PVAP Regulatory & Safety Information

Published on Oct 1, 2025 14 minute(s) read
 

Polyvinyl Acetate Phthalate (PVAP) Regulatory and Safety
Information

Introduction

Polyvinyl Acetate Phthalate (PVAP) is a reaction product of phthalic anhydride, sodium acetate and a partially hydrolyzed polyvinyl alcohol. It contains not less than 55% and not more than 62% of phthalyl (O-carboxybenzoyl C H O ) groups. The polyvinyl alcohol is a low molecular weight grade and is 87 to 89 mole percent hydrolyzed.
 

The PVAP polymer is produced by partial esterification of partially hydrolyzed polyvinyl acetate with phthalic anhydride. It may be represented as:

Depending on the phthalyl content, (a) will vary with (b) in mole percent. The acetyl content (c) remains constant depending on the starting material.
 

PVAP is also co-processed with titanium dioxide to produce polyvinyl acetate phthalate and titanium dioxide
(PVAP-T). Titanium dioxide USP/NF (TiO ) is incorporated into the PVAP polymer matrix at approximately 10 weight% during polymer formation. The incorporation of the TiO inside the polymer matrix provides unique properties which differ from simple blending of the two materials. The co-processed product is then micronized to achieve a target particle size.
PVAP-T is used in the preparation of Sureteric aqueous enteric coating system.

Regulatory Status

PVAP is listed in the FDA’s Inactive Ingredient Database (IID) with a maximum potency of 37.4 mg per unit dose.
 

PVAP-T is not listed in the FDA Inactive Ingredient Database (IID). However, it is used in the Colorcon enteric coating system Coateric which was previously listed in the IID with a maximum potency of 26 mg. Since Coateric contains 74.5% PVAP-T, this corresponds to a maximum potency of 19.37 mg for PVAP-T. The corresponding drug product is still marketed, but the IID listing has been removed since FDA is moving away from listing inactive ingredients by their tradenames. Sureteric , another Colorcon enteric coating system containing PVAP-T, has been commonly used as an enteric coating system in commercial OTC drug products in the U.S. for many years.
 

A monograph with official standards for PVAP is included in the United States Pharmacopeia/National Formulary. PVAP-T cannot be considered NF; however, it meets all NF specifications for PVAP except residue on ignition (due to the presence of 10% TiO ).
 

PVAP is Generally Recognized as Safe (GRAS) for use in printing inks in the United States for marking dietary
supplements. Colorcon conducted a GRAS Expert Panel review of PVAP for this application and the panel concluded the following:
 

“We, the Expert Panel, have independently and collectively critically evaluated the data and information summarized
above and conclude that polyvinyl acetate phthalate (PVAP), as defined in Appendix I, meeting appropriate
food/pharmaceutical grade specifications, and manufactured in compliance with current Good Manufacturing Practice, is Generally Recognized As Safe (GRAS) by scientific procedures for use in monogramming ink formulations to be applied to dietary supplement capsules and tablets.”
 

PVAP and PVAP-T have been used for many years in commercial drug products marketed in various countries in the European and the Asia Pacific Regions. However, PVAP and PVAP-T are not acceptable for use in Japan since a precedence of use has not been established.

Safety Information

PVAP Toxicology Study Results

Colorcon sponsored several studies, all consistent with current Good Laboratory Practice (GLP) and internationally recognized guidelines, to provide additional safety data to support current and new applications for PVAP and PVAP-T. The new studies included a 90-day subchronic dietary study in rats, a developmental toxicity study in rats and two genotoxicity tests. The studies provided additional safety information to support the use of PVAP as a film coating polymer and matrix
polymer in modified release oral solid dosage forms for pharmaceutical applications. The study results are summarized in the following sections. The toxicology study reports are contained in Colorcon’s U.S. Drug Master File at the Center for Drug Evaluation and Research, Food and Drug Administration,

Acute Oral Toxicity Study

The acute oral toxicity of polyvinyl acetate phthalate (PVAP) was assessed in male and female rats that received PVAP by gavage at the maximum (limit) dose. Under the conditions of the study, the acute oral LD50 of PVAP was estimated to be greater than 5000 mg/kg in the rat.

90-day Subchronic Dietary Study

The purpose of this study was to evaluate the potential toxicity and toxicokinetics of polyvinyl acetate phthalate (PVAP) when administered in the diet to Sprague Dawley CRL: CD (SD) rats (20/sex/group) at a dietary concentration of 0.75%, 1.5% and 5.0% for a minimum of 90 days. Control animals (20/sex) received untreated standard laboratory diet.
 

The following evaluations were completed in this study: clinical signs, body weights, body weight changes, food consumption, test article consumption, ophthalmology, full functional observational battery assessments, clinical pathology parameters (hematology, coagulation, clinical chemistry, and urinalysis), gross necropsy findings, organ weights, and histopathologic examinations.
 

Soft stools were observed in 5%-treated males throughout the dosing period. There were no consistent, dose- related, statistically significant PVAP-related adverse effects on body weight, body weight changes, ophthalmic examinations, functional observational data, hematology parameters, coagulation parameters, clinical chemistry parameters, urinalysis parameters (macroscopic and microscopic), or absolute or relative organ weights.
 

Statistically significant mean increases in food consumption of up to 15.9% and 10.2% were observed in 5%-treated males and females, respectively, compared to the controls, likely as a result of compensating for the dilution in calories from the incorporation of PVAP at 5% of the diet. The overall mean PVAP doses were 0.44, 0.87, and 3.12 g/kg/day for the 0.75%, 1.5%, and 5%-treated male animals, respectively, and 0.52, 1.03, and 3.64 g/kg/day for the 0.75%, 1.5%, and 5%-treated female animals, respectively.
 

There were no toxicologically meaningful gross or microscopic changes noted. The toxicokinetic phase could not be completed because an analytical method could not be developed for PVAP in blood plasma.
 

In conclusion, daily administration of polyvinyl acetate phthalate (PVAP) in the diet was well tolerated in male and female rats up to a concentration of 5%. No PVAP-related toxicity or mortality was observed. Based on these results, the no-observed-adverse-effect level (NOAEL) was the 5% dietary concentration, which corresponds to a dose of 3.12 g/kg/day for males and 3.64 g/kg/day for females.

Developmental Toxicity Study

The purpose of this study was to assess the potential developmental toxicity of polyvinyl acetate phthalate (PVAP) in Crl: CD (SD) presumed-pregnant female rats (from implantation to closure of the hard palate). This study was consistent with ICH Harmonized Tripartite Guideline stages C and D of the reproductive process.
 

One hundred presumed pregnant Crl: CD (SD) rats were randomly assigned to four exposure groups (Groups I through IV), 25 rats per group. Polyvinyl acetate phthalate (PVAP) was administered as a dietary admixture in Certified Rodent Diet at concentrations of 0, 0.76, 1.5, and 3.0% Female rats were given continual access to the formulated diets on days 6 through 20 of presumed gestation (DGs 6 through 20). All surviving rats were euthanized and Caesarean-sectioned on DG 21.
 

The following parameters were evaluated: viability, clinical observations, body weights, feed consumption, necropsy observations, Caesarean-sectioning and litter observations, including gravid uterine weights, fetal body weights and sex, and fetal gross external, soft tissue and skeletal alterations. Mean daily doses were 567.0, 1139.1 and 2324.6 mg/kg/day in Groups II, III and IV, respectively, for the entire dosage period (gestation days 6 to 20).

There was no test article-related mortality. There were no test-article related clinical or necropsy observations. Body weights, body weight gains, gravid uterine weights and absolute and relative feed consumption values were unaffected by concentrations of PVAP in the diet as high as 3%.
 

No Caesarean-sectioning or litter parameters were affected by PVAP at levels in the diet as high as 3%. No gross external, soft tissue or skeletal fetal alterations (malformations or variations) were caused by PVAP at levels in the diet as high as 3%. Fetal ossification was comparable among the four groups (control and 3 PVAP-treated groups).
 

In conclusion, there were no consistent, treatment-related, dose-dependent, statistically significant adverse effects on any of the maternal and fetal parameters evaluated. Therefore, the maternal and developmental no-observable- adverse-effect level (NOAEL) of PVAP is the highest concentration administered 3.0% (equivalent to 2324.6 mg PVAP/kg/day).
 

Genotoxicity Tests

A Bacterial Mutation Test and a Chromosome Aberration Test were performed to evaluate the potential genotoxicity of PVAP. There was no evidence of genotoxic activity of PVAP in the in vitro Bacterial Mutation Test and no evidence of clastogenicity in the in vitro Chromosome Aberration Test for induction of chromosome damage.
 

Supporting Historical Toxicological Data for PVAP

Extensive toxicological testing was conducted with PVAP in the 1960’s and Colorcon was able to secure the reports for these studies. The reports did not describe the characterization, specifications or manufacturing process for the test material used in the studies. The studies were conducted consistent with generally accepted guidelines at that time. The studies were critically evaluated by experts and published in Food and Chemical Toxicology in 2003 .
 

Ref: http://www.ncbi.nlm.nih.gov/pubmed/12504173
 

File samples of the test material were not available for analysis but all indications are that the PVAP is similar to the PVAP produced by Colorcon. As reported above, Colorcon has evaluated the toxicity of its PVAP and no adverse effects were reported at the highest levels tested.
 

The acute oral toxicity of PVAP in the rat, mouse and dog is very low (>7500 mg/kg in the dog and >8000 mg/kg in the rat and mouse).
 

PVAP was administered to rats and dogs as a dietary admixture for up to 24 months at levels up to 3000 mg/kg/day in the rat and 1500 mg/kg/day in the dog. The only treatment-related effects reported was gastrointestinal irritation including enlarged and hemorrhagic intestinal lymph nodes, hemorrhage, ulcers, polyps, bloody feces, and cecal wall thickening in rats. A gross pathological finding in dogs revealed only irritation of the gastrointestinal tract including catarrhal colitis with erosions and submucosal fibrosis, mild cattarrhal or chronic gastritis, jejunitis, and ileitis in the two highest groups and was more severe in animals that received the highest dose.
 

PVAP did not adversely affect reproductive function in rats and was not teratogenic in rats and rabbits. PVAP was not carcinogenic in the two-year rat study or in the two-year dog study. These data support the safety/low toxicity of the PVAP produced by Colorcon.
 

The NOAELs (and LOAELs, the lowest observed adverse effect levels, usually the next higher dose level to the NOAEL) determined in these studies were:

SPECIES	STUDY	NOAEL	LOAEL
Rat	Two-year chronic study	500 mg/kg bw/day	1000 mg/kg
Dog	Two-year chronic study	500 mg/kg bw/day	1000 mg/kg
Rat	One-generation reproduction (Segment I)	1000 mg/kg bw/day	(highest dose tested)
Rat	Teratology (Segment II)	200 mg/kg bw/day	1000 mg/kg
Rabbit	Teratology (Segment II)	100 mg/kg bw/day	500 mg/kg
Rat	Perinatal (Segment III)	200 mg/kg bw/day	1000 mg/kg

PVAP-T Toxicology Study Results

Colorcon conducted two GLP studies to provide further supporting information for the safety of PVAP-T. The acute oral toxicity of co-processed polyvinyl acetate phthalate and titanium dioxide (PVAP-T) was assessed when administered by gavage as a single oral dose to Sprague Dawley male and female rats. There were no deaths and no signs of intoxication. The acute oral LD of PVAP-T was estimated to be greater than 5000 mg/kg in the rat, the highest dose tested and the recommended limit dose.
 

A bacterial mutation test was performed to evaluate the potential genotoxicity of PVAP-T. PVAP-T did not show any evidence of genotoxic activity. It was concluded that PVAP-T is not genotoxic.
 

PVAP-T Analytical Studies

The toxicological data for PVAP is used to support the safety of PVAP-T. In order to bridge PVAP-T to the PVAP data, Colorcon conducted several analytical studies to demonstrate that PVAP and TiO are not chemically altered during the manufacturing process or during transit through the gastrointestinal tract.
 

PVAP-T is a co-processed excipient which is manufactured by combining PVAP and TiO using a physical process that results in an intimate mixture of the particles. No chemical modification occurs in the process. A series of studies were performed to determine if the PVAP-T co-processed excipient exhibits the same chemical composition as would exist for a standard physical blend of PVAP and TiO .
 

Three batches of a physical blend of PVAP and TiO and co-processed PVAP-T were manufactured according to the standard operating procedures. The batches used the same lots of raw materials and were individually sampled and tested.
 

Samples were evaluated using standard compendial release testing and other analytical techniques consisting of FTIR spectral analysis, size exclusion chromatography with photodiode array detection, reversed phase HPLC, differential scanning calorimetery, thermogravemetric analysis, powder X-ray diffraction, particle size analysis both wet and dry, headspace gas chromatography, and bio-relevant dissolution testing.

The results of this study clearly demonstrate that there were no chemical differences between a physical blend or co-processed PVAP and titanium dioxide. The routine QC testing met the predetermined specifications and did not show any trends or differences between the blended or co-processed materials.

Testing was performed in USP gastric and intestinal fluid, both with and without enzymes, to evaluate the effects of co-processing on the PVAP polymer with titanium dioxide when exposed to different pH and enzymatic activities. No difference in UV/Vis spectra was observed between the co-processed and blended PVAP-T samples in the four media tested. PVAP was not soluble in either of the fluids.

There is no chemical difference between the PVAP and TiO physical blends and the PVAP-T co-processed product. No signs of any degradation products were found in the PVAP-T samples. This information helps to bridge to the toxicology studies conducted with PVAP to PVAP-T and supports the safety of PVAP-T.

Independent Expert Safety Evaluation of PVAP and PVAP-T

The International Pharmaceutical Excipients Council (IPEC) of the Americas developed a New Excipient Safety Evaluation Procedure. The goal of this process is to provide an independent evaluation of the safety and regulatory acceptance of a new excipient before a regulatory filing. The process is meant to mirror that of regulatory agencies, ideally providing confidence to pharmaceutical manufacturers that the excipient will be acceptable in their formulations. This procedure has been discussed with the U.S. FDA and they acknowledged that this type of review would be very beneficial when evaluating a new excipient. The New Excipient Evaluation Committee (NEEC) is the expert panel that conducts the excipient safety evaluation.
 

The NEEC Expert Panel independently and collectively critically evaluated the data and information summarized for PVAP and PVAP-T and concluded that PVAP and PVAP-T are safe for their intended use as an excipient in film coating formulations and matrix tablet drug products. Based on the toxicology study results, safety assessment and the estimated exposure assessment in the NEEC’s report for PVAP and PVAP-T, the expert panel concluded that PVAP and PVAP-T could safely be used in drug products up to 829 mg per day. The complete NEEC report is available upon request to parties who have signed a confidentiality agreement with Colorcon.

Publication of Colorcon Safety Studies

Pharmaceutical companies conducting material safety reviews on the use of polyvinyl acetate phthalate (PVAP) or co-processed polyvinyl acetate phthalate-TiO (PVAP-T) can now access two articles in the public domain for use in their regulatory filings related to the recent safety studies conducted by Colorcon.
 

One article published in October 2014 reported the maternal and developmental no-observable-adverse-effect level (NOAEL) of PVAP was the highest concentration administered, i.e., 3.0% (equivalent to 2324 mg PVAP/kg/day).

Another article published in August 2014 summarizes 90-day and genotoxicity studies that were also performed. The article also discusses that this data, along with the developmental study, was reviewed by the IPEC New Excipient Safety Evaluation Panel (as mentioned in the previous section), which concluded that the safety data supports usage levels in solid oral dosage forms up to 829 mg of PVAP or PVAP-T per day.

PubMed Abstract links for each article are provided below:

Ref: http://www.ncbi.nlm.nih.gov/pubmed/25084367

Ref: http://www.ncbi.nlm.nih.gov/pubmed/24813760

Summary and Conclusion
 

The series of safety studies conducted by Colorcon with PVAP include a definitive 90-day subchronic toxicity study, a developmental toxicity study and several genotoxicity tests. There were no adverse effects reported in the 90-day subchronic toxicity study and the developmental toxicity study. PVAP was not genotoxic. The no-observed-adverse-effect level (NOAEL) in the GLP 90-day subchronic study was the 5% dietary concentration, which corresponds to a dose of 3.12 g/kg/day for males and 3.64 g/kg/day for females, the highest level tested. The supporting studies from the 1960s provide corroborative data to support the safety of PVAP and PVAP-T when used as excipients. EMA’s review of all this data in 2014 and their conclusion that no PDE is necessary also supports the safety of PVAP.
 

The chemical composition, physiochemical properties and specifications of PVAP-T are unchanged during manufacturing process based on the analytical studies conducted by Colorcon. Therefore, the toxicological data that support the safety of PVAP can be used to support the use of PVAP-T as an excipient.
 

Based on the toxicology study results, safety assessment and the estimated exposure assessment in the NEEC’s report for PVAP and PVAP-T, the expert panel concluded that PVAP and PVAP-T could safely be used in drug products up to 829 mg per day.

References:
1. Schoneker, D.R., DeMerlis, C.C., Borzelleca, J.F. (2003). Evaluation of the toxicity of polyvinylacetate in experimental animals. Food and Chemical Toxicology 41, 405-413.
 

2. DeMerlis C.C., Schoneker D.R., Borzelleca J.F., Oral dietary developmental toxicity study with polyvinyl acetate phthalate (PVAP) in the rat, Regulatory Toxicology and Pharmacology October, 2014.
 

3. DeMerlis C.C., Schoneker D.R., Borzelleca J.F., Safety of PVAP and PVAP-T including a 90-day dietary toxicity study in rats and genotoxicity tests with polyvinyl acetate phthalate (PVAP), Food and Chemical Toxicology , August, 2014

The information contained in this document is proprietary to Colorcon and may not be used or disseminated inappropriately. The information contained in this document is not intended as legal advice, and should not be relied upon for that purpose.

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This document is valid at time of distribution. Distributed 06-Nov-2025(UTC).