in rats exposed to DMCPS at 3.5 mg/L (230 ppm), 6 h/d, 5 d/w for 13 w but not in rats exposed at 1.3 mg/L (90 ppm) (Dow Corning 1995a). The 30-d AC was calculated as follows: 30-d AC = 90 ppm × 390 h/720 h × 1/10 (species) = 5 ppm. The 30-d AC is less than a factor of 2 below the 7-d AC.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 In the same 13-w study used for the respiratory-system injury (Dow Corning 1995a), possible ovarian and testicular effects were reported in the highest-exposure group (230 ppm) but not in the next lower group (90 ppm), nor were they reported in rats exposed for a shorter time (Kelly et al. 1995). The 7-d AC for gonad effects was based on the lack of effects reported in rats exposed at 200 ppm 6 h/d, 5 d/w for 4 w (Kelly et al. 1995). The calculation was as follows: 7-d AC = 200 ppm × 120/168 × 1/10 (species) = 14 ppm. The 30-d AC to avoid injury to the gonads was set at 5 ppm by using the same calculation as that for the respiratory effects. With no data beyond 13 w, the default approach (Haber's rule) was used to extrapolate from the 30-d AC to the 180-d AC. The 180-d AC was set at 1 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 7-3 Acceptable Concentrations for Hexamethylcyclostrisiloxane End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species NOAEL Time Species 1 h 24 h 7 d 30 d 180 d Respiratory system injury Rat 1 HRa 10 — — 10 5 1 NOAEL, 100 ppm for 6 h/d, 7 d/w, 4 w (LPT Report)                   CNS depression Rat 1 1 10 — — 10 10 10 NOAEL, 100 ppm for 6 h/d, 7 d/w, 4 w (LPT Report)                   SMACs (ppm)         NSb NSb 10 5 1 (mg/m3)             90 45 9 a Limits for 30 d and 180 d were set by analogy with OMCTS and DMCPS injury to respiratory system of rats. b Short-term limits were not set because of the lack of data and because there is no need for these values in the spacecraft. HR, Haber's rule. —, not applicable. NS, not set.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 7-4 Acceptable Concentrations for Octamethylcyclotetrasiloxane End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species NOAEL Time Species 1 h 24 h 7 d 30 d 180 d Respiratory system injury Rat 1 HR 10 — — 32 — — NOAEL, 425 ppm for 6 h/d, 5 d/w, 4 w (Appleman et al. 1984)                   NOAEL, 300 ppm for 6 h/d, 5 d/w, 13 w (Ulrich et al. 1991) Rat 1 HR 10 — — — 16 3 CNS depression Rat 1 1 10 — — 23 23 23 NOAEL, 230 ppm for 6 h/d, 5 d/w, 20 d (Dow Corning 1995b)                   Ovarian atrophy Rat 1 HR 10 — — 32 — — NOAEL, 425 ppm for 6 h/d, 5 d/w, 4 w (Appleman et al. 1984)                   NOAEL, 100 ppm for 6 h/d, 5 d/w, 13 w (Mast et al. 1996) Rat 1 HR 10 — — — 5 1 SMACs (ppm)         NSa NSa 23 5 1 (mg/m3)             280 60 12 a Short-term limits were not set because of the lack of data and because there is no need for these values in the spacecraft. HR, Haber's rule. —, not applicable. NS, not set.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 7-5 Acceptable Concentrations for Decamethylcyclopentasiloxane End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species NOAEL Time Species 1 h 24 h 7 d 30 d 180 d Respiratory system injury Rat 1 HR 10 — — 7 — — NOAEL, 100 ppm for 6 h/d, 5 d/w, 4 w (Kelly et al. 1995; Dow Corning 1995a)                   NOAEL, 90 ppm for 6 h/d, 5 d/w, 13 w (Dow Corning 1995a) Rat 1 HR 10 — — — 5 1 Ovarian/testicular histopathology Rat 1 HR 10 — — — 5 1 NOAEL, 90 ppm for 6 h/d, 5 d/w, 13 w (Dow Corning 1995a) NOAEL, 200 ppm for 6 h/d, 5 d/w, 4 w (Kelly et al. 1995) Rat 1 HR 10 — — 14 — — SMACs (ppm)         NSa NSa 7 5 1 (mg/m3)             100 75 15 a Short-term limits were not set because of the lack of data and because there is no need for these values in the spacecraft. HR, Haber's rule. —, not applicable. NS, not set.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RECOMMENDATIONS The descriptive toxicity data base for OMCTS is fairly complete, with the possible exception of short-term exposure effects. It is difficult to imagine a large accidental release of OMCTS that would require a better understanding of the acute effects of this silicone oil. Our understanding of the mechanisms of toxicity of OMCTS would be improved by toxicokinetics studies and further evaluation of the biochemical changes associated with the induction of hepatomegaly. Descriptive toxicity studies of HMCTS and DMCPS would seem to show that their toxicity is comparable to that of OMCTS, but these studies need peer review and publication. REFERENCES Appleman, L.M. 1984. Acute Inhalation Toxicity Study of Silicone Oil KF 994 in Rats. Report No. V 84.074/231263, Netherlands Organization for Applied Scientific Research. Appleman, L.M., C.F. Kuper, and W.G. Roverts. 1984. Sub-Acute Inhalation Toxicity Study of Silicone Oil KF 994 in Rats. Report No. V 84.299/231261, Netherlands Organization for Applied Scientific Research. Bennett, D.R., S.J. Gorzinski, and J.E. LeBeau. 1972. Structure-activity relationships of oral organosiloxanes on the male reproductive system. Toxicol. Appl. Pharmacol. 21:55-67. Burns, L.A., R.W. Mast, D.J. Naas, J.A. McCay, and P.C. Klykken. 1996. Toxicological and humoral immunity assessment in rats exposed for 28 days to decamethylcyclopentasiloxane (D5) vapor. Toxicologist 16:17. Clayton, E.T. 1974. Miscellaneous toxicity studies. Report 37-54, Union Carbide Corp., Danbury, CT. Dow Corning Corp. 1989. Dimethylcyclosiloxane inhalation exposure levels during the use of antiperspirant products. Dow Corning Corp., Midland, MI. Dow Corning Corp. 1995a. Summary of health data for decamethylcyclopentasiloxane (D5). Dow Corning Corp., Midland, MI. Dow Corning Corp. 1995b. Summary of health data for octamethylcyclotetrasiloxane (D4). Dow Corning Corp., Midland, MI Hayden, J.F., and S.A. Barlow. 1972. Structure-activity relationships of organosiloxanes and the female reproductive system. Toxicol. Appl. Pharmacol. 21:68-79 Hobbs, E.J., O.E. Fancher, and J.C. Calandra. 1972. Effect of selected organopolysiloxanes on male rat and rabbit reproductive organs. Toxicol. Appl. Pharmacol. 21:45-54. Isquith, A., D. Matheson, and R. Slesinski. 1988a. Genotoxicity studies on selected organisilicon compounds: In vitro assays. Food Chem. Toxicol. 26:255-61.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Isquith, A., R. Slesinski, and D. Matheson. 1988b. Genotoxicity studies on selected organosilicon compounds: In vivo assays. Food Chem. Toxicol. 26:263-66. James, J.T., T.F. Limero, H.J. Leano, J.F. Boyd, and P.A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the Space Shuttle: STS-26 to STS-55. Aviat. Space Environ. Med.65:851-7. Kelly, D.W., D.J. Neun, P. Thevenaz, R.G. Meeks, and R.W. Mast. 1995. Effects of 4-week inhalation of decamethylcyclopentasiloxane (D5) on Fischer 344 rats. Toxicologist 15:181. Le Fevre, R., F. Coulston, and L. Goldberg. 1972. Action of a copolymer of mixed phenylmethylcyclosiloxanes on reproduction in male rats and rabbits. Toxicol. Appl. Pharmacol. 21:29-44. Looney, R.J., J. Byam, M.W. Frampton, C. Kenaga, R.Mast, P. Klykken, P.E. Morrow, and M.J. Utell. 1996. Immunological effects of respiratory exposure to siloxane in humans. Toxicologist 16:16. Manston, S. 1988. A 28-day oral gavage study of octamethylcyclotetrasiloxane in male and female rats. Dow Corning. Corp., Midland, MI. Mast, R.W., G.B. Kolestar, Ph. Thvenaz, and R.G. Meeks. 1996. The effects of octamethylcyclotetrasiloxane (D4) in a 90-day nose only vapor inhalation study in rats . Toxicologist 16:17. McKim, Jr., J.M., S. Choudhuri, P.C. Wilga, J.G. Green, L.A. Burns, W.L. Alworth, and R.W. Mast. 1996. Induction of hepatic p450 1A1 and 2B1 following repeated inhalation exposure to decamethylcyclopentasiloxane. Toxicologist 16:15. McKim, J.M. Jr., G.B.Kolesar, L.W. Dochterman, P.C. Wilga, B.G. Hubbell, R.W. Mast, and R.G. Meeks. 1995. Effects of octamethylcyclotetrasiloxane (D4) on liver size and cytochrome p450 in F344 rats: A 28-day whole body inhalation study. Toxicologist 15:117. Myers, R.C., L.R. DePass, and F.R. Frank. 1982. Organosilicone fluid VS-7207 acute inhalation studies. Report 45-9, Union Carbide, Export, PA. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. Plotzke, K.P., S.D. Crofoot, J.G. Beattie, K.L. Salyers, and R.W.Mast. 1996. Disposition and metabolism of octamethylcyclotetrasiloxane (D4) in male and female rats following repeated nose-only vapor inhalation exposure. Toxicologist 16:16. Salyers, K.L., S. Varaprath, J.M. McKim, R.W.Mast, and K.P. Plotzke. 1996. Disposition and metabolism of octamethylcyclotetrasiloxane (D4)in F-344 rats: Effect of classical inducing agents. Toxicologist 16:15. Shah, J.J., and H.B. Singh. 1988. Distribution of volatile organic chemicals in outdoor and indoor air. Environ. Sci. Technol. 22:1381-88. Shelanski, M.V. 1974. Evaluation of potential hazards by dermal contact. Union Carbide Corp., Danbury, CT. Siddiqui, W.H., E.B. Hobbs, G.B. Kolesar, and M.A. Zimmer. 1989a. A 28-day repeated dose inhalation study of octamethylcyclotetrasiloxane (D4) in multiple species. Dow Corning Corp., Midland, MI.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Siddiqui, W.H., G.B. Kolesar, M.A. Zimmer, and E.B. Hobbs. 1989b. A 90-day subchronic inhalation toxicity study of octamethylcyclotetrasiloxane (D4) in the rat. Dow Corning Corp., Midland, MI. Ulrich, CE. 1991. Thirteen-week subchronic inhalation toxicity study on octamethylcyclotetrasiloxane (D4) in rats. International Research and Development Corp., Mattawan, MI. Weil, C.S. 1972. Silicone Y-7207 range finding studies. Report 35-54. Union Carbide Corp., Danbury, CT.