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Vaginal Absorption of Polyvinyl Alcohol in Fischer 344 Rats J.M. Sanders and H.B. Matthews Hum Exp Toxicol 1990 9: 71 DOI: 10.1177/096032719000900202 The online version of this article can be found at: http://het.sagepub.com/content/9/2/71
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Vaginal Absorption J.M. Sanders &
of
Polyvinyl
Alcohol in Fischer 344 Rats
H.B. Matthews
National Toxicology Program, National Institute of Environmental Health Research Triangle Park, North Carolina 27709, USA
Sciences, P.O. Box 12233,
Polyvinyl alcohol (PVA) is a polymer with a wide range of molecular weights and uses. Recently, low molecular weight formulations of PVA have been used as components of contraceptive products designed for intravaginal administration in human females. Previous studies in animals have determined that little or no absorption of PVA occurs from the gastrointestinal (GI) tract. However, there is some concern that PVA of lower molecular weights might be absorbed across membranes of the reproductive tract. Consequently, this work has investigated the absorption of low molecular weight PVA across biological membranes of the reproductive and GI tracts of Fischer 344 rats. Oral administration of ten consecutive daily doses of 14 C PVA resulted in little apparent absorption of the dose from the GI tract. In contrast, intravaginal administration of 14 C PVA resulted in increasing concentrations of PVA-derived radioactivity in major tissues following one, three or ten daily doses of the estimated human dose of 3 mg/kg. PVA-derived radioactivity was concentrated mainly in the liver, reaching a peak greater than 1750 ng equivalents/g tissue 24 hours following ten daily doses. Over 300 ng equivalents/g tissue were still present in the liver 30 days following the last dose. Introduction
Polyvinyl alcohol (PVA)
is a polymer, produced in commercial formulations that ranges in average molecular weight up to 300 000. The physical and chemical properties of PVA are dependent upon the molecular weight as well as on the degree of hydrolysis of the polymer. For instance, PVA formulations having molecular weights in the low range are quite water soluble, but the solubility of PVA in water decreases as the molecular weight increases. In 1980 the worldwide production capacity for PVA exceeded 360 000 metric tons. The major portion of PVA produced in the USA is used in the textile industry as a warp sizing or finishing agent. Other uses for domestically produced PVA are as a component of adhesives, as a polymerization aid, and for paper sizing and coating. PVA is also used in grease resistant coatings for food containers such as potato chip bags. The majority of PVA production occurs in Japan, where its main use is as a synthetic textile fibre.1-3 Recently, in a novel application, PVA has been used as a component in contraceptive products that are administered intravaginally. One of these products consists of a film containing the spermicide nonoxynol-9 (28%), glycerol (5%), and 67% PVA with an average molecular weight of 25 000.4 Glycerol
plasticizes the PVA, forming for the spermicide, which is
a solid carrier film released when the film dissolves in the aqueous environment of the
vaginal. 1.4 Large molecules of polymers such generally biological
as PVA are considered to be unabsorbed across membranes and thus thought to have
little or no pharmacological or toxicological effect. These polymers are also difficult to detect by conventional means of analysis, e.g. gas or liquid chromatography. Because of these general characteristics of polymers, only a few studies have been initiated to investigate the biological effects of PVA in animals. An investigation of PVA toxicity in rats by Hueper reported that PVA was not absorbed from the gastrointestinal (GI) tract.~ Daily doses (up to 25) of a 5% aqueous solution of PVA in saline administered i.v. or subcutaneously to rats or rabbits did, however, result in some accumulation and retention of PVA in tissues such as the spleen and liver. Toxicity observed in that study consisted of necrotic lesions associated with the site of administration or in the vascular system. No mention was made as to the molecular weight of the PVA used in those experiments. In an attempt to characterize the toxicity of PVA according to
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72
molecular weight. Hall &’ Hall injected female Holtzman rats subcutaneously with three different weight ranges of PVA.6 Each rat received 28 consecutive daily doses of 1 ml of 5% PVA in physiological saline. Elevation of blood pressure occurred in some rats from all three PVA-treated groups. The medium molecular weight PVA, (average MW = 133 000) caused the greatest toxic effects, which included widespread cardiovascular lesions, severe polydipsia, severe glomerulonephritis, and enlargement of the heart, kidney, liver, and spleen. The large molecular weight PVA (average MW = 185 000) caused renal glomerular swelling, as well as enlargement of the heart, kidney, liver, and spleen. Both the medium and large molecular weight PVA were found in liver, spleen, kidney, and other tissues. However, no low molecular weight (average MW = 37 000) PVA was found in any of the assayed tissues. There have been no investigations of absorption of PVA formulations across biological membranes other than those of the GI tract. It is well known that biological membranes can differ widely in their structure, function, and degree of vascularization, leading to variable rates of xenobiotic absorption. Thus, it is possible that PVA might be more readily absorbed from surfaces other than those in the GI tract. With the development of contraceptive products containing PVA, designed to be administered intravaginally, it became relevant that PVA absorption following this route of exposure be determined. Consequently, this work has investigated the absorption of low molecular weight PVA following intravaginal as well as oral administration.
Methods
Preparation of 14C PVA dosing solutions A poly(U-14C)vinyl alcohol (PVA) formulation with a specific activity of 477 RCi mg-1 was synthesized by Amersham Corp. (Arlington Heights, IL). The 14C PVA was dissolved in HPLC grade water (Fisher Scientific Co., Fair Lawn, NJ) at room temperature for preparation of dosing solutions. Fractionation of this mixture by gel filtration was not effective for either this material or samples of PVA of known molecular weight obtained commercially from Sigma Chemical Co. (St. Louis, MO). However, 100% of the 14C PVA used in the dosing solutions passed through a YM 100 ultrafiltration membrane (MW cut-off = 100 000) contained in an Amicon (Danvers, MA) model TCF2 ultrafiltration unit, and approximately 90% of the ~4C PVA passed through an Amicon XM 50 ultrafiltration membrane (MW cut-off 50 000). Only 4% of =
the ’4C PVA passed through an Amicon YM 5 ultrafiltration membrane (MW cut-off = 5000).
Animals and treatments Male Fischer 344 rats, 10-12-weeks-old (average 250 g), or female Fischer 344 rats, weight 170 g), were 10-12-weeks-old (average weight obtained from Charles River Breeding Laboratories (Raleigh, NC). PVA was administered by gavage to male rats, and by oral, i.v., or intravaginal administration to female rats. Three male rats each received a single dose of 0.01 mg PVA kg containing 4.8 pci of ’4C PVA in 1 ml kg water (prepared as described above) by gavage for an initial investigation of the absorption, distribution, and excretion of PVAderived radioactivity. Each animal was housed in a Metabowl Mark III glass metabolism cage =
=
(Jencons,
Hemel Hempstead, Hertfordshire, which allowed for the collection of expired C02 and volatiles, and for separation of urine and faeces. A total air flow of 0.4-0.5 1 min-’, maintained through each cage, was passed first through 200 ml of ethanol for the collection of expired volatiles, then through a trap containing 200 ml of a 7:3, v/v, mixture of 2-methoxyethanol-ethanolamine for ~4C02 collection. These traps were changed and sampled for PVA-derived radioactivity at 1, 2, 4, 6, 24, and 48 h. NIH 31 rat chow and water were provided to each animal ad libitum. Forty-eight hours after administration of PVA each animal was killed by asphyxiation with C02, and blood and other selected tissues were collected and stored at -20°C until assayed. The 14 C radioactivity in tissues was determined by combusting triplicate 50 or 100 mg samples to 14 C02, in a Packard Tri-Carb sample oxidizer (Packard Instrument Co., Downers Grove, IL), and counting the 14 C02 in a Beckman model LS-9800 liquid scintillation counter (Beckman Instruments, Inc., Fullerton, CA). Estimates for body composition were 8% for blood, 50% for muscle, 11% for adipose tissue, and 16% for skin.7,8 All other tissue weights were determined gravimetrically. Excretion of PVA-derived radioactivity was determined by complete collection of urine, faeces and expired air. Triplicate 0.05 ml urine samples or 1 ml samples of the expired air trapping solutions were pippetted directly into Ecolume (ICN Biomedicals, Inc., Irvine, CA) and counted in the scintillation counter. Faceal samples were air-dryed, weighed, and ground to a fine powder. Triplicate 100 mg samples of faeces were combusted and the radioactivity was determined as described above. Three additional male rats received an oral dose of 0.1 mg PVA ml-1 kg-1 containing 48 pci of ’4C PVA daily for ten consecutive days to investigate
England)
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possible bioaccumulation of PVA-derived radioactivity in tissues. Urine and faeces were collected at 24 h intervals, and animals were killed 24 h after the last dose by C02 asphyxiation. Distribution and excretion of PVA-derived radioactivity were determined as previously described. Female rats were used throughout the remaining work. Sacrifice of animals and collection and analysis of PVA-derived radioactivity in tissues and excreta were accomplished as described for the male rats, with the exception that expired air was not collected. Female rats received PVA by either i.v., intravaginal, or oral administration. The i.v. dose of 0.1 mg PVA kg containing 48 pci 14C PVA was administered in 1 ml water kg injected into a tail vein. For vaginal doses, VCF Vaginal Contraceptive Film (Apothecus, Inc., Great Neck, NY), containing 67% PVA, was dissolved in water with 14C PVA to approximate the mg kg does of PVA received by a 5060 kg human female using a single contraceptive film. This dose, containing 28 [tCi 3 mg PVA-1 kg 1, was administered intravaginally in 5 ~.1 of water to each rat using an 18 gauge feeding needle attached to a 100 ~1 volume gastight syringe. The initial set (n = 5) of animals dosed with an i.p. intravaginally was anaesthetized 1 injection of 50 mg kg Nembutal (Abbott Laboratories, North Chicago, IL). After hair around the vaginal opening of each animal was removed with animal clipers, the dose was administered by gentle insertion of the tip of the feeding needle into the vagina. A stainless steel screen (Lipshaw, Detroit, MI) was then attached directly over the vaginal opening with cyanoacrylate glue to reduce the possibility of grooming of the area. The screen permitted normal urination and defaecation and caused no apparent discomfort to the animal during the 4-day holding period. Bioaccumulation of PVA-derived radioactivity was investigated in tissues following daily vaginal doses by similarly dosing animals that were lightly anesthetized with C02. No effort was made to prevent grooming of the vagina in these repeat-dose studies. Rats received one, three, or ten consecutive daily doses (3 mg kg1 in a dose volume of 5 ¡..tl per rat) and were killed 1, 3, 10, or 30 days following the last dose. An additional set (n 4) of rats received by gavage a single 5 ~.1 volume of the PVA formulation prepared for intravaginal administration.
the PVA-derived radioactivity was excreted in the faeces with only trace amounts detected in the urine (0.18 ± 0.04% total dose). No PVAderived radioactivity was detected as 14C 02 or volatiles. Analysis of tissues for 1 C by oxidation and liquid scintillation counting failed to detect any accumulation of radioactivity significantly above background. Three additional male rats were administered a daily dose of 48 p.Ci 0.1 mg PVA-1 ml-1 kg by gavage for 10 consecutive days to investigate possible bioaccumulation of PVA in tissues. Twenty-four hours after the last dose the total PVA-derived radioactivity in the major tissues (blood, liver, kidneys, skin, muscle, and adipose) represented only 0.05% ± 0.01 % of the total dose. Virtually all PVA-derived radioactivity was excreted in the faeces, with only a trace detected in urine (0.2 ± 0.07% total dose). The tissue distribution and excretion of PVAderived radioactivity was investigated in female Fischer 344 rats following tail vein injections of 48 pci 0.1 mg ml-1 kg 1. Rats killed 24 h after receiving an i.v. dose, retained over 17% of the total dose in liver with lesser amounts in other tissues (Table 1). In the first 24 h the major portion of the dose was excreted in the urine (64%) with only 3% excreted in the faeces. Three days following a single i.v. dose the amount of PVA-derived radioactivity in the liver had decreased to 12% of the total dose with little additional excretion in urine, but excretion in the faeces increased to 5% of the total dose. Ten days following administration, 4% of the total dose remained in the liver with cumulative excretion in the faeces accounting for 13% of the dose. Only a trace of PVA-radioactivity was excreted in the urine between days 3 to 10. The possible absorption of PVA following
expired
Table 1 Distribution and cumulative excretion of PVAderived radioactivity versus time following i.v. administrationa a
=
Results In
an initial experiment, three male rats were administered 4.8 pci 0.01 mg PVA-1 ml-1 kg1 by gavage and held for 48 h after dosing to allow complete elimination of the dose. Over 98% of
a
b
0.1 mg kg-’. Mean ± s.d. from three to four rats.
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’
74
was investigated in female Fischer 344 rats. An initial five rats were anaesthetized and 5 ~1 of water containing 0.5 mg PVA (4.7 pci) was introduced into the vagina as described in the Methods section. All animals were held 4 days to permit maximum absorption of PVA from the vagina and to allow elimination of PVA from the vagina with fluids and cellular material formed during the oestrous cycle. Upon analysis of the major tissues, it was found that PVA-derived radioactivity had been absorbed from the vagina and distributed to the tissues. As with i.v. administration, PVA-derived radioactivity was concentrated mainly in the liver (Table 2). Although small, the tissue residues of PVA-derived radioactivity represented a significantly greater absorption of the dose than observed following oral administration. Large deviations from the means of several tissues indicated varying degrees of absorption among individual animals. This variation would be expected, both because of the changing environment of the vagina due to differences in the oestrous cycle, and because of likely variable loss of dosing solution directly from the vagina. The amount of the dose remaining in the vagina of each rat at sacrifice varied from a trace to 19% of the total dose. Most of the PVA-derived radioactivity was found in either urine or faeces. The radioactivity in urine probably represented leakage of the dose from the vagina as well as excretion of PVA-derived material following absorption. The occurrence of PVA-derived radioactivity in faeces probably resulted from ingestion of a portion of the dose due to oral grooming of the stainless steel screen placed over the vaginal opening.
intravaginal administration
possible. Only light C02 anaesthesia was used, allowing quick recovery to normal activity following dosing, and the vaginal opening was not covered. Although vaginal absorption again varied among individual animals, PVA-derived radioactivity was increasingly concentrated in the liver and other assayed tissues, except blood, 24 h following one, three, or ten daily doses (Figure 1, Table 3). The mean concentration of PVAderived radioactivity in blood 24 h following the last of ten daily doses (Tables 3 and 4) appeared to be an outlier, but this value was confirmed by reassaying blood samples from this group of animals. At present, we have no explanation for this apparent deviation of PVA clearance from blood. Peak concentrations of radioactivity reached 1757 ± 669 ng equivalents PVA g liver-’ 24 h after ten daily doses and remained near that level 3 days following the 10th daily dose (Figure 1, Table 4). Clearance of PVA-derived radioactivity from the liver was relatively slow, with significant amounts of PVA-derived radioactivity remaining in liver up to 30 days following the last of ten daily doses (Figure 1, Table 4). Although the concentrations were not as high as observed in liver, PVA-derived radioactivity in kidneys and other tissues followed the same trends with time (Tables 3 and 4). Oral administration of the same dose preparation used for studies of female rats, either fed
vaginal absorption to or deprived of food overnight to promote gastrointestinal absorption, resulted in minimal absorption from the GI tract.
More than 98% of the dose was excreted in the faeces. The PVA-derived radioactivity detected
Subsequent experiments were designed to investigate the possible accumulation of PVAderived radioactivity in tissues, primarily the liver, following repeated intravaginal administration. To better mimic human exposure to PVA by the vaginal route, animals were maintained under the most stress-free conditions Table 2 PVA-derived
radioactivity in major tissues days following intravaginal administration’
4
1 Concentration of PVA-derived radioactivity in liver versus time following intravaginal administration. 0, 24h following a single dose; 0, 24 h following 3 consecutive daily doses; A, 24 h following 10 consecutive daily doses; and 0, 3, 10, and 30 days following the last of 10 consecutive daily doses.
Figure
’3mgkg-B b
Mean ± s.d. from five rats.
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75
Table 3 Concentration of PVA-derived administrationa
3b 3 mg kg-I.
Mean ± s.d. from three rats
b
3 mg kg 1. Mean ± s.d. from three rats
radioactivity in
following repeated daily intravaginal
tissues
versus
time
following
10
daily vaginal
dosesa
(ng equivalents g tissue-’).
in liver 24 h following a single 3 mg kg oral dose amounted to approximately 0.03% of the total dose, which was less than 5% of the concentration in liver 24 h following intravaginal administration of a comparable dose (data not shown). 14C PVA concentrations in other assayed tissues following oral administration were at or near background levels. ’
Discussion alcohols are a widely used, but little studied class of organic polymers. These compounds cannot be detected by conventional methods of chemical analysis and the methods of analysis that are available are not very sensitive. Consequently, the extent of PVA present in the environment, food supply, or even animal and human tissues is presently unknown. PVA has been assumed to be unabsorbed across biological membranes because of its large molecular weight. To date there has been little data to contradict this assumption and little evidence of toxicity associated with many years of PVA use. However, formulations containing relatively low molecular
Polyvinyl
in tissues 24 h
(ng equivalents g tissue-’).
Table 4 Concentration of PVA-derived
a
radioactivity
PVA are now being used in some novel commercial contraceptive products designed for intravaginal administration. Because of a lack of information concerning health risks associated with this use of PVA, the present study was undertaken to investigate the absorption of low molecular weight PVA from the GI tract and from the vagina of the rat. The use of radiolabelled material in this work permitted the administration and detection of small doses of PVA, such as those which humans might be exposed to following the use of contraceptive products containing PVA or in the consumption of food from containers lined with PVA. Results from this work indicate that a dose of PVA present in the body following an i.v. injection was fractioned by the body to be excreted both in the urine and faeces (Table 1). The majority of the radioactivity was rapidly excreted in the urine within 24 h following i.v. administration, but subsequent excretion was almost entirely in the faeces. Polymers such as PVA are generally not metabolized and no evidence of metabolism was observed in this study, therefore this fractionation of the dose was probably due to the range of molecular weights
weight
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76
making up this PVA formulation. That portion of the 1°C PVA dose, rapidly excreted in the urine following i.v. administration, was most likely of a molecular weight less than the upper limit for glomerular filtration by the kidney. The 14C PVA retained in the tissues was slowly eliminated from the body via the faeces rather than in urine, probably because this material was of a molecular weight too large to enter the glomerular filtrate. Oral administration of PVA resulted in little apparent absorption from the GI tract. Even the administration of high doses of radioactivity (2.7 X 107 dpm 14 C daily for 10 consecutive days) resulted in only marginally detectable levels of radioactivity in major organs and tissues and only a trace (0.2%) excreted in urine. In contract to
gastrointestinal absorption, a quantifiable amount of PVA-derived radioactivity was absorbed from the vaginas of female Fischer 344 rats (Table 2). Although absorption from the vagina exceeded gastrointestinal absorption, the fraction of the dose that was present in the major tissues at the time of sampling never exceeded 2% of the total dose. Total absorption no doubt exceeded this figure because most of the dose following i.v. administration was eliminated in the urine within 24 h. In an effort to simulate human exposure more closely, the vaginas of treated rats were not sealed. This resulted in contamination of urine with PVA lost from the vagina, making an accurate estimate of PVA excretion in the urine impossible. That portion of the PVA dose absorbed from the vagina and retained by the tissues was concentrated mainly in the liver, and to a lesser extent the kidney, and was still easily quantifiable 4 days following administration of a single dose. These data also indicate that PVAderived radioactivity absorbed from the vagina and deposited in the liver and kidney was slowly removed from these tissues, as was observed following i.v. administration. Since detectable amounts of PVA-derived radioactivity still remained in the liver and other tissues up to 4 days following a single intravaginal dose, it was speculated that bioaccumulation of this material might occur following repeated exposure to PVA. Since the vascularity of the vagina changes during the oestrous cycle and the cycle of the rat is 4-5 days long, the use of a 10-day dosing period guaranteed that each rat would be dosed during every part of the cycle.99 The experimental design of the repeat-dose study was modified to provide conditions which would further simulate human exposure to PVA by intravaginal administration. The initial experimental design, in which the animals were heavily anaesthetized and the vaginal opening covered with a mesh screen, seemed to promote absorption of PVA from the vagina. Concentrations of
radioactivity in tissues (except blood) of animals held 4 days following a single intravaginal dose were higher than concentrations in tissues of rats held 1 day following a similar dose using the modified procedure (Tables 2 and 3). The initial group of dosed animals remained in a supine position for several hours due to the PVA-derived
effect of the anaesthesia. These animals were also prohibited from removing PVA directly from the vaginal area by grooming because of the attached mesh screen. Either or both of these conditions might have promoted additional absorption of PVA from the vagina. In the modified procedure the protective covering over the vaginal opening was not used so that the animals could groom normally. Additionally, only light C02 anaesthesia was used in this procedure, allowing animals to recover to a normal unrestrained position within minutes following administration of the dose. These factors could have contributed to loss of PVA from the vagina prior to absorption. Results obtained from repeated daily intravaginal administration of PVA indicated that PVA accumulated in increasing concentrations over time in the liver and other tissues (Table 3). Further, this material was only slowly removed from tissues following cessation of dosing (Table 4). It should be pointed out, however, that based on observations reported here, bioaccumulation of PVA-derived radioactivity in tissues represents very little material. The peak concentration in liver 24 hours following 10 consecutive daily doses of 3 mg kg-1 represented only approximately 2 ppm. The data were too variable to provide an accurate estimate of the half-life of the PVA-derived radioactivity concentrated in the liver, but it appeared to be slightly less than 10 days. In that event, peak levels of PVAderived radioactivity in the liver following chronic exposure to the dose used in this study should be in the range of 10-20 ppm. No symptoms of toxicity, such as weight loss, or erythema of the vaginal area were observed in any animal groups receiving intravaginally administered doses. Furthermore, we are not aware that any concenration of PVA-derived material in tissues following oral or intravaginal administration results in toxicity, but only report that accumulation of PVA-derived radioactivity in tissues was quantifiable following intravaginal, but not oral,
administration. Absorption of xenobiotics from the vagina is well documented in a review of the subject published by Benziger & Edelson.10 Substances absorbed from the vagina range from organic compounds such as steroids and prostoglandins to inorganic compounds such as iodine and arsenic. The polymeric spermicide nonoxynol-9,
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77
present in the PVA formulation used in this
study, has also been shown to be absorbed from the vagina into the systemic circulation.’ 1,12 In some instances, blood levels of a compound following absorption from the vagina can exceed those for the same compound following absorption from the GI tract. For example, Patel et al. 13 demonstrated that blood concentrations of pro-
pranolol
were
greater following intravaginal
rather than oral administration. These authors were unsure, however, whether total absorption from the vagina exceeded that from the GI tract and pointed out that the higher blood concentra-
tions following intravaginal administration may have resulted from greater metabolism of the oral dose on its ’first pass’ through the liver. In any event, it appears that most compounds which are absorbed from the vagina are also absorbed from the GI tract. PVA, a large molecule, seems to be an exception because it can be absorbed from the vagina but not from the GI tract. These data suggest that the molecular weight cut-off above which absorption of a compound does not occur may be significantly greater for the vagina than most, if not all, other readily assessable epidermal surfaces.
References 1 Linderman MK. Vinyl alcohol polymers. In: Encyclopedia of Polymer Science and Technology, ed. NM Bikales, vol. 14, pp. 149-207. New York: John Wiley and Sons, 1971.
2
Some
and
synthetic polymers. IARC (International Agency for Research Cancer) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 1979; 19: 351-66. Cincera DL. Poly(vinyl alcohol). In: Kirk-Othmer Encyclopedia of Chemical Toxicology, ed. M. Grayson 3rd edn, vol. 23, pp. 848-65. New York: John Wiley and Sons,
Anonymous.
monomers,
elastomers, and acrolein. Vinyl
plastics
acetate and
on
3
Drug Metabolism and Disposition 1975; 3: 211-19. 8 Birnbaum LS, Decad GM & Matthews HB. Disposition and excretion of 2,3,7,8-tetrachlorodibenzofuran in the rat. Toxicology and Applied Pharmacology 1980; 55: 342-52. 9 Harkness JE & Wagner JE. Biology and husbandry. In: The Biology and Medicine of Rabbits and Rodents, 2nd edn pp. 7-51.
11
1983. 4
Leon S. VCF Vaginal Contraceptive Film Information Leaflet. Apothecus, Inc., Great Neck, NY. 5 Hueper WC. Organic lesions produced by polyvinyl alcohol in rats and rabbits. Archives of Pathology 1939; 28: 510-31. 6 Hall CH & Hall O. Polyvinyl alcohol nephrosis: relationship of degree of polymerization to pathophysiologic effects. Proceedings of the Society for Experimental Biology and Medicine 1983; 112: 86-91. 7 Matthews HB & Anderson MW. The distribution and excretion of 2,4,5,2’,5’-pentachlorobiphenyl in the rat.
Philadelphia: Lea and Febiger, 1983. DP & Edelson J. Absorption from the vagina. Drug Metabolism Reviews 1983; 14: 137-68. Buttar HS. Transvaginal absorption and disposition of nonoxynol-9 in gravid rats. Toxicology Letters 1982; 13: 211-16. Walter BA, Agha BJ & Digenis GA. Disposition of C] 14 [ nonoxynol-9 after intravenous or vaginal administration to female Sprague-Dawley rats. Toxicology and Applied Pharmacology 1988; 96: 258-68. Patel LG, Warrington SJ, & Pearson RM. Propranolol concentrations in plasma after insertion into the vagina. British Medical Journal 1983; 287: 1247-48.
10 Benziger
12
13
(Received 6 June 1989; accepted 21 July 1989)
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Vaginal Absorption of Polyvinyl Alcohol in Fischer 344 Rats J.M. Sanders and H.B. Matthews Hum Exp Toxicol 1990 9: 71 DOI: 10.1177/096032719000900202 The online version of this article can be found at: http://het.sagepub.com/content/9/2/71
Published by: http://www.sagepublications.com
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>> Version of Record - Jan 1, 1990 What is This?
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Vaginal Absorption J.M. Sanders &
of
Polyvinyl
Alcohol in Fischer 344 Rats
H.B. Matthews
National Toxicology Program, National Institute of Environmental Health Research Triangle Park, North Carolina 27709, USA
Sciences, P.O. Box 12233,
Polyvinyl alcohol (PVA) is a polymer with a wide range of molecular weights and uses. Recently, low molecular weight formulations of PVA have been used as components of contraceptive products designed for intravaginal administration in human females. Previous studies in animals have determined that little or no absorption of PVA occurs from the gastrointestinal (GI) tract. However, there is some concern that PVA of lower molecular weights might be absorbed across membranes of the reproductive tract. Consequently, this work has investigated the absorption of low molecular weight PVA across biological membranes of the reproductive and GI tracts of Fischer 344 rats. Oral administration of ten consecutive daily doses of 14 C PVA resulted in little apparent absorption of the dose from the GI tract. In contrast, intravaginal administration of 14 C PVA resulted in increasing concentrations of PVA-derived radioactivity in major tissues following one, three or ten daily doses of the estimated human dose of 3 mg/kg. PVA-derived radioactivity was concentrated mainly in the liver, reaching a peak greater than 1750 ng equivalents/g tissue 24 hours following ten daily doses. Over 300 ng equivalents/g tissue were still present in the liver 30 days following the last dose. Introduction
Polyvinyl alcohol (PVA)
is a polymer, produced in commercial formulations that ranges in average molecular weight up to 300 000. The physical and chemical properties of PVA are dependent upon the molecular weight as well as on the degree of hydrolysis of the polymer. For instance, PVA formulations having molecular weights in the low range are quite water soluble, but the solubility of PVA in water decreases as the molecular weight increases. In 1980 the worldwide production capacity for PVA exceeded 360 000 metric tons. The major portion of PVA produced in the USA is used in the textile industry as a warp sizing or finishing agent. Other uses for domestically produced PVA are as a component of adhesives, as a polymerization aid, and for paper sizing and coating. PVA is also used in grease resistant coatings for food containers such as potato chip bags. The majority of PVA production occurs in Japan, where its main use is as a synthetic textile fibre.1-3 Recently, in a novel application, PVA has been used as a component in contraceptive products that are administered intravaginally. One of these products consists of a film containing the spermicide nonoxynol-9 (28%), glycerol (5%), and 67% PVA with an average molecular weight of 25 000.4 Glycerol
plasticizes the PVA, forming for the spermicide, which is
a solid carrier film released when the film dissolves in the aqueous environment of the
vaginal. 1.4 Large molecules of polymers such generally biological
as PVA are considered to be unabsorbed across membranes and thus thought to have
little or no pharmacological or toxicological effect. These polymers are also difficult to detect by conventional means of analysis, e.g. gas or liquid chromatography. Because of these general characteristics of polymers, only a few studies have been initiated to investigate the biological effects of PVA in animals. An investigation of PVA toxicity in rats by Hueper reported that PVA was not absorbed from the gastrointestinal (GI) tract.~ Daily doses (up to 25) of a 5% aqueous solution of PVA in saline administered i.v. or subcutaneously to rats or rabbits did, however, result in some accumulation and retention of PVA in tissues such as the spleen and liver. Toxicity observed in that study consisted of necrotic lesions associated with the site of administration or in the vascular system. No mention was made as to the molecular weight of the PVA used in those experiments. In an attempt to characterize the toxicity of PVA according to
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molecular weight. Hall &’ Hall injected female Holtzman rats subcutaneously with three different weight ranges of PVA.6 Each rat received 28 consecutive daily doses of 1 ml of 5% PVA in physiological saline. Elevation of blood pressure occurred in some rats from all three PVA-treated groups. The medium molecular weight PVA, (average MW = 133 000) caused the greatest toxic effects, which included widespread cardiovascular lesions, severe polydipsia, severe glomerulonephritis, and enlargement of the heart, kidney, liver, and spleen. The large molecular weight PVA (average MW = 185 000) caused renal glomerular swelling, as well as enlargement of the heart, kidney, liver, and spleen. Both the medium and large molecular weight PVA were found in liver, spleen, kidney, and other tissues. However, no low molecular weight (average MW = 37 000) PVA was found in any of the assayed tissues. There have been no investigations of absorption of PVA formulations across biological membranes other than those of the GI tract. It is well known that biological membranes can differ widely in their structure, function, and degree of vascularization, leading to variable rates of xenobiotic absorption. Thus, it is possible that PVA might be more readily absorbed from surfaces other than those in the GI tract. With the development of contraceptive products containing PVA, designed to be administered intravaginally, it became relevant that PVA absorption following this route of exposure be determined. Consequently, this work has investigated the absorption of low molecular weight PVA following intravaginal as well as oral administration.
Methods
Preparation of 14C PVA dosing solutions A poly(U-14C)vinyl alcohol (PVA) formulation with a specific activity of 477 RCi mg-1 was synthesized by Amersham Corp. (Arlington Heights, IL). The 14C PVA was dissolved in HPLC grade water (Fisher Scientific Co., Fair Lawn, NJ) at room temperature for preparation of dosing solutions. Fractionation of this mixture by gel filtration was not effective for either this material or samples of PVA of known molecular weight obtained commercially from Sigma Chemical Co. (St. Louis, MO). However, 100% of the 14C PVA used in the dosing solutions passed through a YM 100 ultrafiltration membrane (MW cut-off = 100 000) contained in an Amicon (Danvers, MA) model TCF2 ultrafiltration unit, and approximately 90% of the ~4C PVA passed through an Amicon XM 50 ultrafiltration membrane (MW cut-off 50 000). Only 4% of =
the ’4C PVA passed through an Amicon YM 5 ultrafiltration membrane (MW cut-off = 5000).
Animals and treatments Male Fischer 344 rats, 10-12-weeks-old (average 250 g), or female Fischer 344 rats, weight 170 g), were 10-12-weeks-old (average weight obtained from Charles River Breeding Laboratories (Raleigh, NC). PVA was administered by gavage to male rats, and by oral, i.v., or intravaginal administration to female rats. Three male rats each received a single dose of 0.01 mg PVA kg containing 4.8 pci of ’4C PVA in 1 ml kg water (prepared as described above) by gavage for an initial investigation of the absorption, distribution, and excretion of PVAderived radioactivity. Each animal was housed in a Metabowl Mark III glass metabolism cage =
=
(Jencons,
Hemel Hempstead, Hertfordshire, which allowed for the collection of expired C02 and volatiles, and for separation of urine and faeces. A total air flow of 0.4-0.5 1 min-’, maintained through each cage, was passed first through 200 ml of ethanol for the collection of expired volatiles, then through a trap containing 200 ml of a 7:3, v/v, mixture of 2-methoxyethanol-ethanolamine for ~4C02 collection. These traps were changed and sampled for PVA-derived radioactivity at 1, 2, 4, 6, 24, and 48 h. NIH 31 rat chow and water were provided to each animal ad libitum. Forty-eight hours after administration of PVA each animal was killed by asphyxiation with C02, and blood and other selected tissues were collected and stored at -20°C until assayed. The 14 C radioactivity in tissues was determined by combusting triplicate 50 or 100 mg samples to 14 C02, in a Packard Tri-Carb sample oxidizer (Packard Instrument Co., Downers Grove, IL), and counting the 14 C02 in a Beckman model LS-9800 liquid scintillation counter (Beckman Instruments, Inc., Fullerton, CA). Estimates for body composition were 8% for blood, 50% for muscle, 11% for adipose tissue, and 16% for skin.7,8 All other tissue weights were determined gravimetrically. Excretion of PVA-derived radioactivity was determined by complete collection of urine, faeces and expired air. Triplicate 0.05 ml urine samples or 1 ml samples of the expired air trapping solutions were pippetted directly into Ecolume (ICN Biomedicals, Inc., Irvine, CA) and counted in the scintillation counter. Faceal samples were air-dryed, weighed, and ground to a fine powder. Triplicate 100 mg samples of faeces were combusted and the radioactivity was determined as described above. Three additional male rats received an oral dose of 0.1 mg PVA ml-1 kg-1 containing 48 pci of ’4C PVA daily for ten consecutive days to investigate
England)
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possible bioaccumulation of PVA-derived radioactivity in tissues. Urine and faeces were collected at 24 h intervals, and animals were killed 24 h after the last dose by C02 asphyxiation. Distribution and excretion of PVA-derived radioactivity were determined as previously described. Female rats were used throughout the remaining work. Sacrifice of animals and collection and analysis of PVA-derived radioactivity in tissues and excreta were accomplished as described for the male rats, with the exception that expired air was not collected. Female rats received PVA by either i.v., intravaginal, or oral administration. The i.v. dose of 0.1 mg PVA kg containing 48 pci 14C PVA was administered in 1 ml water kg injected into a tail vein. For vaginal doses, VCF Vaginal Contraceptive Film (Apothecus, Inc., Great Neck, NY), containing 67% PVA, was dissolved in water with 14C PVA to approximate the mg kg does of PVA received by a 5060 kg human female using a single contraceptive film. This dose, containing 28 [tCi 3 mg PVA-1 kg 1, was administered intravaginally in 5 ~.1 of water to each rat using an 18 gauge feeding needle attached to a 100 ~1 volume gastight syringe. The initial set (n = 5) of animals dosed with an i.p. intravaginally was anaesthetized 1 injection of 50 mg kg Nembutal (Abbott Laboratories, North Chicago, IL). After hair around the vaginal opening of each animal was removed with animal clipers, the dose was administered by gentle insertion of the tip of the feeding needle into the vagina. A stainless steel screen (Lipshaw, Detroit, MI) was then attached directly over the vaginal opening with cyanoacrylate glue to reduce the possibility of grooming of the area. The screen permitted normal urination and defaecation and caused no apparent discomfort to the animal during the 4-day holding period. Bioaccumulation of PVA-derived radioactivity was investigated in tissues following daily vaginal doses by similarly dosing animals that were lightly anesthetized with C02. No effort was made to prevent grooming of the vagina in these repeat-dose studies. Rats received one, three, or ten consecutive daily doses (3 mg kg1 in a dose volume of 5 ¡..tl per rat) and were killed 1, 3, 10, or 30 days following the last dose. An additional set (n 4) of rats received by gavage a single 5 ~.1 volume of the PVA formulation prepared for intravaginal administration.
the PVA-derived radioactivity was excreted in the faeces with only trace amounts detected in the urine (0.18 ± 0.04% total dose). No PVAderived radioactivity was detected as 14C 02 or volatiles. Analysis of tissues for 1 C by oxidation and liquid scintillation counting failed to detect any accumulation of radioactivity significantly above background. Three additional male rats were administered a daily dose of 48 p.Ci 0.1 mg PVA-1 ml-1 kg by gavage for 10 consecutive days to investigate possible bioaccumulation of PVA in tissues. Twenty-four hours after the last dose the total PVA-derived radioactivity in the major tissues (blood, liver, kidneys, skin, muscle, and adipose) represented only 0.05% ± 0.01 % of the total dose. Virtually all PVA-derived radioactivity was excreted in the faeces, with only a trace detected in urine (0.2 ± 0.07% total dose). The tissue distribution and excretion of PVAderived radioactivity was investigated in female Fischer 344 rats following tail vein injections of 48 pci 0.1 mg ml-1 kg 1. Rats killed 24 h after receiving an i.v. dose, retained over 17% of the total dose in liver with lesser amounts in other tissues (Table 1). In the first 24 h the major portion of the dose was excreted in the urine (64%) with only 3% excreted in the faeces. Three days following a single i.v. dose the amount of PVA-derived radioactivity in the liver had decreased to 12% of the total dose with little additional excretion in urine, but excretion in the faeces increased to 5% of the total dose. Ten days following administration, 4% of the total dose remained in the liver with cumulative excretion in the faeces accounting for 13% of the dose. Only a trace of PVA-radioactivity was excreted in the urine between days 3 to 10. The possible absorption of PVA following
expired
Table 1 Distribution and cumulative excretion of PVAderived radioactivity versus time following i.v. administrationa a
=
Results In
an initial experiment, three male rats were administered 4.8 pci 0.01 mg PVA-1 ml-1 kg1 by gavage and held for 48 h after dosing to allow complete elimination of the dose. Over 98% of
a
b
0.1 mg kg-’. Mean ± s.d. from three to four rats.
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’
74
was investigated in female Fischer 344 rats. An initial five rats were anaesthetized and 5 ~1 of water containing 0.5 mg PVA (4.7 pci) was introduced into the vagina as described in the Methods section. All animals were held 4 days to permit maximum absorption of PVA from the vagina and to allow elimination of PVA from the vagina with fluids and cellular material formed during the oestrous cycle. Upon analysis of the major tissues, it was found that PVA-derived radioactivity had been absorbed from the vagina and distributed to the tissues. As with i.v. administration, PVA-derived radioactivity was concentrated mainly in the liver (Table 2). Although small, the tissue residues of PVA-derived radioactivity represented a significantly greater absorption of the dose than observed following oral administration. Large deviations from the means of several tissues indicated varying degrees of absorption among individual animals. This variation would be expected, both because of the changing environment of the vagina due to differences in the oestrous cycle, and because of likely variable loss of dosing solution directly from the vagina. The amount of the dose remaining in the vagina of each rat at sacrifice varied from a trace to 19% of the total dose. Most of the PVA-derived radioactivity was found in either urine or faeces. The radioactivity in urine probably represented leakage of the dose from the vagina as well as excretion of PVA-derived material following absorption. The occurrence of PVA-derived radioactivity in faeces probably resulted from ingestion of a portion of the dose due to oral grooming of the stainless steel screen placed over the vaginal opening.
intravaginal administration
possible. Only light C02 anaesthesia was used, allowing quick recovery to normal activity following dosing, and the vaginal opening was not covered. Although vaginal absorption again varied among individual animals, PVA-derived radioactivity was increasingly concentrated in the liver and other assayed tissues, except blood, 24 h following one, three, or ten daily doses (Figure 1, Table 3). The mean concentration of PVAderived radioactivity in blood 24 h following the last of ten daily doses (Tables 3 and 4) appeared to be an outlier, but this value was confirmed by reassaying blood samples from this group of animals. At present, we have no explanation for this apparent deviation of PVA clearance from blood. Peak concentrations of radioactivity reached 1757 ± 669 ng equivalents PVA g liver-’ 24 h after ten daily doses and remained near that level 3 days following the 10th daily dose (Figure 1, Table 4). Clearance of PVA-derived radioactivity from the liver was relatively slow, with significant amounts of PVA-derived radioactivity remaining in liver up to 30 days following the last of ten daily doses (Figure 1, Table 4). Although the concentrations were not as high as observed in liver, PVA-derived radioactivity in kidneys and other tissues followed the same trends with time (Tables 3 and 4). Oral administration of the same dose preparation used for studies of female rats, either fed
vaginal absorption to or deprived of food overnight to promote gastrointestinal absorption, resulted in minimal absorption from the GI tract.
More than 98% of the dose was excreted in the faeces. The PVA-derived radioactivity detected
Subsequent experiments were designed to investigate the possible accumulation of PVAderived radioactivity in tissues, primarily the liver, following repeated intravaginal administration. To better mimic human exposure to PVA by the vaginal route, animals were maintained under the most stress-free conditions Table 2 PVA-derived
radioactivity in major tissues days following intravaginal administration’
4
1 Concentration of PVA-derived radioactivity in liver versus time following intravaginal administration. 0, 24h following a single dose; 0, 24 h following 3 consecutive daily doses; A, 24 h following 10 consecutive daily doses; and 0, 3, 10, and 30 days following the last of 10 consecutive daily doses.
Figure
’3mgkg-B b
Mean ± s.d. from five rats.
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75
Table 3 Concentration of PVA-derived administrationa
3b 3 mg kg-I.
Mean ± s.d. from three rats
b
3 mg kg 1. Mean ± s.d. from three rats
radioactivity in
following repeated daily intravaginal
tissues
versus
time
following
10
daily vaginal
dosesa
(ng equivalents g tissue-’).
in liver 24 h following a single 3 mg kg oral dose amounted to approximately 0.03% of the total dose, which was less than 5% of the concentration in liver 24 h following intravaginal administration of a comparable dose (data not shown). 14C PVA concentrations in other assayed tissues following oral administration were at or near background levels. ’
Discussion alcohols are a widely used, but little studied class of organic polymers. These compounds cannot be detected by conventional methods of chemical analysis and the methods of analysis that are available are not very sensitive. Consequently, the extent of PVA present in the environment, food supply, or even animal and human tissues is presently unknown. PVA has been assumed to be unabsorbed across biological membranes because of its large molecular weight. To date there has been little data to contradict this assumption and little evidence of toxicity associated with many years of PVA use. However, formulations containing relatively low molecular
Polyvinyl
in tissues 24 h
(ng equivalents g tissue-’).
Table 4 Concentration of PVA-derived
a
radioactivity
PVA are now being used in some novel commercial contraceptive products designed for intravaginal administration. Because of a lack of information concerning health risks associated with this use of PVA, the present study was undertaken to investigate the absorption of low molecular weight PVA from the GI tract and from the vagina of the rat. The use of radiolabelled material in this work permitted the administration and detection of small doses of PVA, such as those which humans might be exposed to following the use of contraceptive products containing PVA or in the consumption of food from containers lined with PVA. Results from this work indicate that a dose of PVA present in the body following an i.v. injection was fractioned by the body to be excreted both in the urine and faeces (Table 1). The majority of the radioactivity was rapidly excreted in the urine within 24 h following i.v. administration, but subsequent excretion was almost entirely in the faeces. Polymers such as PVA are generally not metabolized and no evidence of metabolism was observed in this study, therefore this fractionation of the dose was probably due to the range of molecular weights
weight
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making up this PVA formulation. That portion of the 1°C PVA dose, rapidly excreted in the urine following i.v. administration, was most likely of a molecular weight less than the upper limit for glomerular filtration by the kidney. The 14C PVA retained in the tissues was slowly eliminated from the body via the faeces rather than in urine, probably because this material was of a molecular weight too large to enter the glomerular filtrate. Oral administration of PVA resulted in little apparent absorption from the GI tract. Even the administration of high doses of radioactivity (2.7 X 107 dpm 14 C daily for 10 consecutive days) resulted in only marginally detectable levels of radioactivity in major organs and tissues and only a trace (0.2%) excreted in urine. In contract to
gastrointestinal absorption, a quantifiable amount of PVA-derived radioactivity was absorbed from the vaginas of female Fischer 344 rats (Table 2). Although absorption from the vagina exceeded gastrointestinal absorption, the fraction of the dose that was present in the major tissues at the time of sampling never exceeded 2% of the total dose. Total absorption no doubt exceeded this figure because most of the dose following i.v. administration was eliminated in the urine within 24 h. In an effort to simulate human exposure more closely, the vaginas of treated rats were not sealed. This resulted in contamination of urine with PVA lost from the vagina, making an accurate estimate of PVA excretion in the urine impossible. That portion of the PVA dose absorbed from the vagina and retained by the tissues was concentrated mainly in the liver, and to a lesser extent the kidney, and was still easily quantifiable 4 days following administration of a single dose. These data also indicate that PVAderived radioactivity absorbed from the vagina and deposited in the liver and kidney was slowly removed from these tissues, as was observed following i.v. administration. Since detectable amounts of PVA-derived radioactivity still remained in the liver and other tissues up to 4 days following a single intravaginal dose, it was speculated that bioaccumulation of this material might occur following repeated exposure to PVA. Since the vascularity of the vagina changes during the oestrous cycle and the cycle of the rat is 4-5 days long, the use of a 10-day dosing period guaranteed that each rat would be dosed during every part of the cycle.99 The experimental design of the repeat-dose study was modified to provide conditions which would further simulate human exposure to PVA by intravaginal administration. The initial experimental design, in which the animals were heavily anaesthetized and the vaginal opening covered with a mesh screen, seemed to promote absorption of PVA from the vagina. Concentrations of
radioactivity in tissues (except blood) of animals held 4 days following a single intravaginal dose were higher than concentrations in tissues of rats held 1 day following a similar dose using the modified procedure (Tables 2 and 3). The initial group of dosed animals remained in a supine position for several hours due to the PVA-derived
effect of the anaesthesia. These animals were also prohibited from removing PVA directly from the vaginal area by grooming because of the attached mesh screen. Either or both of these conditions might have promoted additional absorption of PVA from the vagina. In the modified procedure the protective covering over the vaginal opening was not used so that the animals could groom normally. Additionally, only light C02 anaesthesia was used in this procedure, allowing animals to recover to a normal unrestrained position within minutes following administration of the dose. These factors could have contributed to loss of PVA from the vagina prior to absorption. Results obtained from repeated daily intravaginal administration of PVA indicated that PVA accumulated in increasing concentrations over time in the liver and other tissues (Table 3). Further, this material was only slowly removed from tissues following cessation of dosing (Table 4). It should be pointed out, however, that based on observations reported here, bioaccumulation of PVA-derived radioactivity in tissues represents very little material. The peak concentration in liver 24 hours following 10 consecutive daily doses of 3 mg kg-1 represented only approximately 2 ppm. The data were too variable to provide an accurate estimate of the half-life of the PVA-derived radioactivity concentrated in the liver, but it appeared to be slightly less than 10 days. In that event, peak levels of PVAderived radioactivity in the liver following chronic exposure to the dose used in this study should be in the range of 10-20 ppm. No symptoms of toxicity, such as weight loss, or erythema of the vaginal area were observed in any animal groups receiving intravaginally administered doses. Furthermore, we are not aware that any concenration of PVA-derived material in tissues following oral or intravaginal administration results in toxicity, but only report that accumulation of PVA-derived radioactivity in tissues was quantifiable following intravaginal, but not oral,
administration. Absorption of xenobiotics from the vagina is well documented in a review of the subject published by Benziger & Edelson.10 Substances absorbed from the vagina range from organic compounds such as steroids and prostoglandins to inorganic compounds such as iodine and arsenic. The polymeric spermicide nonoxynol-9,
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present in the PVA formulation used in this
study, has also been shown to be absorbed from the vagina into the systemic circulation.’ 1,12 In some instances, blood levels of a compound following absorption from the vagina can exceed those for the same compound following absorption from the GI tract. For example, Patel et al. 13 demonstrated that blood concentrations of pro-
pranolol
were
greater following intravaginal
rather than oral administration. These authors were unsure, however, whether total absorption from the vagina exceeded that from the GI tract and pointed out that the higher blood concentra-
tions following intravaginal administration may have resulted from greater metabolism of the oral dose on its ’first pass’ through the liver. In any event, it appears that most compounds which are absorbed from the vagina are also absorbed from the GI tract. PVA, a large molecule, seems to be an exception because it can be absorbed from the vagina but not from the GI tract. These data suggest that the molecular weight cut-off above which absorption of a compound does not occur may be significantly greater for the vagina than most, if not all, other readily assessable epidermal surfaces.
References 1 Linderman MK. Vinyl alcohol polymers. In: Encyclopedia of Polymer Science and Technology, ed. NM Bikales, vol. 14, pp. 149-207. New York: John Wiley and Sons, 1971.
2
Some
and
synthetic polymers. IARC (International Agency for Research Cancer) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 1979; 19: 351-66. Cincera DL. Poly(vinyl alcohol). In: Kirk-Othmer Encyclopedia of Chemical Toxicology, ed. M. Grayson 3rd edn, vol. 23, pp. 848-65. New York: John Wiley and Sons,
Anonymous.
monomers,
elastomers, and acrolein. Vinyl
plastics
acetate and
on
3
Drug Metabolism and Disposition 1975; 3: 211-19. 8 Birnbaum LS, Decad GM & Matthews HB. Disposition and excretion of 2,3,7,8-tetrachlorodibenzofuran in the rat. Toxicology and Applied Pharmacology 1980; 55: 342-52. 9 Harkness JE & Wagner JE. Biology and husbandry. In: The Biology and Medicine of Rabbits and Rodents, 2nd edn pp. 7-51.
11
1983. 4
Leon S. VCF Vaginal Contraceptive Film Information Leaflet. Apothecus, Inc., Great Neck, NY. 5 Hueper WC. Organic lesions produced by polyvinyl alcohol in rats and rabbits. Archives of Pathology 1939; 28: 510-31. 6 Hall CH & Hall O. Polyvinyl alcohol nephrosis: relationship of degree of polymerization to pathophysiologic effects. Proceedings of the Society for Experimental Biology and Medicine 1983; 112: 86-91. 7 Matthews HB & Anderson MW. The distribution and excretion of 2,4,5,2’,5’-pentachlorobiphenyl in the rat.
Philadelphia: Lea and Febiger, 1983. DP & Edelson J. Absorption from the vagina. Drug Metabolism Reviews 1983; 14: 137-68. Buttar HS. Transvaginal absorption and disposition of nonoxynol-9 in gravid rats. Toxicology Letters 1982; 13: 211-16. Walter BA, Agha BJ & Digenis GA. Disposition of C] 14 [ nonoxynol-9 after intravenous or vaginal administration to female Sprague-Dawley rats. Toxicology and Applied Pharmacology 1988; 96: 258-68. Patel LG, Warrington SJ, & Pearson RM. Propranolol concentrations in plasma after insertion into the vagina. British Medical Journal 1983; 287: 1247-48.
10 Benziger
12
13
(Received 6 June 1989; accepted 21 July 1989)
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