VP/VP Copolymer Toxicokinetics, toxicity
1. Material : VP/VP Copolymer
2. Toxicity Information
2.1. Toxicokinetics - Storage and Excretion
PVP/VA copolymer storage in the body was studied in 30 female Wistar rats by injecting it under the skin of the back. Up to seven daily 2㎖ doses of a solution containing 10g solid copolymer in 15㎖ physiological saline were given to the rats. The rats were sacrificed between 1 and 365 days later, and the tissues were examined. Most of the copolymer was found in the spleen, and repeated injections caused an up-to-80% increase in splenic weight. Two to three days after the treatment, large reticular cells were found in the spleen; later, similar but vacuolated cells were found. There were also macrophages in the follicular germinal center. After 1 to 6 months, the copolymer-containing macrophages decreased in size and number and often showed an iron-positive reaction. Large vacuolated cells were also present in the portal regions of the liver lobes. The podocytes of the kidney glomeruli contained PVP/VA, and some kidney specimens showed large aggregates of foam cells. Some PVP/VA seemed to be stored in the epithelial cells and in the lymphatics of the testes. There were no inflammatory changes in any of the tissues. Some reticular cells in the bone marrow and lymph nodes showed PVP/VA copolymer storage, and large macrophages were found in the interstitial tissue of the lungs. After 12 months, there was no evidence of tumors or systemic disease related to the administration of the compound. The author reported that half an hour after a single subcutaneous 2㎖ dose was administered, a color reaction was induced in the urine by a KJ3 solution; this indicated that PVP/VA was in the urine. Maximum excretion occurred 1 ½ hours after injection.
2.2. Acute toxicity
2.2.1. Oral
The acute oral toxicity of PVP/VA copolymer in aqueous alcohol solutions and in formulations was studied. Five lots of 50% PVP/VA copolymer in alcohol were tested in albino rats. One sample was tested at a 50% concentration, and four at 25% (w/v) aqueous suspensions (final concentration: 12.5%). In these four tests on the 12.5% copolymer, 5 g/kg of the material was administered by gastric intubation into ten young, fasted albino rats per solution. During the following 14 days, the animals showed decreased activity and ataxia for an unspecified length of time, but none died. These results showed that the test solutions were slightly toxic according to the classification system of Hodge and Sterner [22-26]. A dose of 5 ml/kg (4.78 g/kg) of the 50% solution administered orally through a stomach tube caused piloerection in some of the six rats. None of the rats died, and the necropsy examinations showed no pathology. This solution is also practically non-toxic.
Five product formulations containing actual 0.25% (setting lotion), 0.5% (setting lotion), 1.75% (mascara), 4.0% (setting lotion), and 24% (setting lotion) PVP/VA copolymer concentrations in 5.0-15 g/kg doses were administered orally through a stomach tube to groups of Sherman-Wistar and Sprague-Dawley albino rats. Two of the five animals died after the administration of the hair setting formulation containing 4.0% PVP/VA copolymer in a 15 g/kg dose; none of the rats that survived showed signs of toxicity during the 7- to 13-day observation periods. None of the other formulations produced toxicity.
2.2.2. Inhalation
In an acute inhalation study, Draize et al. exposed five rabbits to 30-second spray releases of an aerosol product containing 1.72% PVP/VA copolymer. The sprayings were released every half hour until the contents of the container were exhausted, but the investigators did not report the duration of the exposure. Each 30-second spray released approximately 30 g of the material. The animals were inspected during their exposure and during the next 4 days; they were then sacrificed for gross and histopathological examination. The tissues and behavior of the animals during and after their inhalation of the material were normal.
2.3. Subchronic
2.3.1. Dermal
A hair product containing 1% PVP/VA copolymer was tested in a 6-week subchronic dermal toxicity study on 50 albino rats. In the test, 2.0 ml/kg volumes of the product were applied five days a week for 6 weeks, for a total of 30 applications to the clipped skin of the animals. All the rats survived, and their body weight, physical appearance, behavior, and gross and microscopic anatomy were normal. No systemic toxic effects could be attributed to the test material.
2.3.2. Inhalation
Rats and hamsters were exposed for 13 weeks to a spray containing 4.0% PVP/VA copolymer. Each of the three groups consisted of 12 rats and 12 hamsters, which inhaled the spray for 4 hours a day, 5 days a week, for a total of 13 weeks, in 5.4 mg/m3 doses (calculated to be the equivalent of 100 times the normal human use level of the product). No gross or microscopic changes occurred that could be attributed to the test material. The lungs and other tissues were similar in the control and tested animals.
2.4. Chronic
2.4.1. Oral
White mice and rats were given an aqueous 10.2 mg/l solution of PVP/VA copolymer in their drinking water daily for one year. Each mouse ingested an average of 2-3 ml per day and 650 ml for the duration of the experiment, and each rat ingested 15-20 ml per 24 hours and 4140 ml for one year. There were no changes attributable to the copolymer in either the mice or the rats. Furthermore, there were no histological changes in the internal organs.
2.4.2. Inhalation
Mokler et al. conducted a chronic study of hair spray aerosols containing high and low concentrations of PVP/VA copolymer. Thirty-six male and 36 female Syrian hamsters were exposed to a low concentration (0.08±0.08 mg/l) of PVP/VA in air 4-32 minutes a day, once a week, for up to two years. The high-level group consisted of 36 male and 36 female hamsters exposed to 0.35±0.09 mg/l 9-35 minutes a day, once a week, for up to two years. A similar group of 36 males and 36 females was exposed to air as a control. All the animals were repeatedly exposed by inhalation until they were sacrificed. Six males and six females from each group were sacrificed at 3, 6, and 9 months. This ensured that at least 12 animals (6 males, 6 females) were available for study at each time period, and that 36 animals were available for long-term (2-year) study. Necropsies were performed on all the animals that were sacrificed or that died spontaneously. The survival time, body weight, and weight and appearance of the lungs were similar in the control and aerosol-exposed animals.
Draize et al. (46) exposed five rabbits to a spray formulation containing 1.72% PVP/VA copolymer. During the go-day test, the animals received one-time 30-second exposure each morning and afternoon, and were left in the spray atmosphere for 15 minutes. The animals remained normal during the entire study, as shown in the radiographs of the chest and upper body and by the results of the hematological tests.
2.5. Mutagenicity
The residual monomers of PVP/VA copolymer, vinyl acetate and vinyl pyrrolidone, found at 1.0 and 0.5% concentrations, respectively, were tested for their mutagenic potential. Salmonella typhimurium strains TA100, TA98, TA1530, TA1535, and TA1537 were exposed to vinyl acetate. No mutagenic effects were detected when the organisms were exposed to the chemical with and without the addition of rat liver metabolic activation preparation.
2.6. Irritation and sensitization
2.6.1. Skin
PVP/VA copolymer in an alcohol solution and in a formulation was tested for acute skin irritation. Four 50% solutions of PVP/VA copolymer in alcohol and one solid 100% concentration were each applied to the backs of six albino rabbits. In one test, three repeated applications of the 50% solution caused definite erythema in five of the six animals [27]. The remaining three 50% solutions were each applied in 0.5 ml (approximately 0.5 g) volumes under occlusive patching to the clipped abraded and intact skin of the rabbits. The patches were removed after 24 hours, and the sites were graded using the Draize method 24 and 72 hours after the application. The solutions were mildly to moderately irritating.
A primary dermal irritation test of solid, 100% PVP/VA copolymer on six albino rabbits produced no irritation.
Five formulations containing varying concentrations of PVP/VA copolymer were tested for primary skin irritation on rabbits. Of these, one hair setting lotion containing 0.25% PVP/VA copolymer and another setting lotion having 0.50% copolymer were each applied in 0.5 g amounts under an occlusive dressing to the clipped intact and abraded skin of six albino rabbits, and were allowed to remain for 24 hours. The sites were scored 24 and 72 hours after the application. Based on the Draize method, neither product produced irritation.
A hair conditioner formulation containing 1.5% PVP/VA copolymer was tested on the abraded and intact skin of three rabbits. The 0.5 ml volume of the test material was applied under occlusion, and readings were taken 24 and 72 hours after the application. The product caused no irritation.
A mascara and a hair setting formulation containing 1.75% and 4.0% PVP/VA copolymer, respectively, were tested using a modified Draize method. A 0.1 ml volume of each formulation was applied under occlusion to the shaved skin of nine albino rabbits for 24 hours. The sites were read 2 and 24 hours after the patch removal. The mascara caused minimal irritation, and the hair setting lotion caused no irritation.
2.6.2. Ocular
Formulations and solutions containing PVP/VA copolymer were studied for acute ocular toxicity. A Draize eye irritation test of a 50% alcohol solution of PVP/VA copolymer was performed on six rabbits. This same solution was then diluted in petrolatum to 75 and 50% of its original concentration (actual copolymer concentrations: 37.5 and 25%) and was tested on the rabbits. A 0.1 ml volume of each solution was instilled into one eye of each of the six animals, with no rinsing. The observations made for 7 days were scored based on the Draize method (maximum irritation score: 110). The 25% solution of PVP/VA in petrolatum was minimally irritating on the first observation day, and the irritation had disappeared by day 7. The 37.5% solution was mildly irritating on day 1 and practically non-irritating on day 7. The 50% solution in alcohol produced moderate irritation on day 1 and minimal irritation on day 7.
A 50% solution of PVP/VA copolymer in alcohol was tested for ocular irritation using the Draize method in three different studies. For each of nine rabbits, 0.1 ml of the solution was instilled in one eye; the other eye was used as the control. In three of the nine animals, the eye was washed four seconds after instillation, and observations were made for seven days. Moderate irritation occurred in the unwashed eyes into which two of the 50% test solutions were instilled, and severe irritation was caused by the third solution when it was not washed out. The eyes that had been irrigated after four seconds were moderately irritated. In most of the rabbits, the irritation persisted throughout the seven days.
2.6.3. Sensitization
The skin sensitization potential of PVP/VA copolymer in a product formulation was studied. A hair conditioner containing 1.5% PVP/VA copolymer was diluted in physiological saline to make the actual copolymer concentration 0.015%; this was injected intradermally into eight guinea pigs. A 4 cm area of skin was clipped, and injections were given every other day, the first at a 0.05 ml dose and the subsequent nine at 0.2 ml each. A 0.05 ml injection was administered two weeks after the last injection, and the skin was inspected 24 hours after each injection. The material was non-sensitizing to the guinea pigs.
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