Safety of Excipients for Enteric Coating of Pharmaceutical Products – A Review
Abstract
Deleterious effects of stomach acid on a variety of orally-administered pharmaceutical products has
been appreciated for decades. To preserve the integrity of these labile products in the acidic
environment of the stomach, specific excipient materials have been developed to provide an enteric
coating on the final formulated products. This enteric coating remains intact in acidic media, and
dissolves in the relatively neutral environment of the intestines, where dissolution and absorption of
the products occur. Some of the earliest materials to be developed for this purpose were polymers
containing ortho phthalic acid as a substituent, and many of these same materials continue to be used
extensively today. During this time, other compounds containing short-chain alcohols esterified with
ortho-phthalic had been developed for use as plasticizers, and recent data suggest that many of these
phthalate plasticizers pose significant hazards to human health and the environment. Despite
substantial differences in the chemical properties between the phthalate plasticizers and polymers
containing ortho-phthalate acid, recent safety concerns for the phthalate plasticizers has prompted
some scientists to question whether the polymers that are used as excipients for enteric coatings of
pharmaceuticals pose similar safety concerns. Accordingly, this review serves to clarify the underlying
physical/chemical properties of these excipients and to summarize the data which supports the
continued save usage of these materials.
TABLE OF CONTENTS
1. Introduction ……………………………………………………………………………………………………………….. 9
2. Definitions ………………………………………………………………………………………………………………….. 10
3. Cellulose polymers …………………………………………………………………………..…………………………. 13
3.1. Cellulose Acetate Phthalate ……………………………………………………………………………………
3.1.1. Identity and physical/chemical properties ……………………………………………….
3.1.1.1. Nomenclature ……………………………………………………………………………
3.1.1.2. Chemical structures …………………………………………………………………..
3.1.1.3. Chemical properties …………………………………………………………………..
3.1.2. Effects on laboratory mammals and in vitro test systems ………………………….
3.1.2.1. Acute exposure ………………………………………………………………………….
3.1.2.2. Irritation/sensitization ……………………………………………………………….
3.1.2.3. Subchronic exposure ………………………………………………………………….
3.1.2.4. Chronic exposure ……………………………………………………………………….
3.1.2.5. Reproductive/developmental endpoints ……………………………………
3.1.2.6. Genotoxicity and related endpoints …………………………………………..
3.1.2.7. Immunological and neurological effects …………………………………….
3.1.3. Effects on humans ……………………………………………………………………………………..
3.1.4. Effects on other organisms in the laboratory and field ………………………………
3.1.4.1. Aquatic organisms ……………………………………………………………………….
3.1.4.2. Terrestrial organisms …………………………………………………………………..
3.1.5. Evaluation of health effects ……………………………………………………………………….
3.1.5.1. Hazard identification and dose-response assessment …………………..
3.1.5.2. Criteria for setting tolerable intakes …………………………………………..
3.1.6. Evaluation of environmental effects ………………………………………………………….
3.2. Cellulose Acetate Trimelliate ..…………………………………………………………………………………
3.2.1. Identity and physical/chemical properties ……….……………………………………….
3.2.1.1. Nomenclature …………………………………….………………………………………
3.2.1.2. Chemical structures …………………………….……………………………………..
3.2.1.3. Chemical properties …………………………………………………………………..
3.2.2. Effects on laboratory mammals and in vitro test systems ………………………….
3.2.2.1. Acute exposure ………………………………………………………………………….
3.2.2.2. Irritation/sensitization ……………………………………………………………….
3.2.2.3. Subchronic exposure ………………………………………………………………….
3.2.2.4. Chronic exposure ……………………………………………………………………….
3.2.2.5. Reproductive/developmental endpoints ……………………………………
3.2.2.6. Genotoxicity and related endpoints …………………………………………..
3.2.2.7. Immunological and neurological effects …………………………………….
3.2.3. Effects on humans ……………………………………………………………………………………..
3.2.4. Effects on other organisms in the laboratory and field ………………………………
3.2.4.1. Aquatic organisms ……………………………………………………………………….
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3.2.4.2. Terrestrial organisms …………………………………………………………………..
3.2.5. Evaluation of health effects ……………………………………………………………………….
3.2.5.1. Hazard identification and dose-response assessment …………………..
3.2.5.2. Criteria for setting tolerable intakes …………………………………………..
3.2.6. Evaluation of environmental effects ………………………………………………………….
3.3. Hypromellose Phthalate ……………………………………………………………………………………
3.3.1. Identity and physical/chemical properties ……………………………………………….
3.3.1.1. Nomenclature ……………………………………………………………………………
3.3.1.2. Chemical structures …………………………………………………………………..
3.3.1.3. Chemical properties …………………………………………………………………..
3.3.2. Effects on laboratory mammals and in vitro test systems ………………………….
3.3.2.1. Acute exposure ………………………………………………………………………….
3.3.2.2. Irritation/sensitization ……………………………………………………………….
3.3.2.3. Subchronic exposure ………………………………………………………………….
3.3.2.4. Chronic exposure ……………………………………………………………………….
3.3.2.5. Reproductive/developmental endpoints ……………………………………
3.3.2.6. Genotoxicity and related endpoints …………………………………………..
3.3.2.7. Immunological and neurological effects …………………………………….
3.3.3. Effects on humans ……………………………………………………………………………………..
3.3.4. Effects on other organisms in the laboratory and field ………………………………
3.3.4.1. Aquatic organisms ……………………………………………………………………….
3.3.4.2. Terrestrial organisms …………………………………………………………………..
3.3.5. Evaluation of health effects ……………………………………………………………………….
3.3.5.1. Hazard identification and dose-response assessment …………………..
3.3.5.2. Criteria for setting tolerable intakes …………………………………………..
3.3.6. Evaluation of environmental effects ………………………………………………………….
4. Vinyl acetate polymers ……………………………………………………………………………………………………………
4.1. Vinyl Acetate Phthalate ……………….…………………………………………………………………………
4.1.1. Identity and physical/chemical properties ……………………………………………….
4.1.1.1. Nomenclature ……………………………………………………………………………
4.1.1.2. Chemical structures …………………………………………………………………..
4.1.1.3. Chemical properties …………………………………………………………………..
4.1.2. Effects on laboratory mammals and in vitro test systems ………………………….
4.1.2.1. Acute exposure ………………………………………………………………………….
4.1.2.2. Irritation/sensitization ……………………………………………………………….
4.1.2.3. Subchronic exposure ………………………………………………………………….
4.1.2.4. Chronic exposure ……………………………………………………………………….
4.1.2.5. Reproductive/developmental endpoints ……………………………………
4.1.2.6. Genotoxicity and related endpoints …………………………………………..
4.1.2.7. Immunological and neurological effects …………………………………….
4.1.3. Effects on humans ……………………………………………………………………………………..
2
4.1.4. Effects on other organisms in the laboratory and field ………………………………
4.1.4.1. Aquatic organisms ……………………………………………………………………….
4.1.4.2. Terrestrial organisms …………………………………………………………………..
4.1.5. Evaluation of health effects ……………………………………………………………………….
4.1.5.1. Hazard identification and dose-response assessment …………………..
4.1.5.2. Criteria for setting tolerable intakes …………………………………………..
4.1.6. Evaluation of environmental effects ………………………………………………………….
5. Methacrylic Acid copolymers ………………………………………………………………………………………………….
5.1. Eudragit®L ……………………………………………………………………………………
5.1.1. Identity and physical/chemical properties ……………………………………………….
5.1.1.1. Nomenclature ……………………………………………………………………………
5.1.1.2. Chemical structures …………………………………………………………………..
5.1.1.3. Chemical properties …………………………………………………………………..
5.1.2. Effects on laboratory mammals and in vitro test systems ………………………….
5.1.2.1. Acute exposure ………………………………………………………………………….
5.1.2.2. Irritation/sensitization ……………………………………………………………….
5.1.2.3. Subchronic exposure ………………………………………………………………….
5.1.2.4. Chronic exposure ……………………………………………………………………….
5.1.2.5. Reproductive/developmental endpoints ……………………………………
5.1.2.6. Genotoxicity and related endpoints …………………………………………..
5.1.2.7. Immunological and neurological effects …………………………………….
5.1.3. Effects on humans ……………………………………………………………………………………..
5.1.4. Effects on other organisms in the laboratory and field ………………………………
5.1.4.1. Aquatic organisms ……………………………………………………………………….
5.1.4.2. Terrestrial organisms …………………………………………………………………..
5.1.5. Evaluation of health effects ……………………………………………………………………….
5.1.5.1. Hazard identification and dose-response assessment …………………..
5.1.5.2. Criteria for setting tolerable intakes …………………………………………..
5.1.6. Evaluation of environmental effects ………………………………………………………….
5.2. Eudragit® S ………………………………………………………………………………………………………….……
5.2.1. Identity and physical/chemical properties ……………………………………………….
5.2.1.1. Nomenclature ……………………………………………………………………………
5.2.1.2. Chemical structures …………………………………………………………………..
5.2.1.3. Chemical properties …………………………………………………………………..
5.2.2. Effects on laboratory mammals and in vitro test systems ………………………….
5.2.2.1. Acute exposure ………………………………………………………………………….
5.2.2.2. Irritation/sensitization ……………………………………………………………….
5.2.2.3. Subchronic exposure ………………………………………………………………….
5.2.2.4. Chronic exposure ……………………………………………………………………….
5.2.2.5. Reproductive/developmental endpoints ……………………………………
5.2.2.6. Genotoxicity and related endpoints …………………………………………..
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5.2.2.7. Immunological and neurological effects …………………………………….
5.2.3. Effects on humans ……………………………………………………………………………………..
5.2.4. Effects on other organisms in the laboratory and field ………………………………
5.2.4.1. Aquatic organisms ……………………………………………………………………….
5.2.4.2. Terrestrial organisms …………………………………………………………………..
5.2.5. Evaluation of health effects ……………………………………………………………………….
5.2.5.1. Hazard identification and dose-response assessment …………………..
5.2.5.2. Criteria for setting tolerable intakes …………………………………………..
5.2.6. Evaluation of environmental effects ………………………………………………………….
5.3. Divinyl azobenzend crosslinked methacrylates……….…………………………………………………
5.3.1. Identity and physical/chemical properties ……………………………………………….
5.3.1.1. Nomenclature ……………………………………………………………………………
5.3.1.2. Chemical structures …………………………………………………………………..
5.3.1.3. Chemical properties …………………………………………………………………..
5.3.2. Effects on laboratory mammals and in vitro test systems ………………………….
5.3.2.1. Acute exposure ………………………………………………………………………….
5.3.2.2. Irritation/sensitization ……………………………………………………………….
5.3.2.3. Subchronic exposure ………………………………………………………………….
5.3.2.4. Chronic exposure ……………………………………………………………………….
5.3.2.5. Reproductive/developmental endpoints ……………………………………
5.3.2.6. Genotoxicity and related endpoints …………………………………………..
5.3.2.7. Immunological and neurological effects …………………………………….
5.3.3. Effects on humans ……………………………………………………………………………………..
5.3.4. Effects on other organisms in the laboratory and field ………………………………
5.3.4.1. Aquatic organisms ……………………………………………………………………….
5.3.4.2. Terrestrial organisms …………………………………………………………………..
5.3.5. Evaluation of health effects ……………………………………………………………………….
5.3.5.1. Hazard identification and dose-response assessment …………………..
5.3.5.2. Criteria for setting tolerable intakes …………………………………………..
5.3.6. Evaluation of environmental effects ………………………………………………………….
6. Biodegradable polysaccharides ….……………………………………………………………………………………………..
6.1. Chitosan …………………………….. ……………………………………………………………………………………
6.1.1. Identity and physical/chemical properties ……………………………………………….
6.1.1.1. Nomenclature ……………………………………………………………………………
6.1.1.2. Chemical structures …………………………………………………………………..
6.1.1.3. Chemical properties …………………………………………………………………..
6.1.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.1.2.1. Acute exposure ………………………………………………………………………….
6.1.2.2. Irritation/sensitization ……………………………………………………………….
6.1.2.3. Subchronic exposure ………………………………………………………………….
6.1.2.4. Chronic exposure ……………………………………………………………………….
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6.1.2.5. Reproductive/developmental endpoints ……………………………………
6.1.2.6. Genotoxicity and related endpoints …………………………………………..
6.1.2.7. Immunological and neurological effects …………………………………….
6.1.3. Effects on humans ……………………………………………………………………………………..
6.1.4. Effects on other organisms in the laboratory and field ………………………………
6.1.4.1. Aquatic organisms ……………………………………………………………………….
6.1.4.2. Terrestrial organisms …………………………………………………………………..
6.1.5. Evaluation of health effects ……………………………………………………………………….
6.1.5.1. Hazard identification and dose-response assessment …………………..
6.1.5.2. Criteria for setting tolerable intakes …………………………………………..
6.1.6. Evaluation of environmental effects ………………………………………………………….
6.2. Pectin ………………………………………………………………………………………………………………………
6.2.1. Identity and physical/chemical properties ……………………………………………….
6.2.1.1. Nomenclature ……………………………………………………………………………
6.2.1.2. Chemical structures …………………………………………………………………..
6.2.1.3. Chemical properties …………………………………………………………………..
6.2.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.2.2.1. Acute exposure ………………………………………………………………………….
6.2.2.2. Irritation/sensitization ……………………………………………………………….
6.2.2.3. Subchronic exposure ………………………………………………………………….
6.2.2.4. Chronic exposure ……………………………………………………………………….
6.2.2.5. Reproductive/developmental endpoints ……………………………………
6.2.2.6. Genotoxicity and related endpoints …………………………………………..
6.2.2.7. Immunological and neurological effects …………………………………….
6.2.3. Effects on humans ……………………………………………………………………………………..
6.2.4. Effects on other organisms in the laboratory and field ………………………………
6.2.4.1. Aquatic organisms ……………………………………………………………………….
6.2.4.2. Terrestrial organisms …………………………………………………………………..
6.2.5. Evaluation of health effects ……………………………………………………………………….
6.2.5.1. Hazard identification and dose-response assessment …………………..
6.2.5.2. Criteria for setting tolerable intakes …………………………………………..
6.2.6. Evaluation of environmental effects ………………………………………………………….
6.3 Amylose ……………………………………………………………………………………………………………………
6.3.1. Identity and physical/chemical properties ……………………………………………….
6.3.1.1. Nomenclature ……………………………………………………………………………
6.3.1.2. Chemical structures …………………………………………………………………..
6.3.1.3. Chemical properties …………………………………………………………………..
6.3.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.3.2.1. Acute exposure ………………………………………………………………………….
6.3.2.2. Irritation/sensitization ……………………………………………………………….
6.3.2.3. Subchronic exposure ………………………………………………………………….
6.3.2.4. Chronic exposure ……………………………………………………………………….
5
6.3.2.5. Reproductive/developmental endpoints ……………………………………
6.3.2.6. Genotoxicity and related endpoints …………………………………………..
6.3.2.7. Immunological and neurological effects …………………………………….
6.3.3. Effects on humans ……………………………………………………………………………………..
6.3.4. Effects on other organisms in the laboratory and field ………………………………
6.3.4.1. Aquatic organisms ……………………………………………………………………….
6.3.4.2. Terrestrial organisms …………………………………………………………………..
6.3.5. Evaluation of health effects ……………………………………………………………………….
6.3.5.1. Hazard identification and dose-response assessment …………………..
6.3.5.2. Criteria for setting tolerable intakes …………………………………………..
6.3.6. Evaluation of environmental effects ………………………………………………………….
6.4 Guar gum ……………………………..……………………………………………………………………………………
6.4.1. Identity and physical/chemical properties ……………………………………………….
6.4.1.1. Nomenclature ……………………………………………………………………………
6.4.1.2. Chemical structures …………………………………………………………………..
6.4.1.3. Chemical properties …………………………………………………………………..
6.4.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.4.2.1. Acute exposure ………………………………………………………………………….
6.4.2.2. Irritation/sensitization ……………………………………………………………….
6.4.2.3. Subchronic exposure ………………………………………………………………….
6.4.2.4. Chronic exposure ……………………………………………………………………….
6.4.2.5. Reproductive/developmental endpoints ……………………………………
6.4.2.6. Genotoxicity and related endpoints …………………………………………..
6.4.2.7. Immunological and neurological effects …………………………………….
6.4.3. Effects on humans ……………………………………………………………………………………..
6.4.4. Effects on other organisms in the laboratory and field ………………………………
6.4.4.1. Aquatic organisms ……………………………………………………………………….
6.4.4.2. Terrestrial organisms …………………………………………………………………..
6.4.5. Evaluation of health effects ……………………………………………………………………….
6.4.5.1. Hazard identification and dose-response assessment …………………..
6.4.5.2. Criteria for setting tolerable intakes …………………………………………..
6.4.6. Evaluation of environmental effects ………………………………………………………….
6.5 Inulin …………………………………..……………………………………………………………………………………
6.5.1. Identity and physical/chemical properties ……………………………………………….
6.5.1.1. Nomenclature ……………………………………………………………………………
6.5.1.2. Chemical structures …………………………………………………………………..
6.5.1.3. Chemical properties …………………………………………………………………..
6.5.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.5.2.1. Acute exposure ………………………………………………………………………….
6.5.2.2. Irritation/sensitization ……………………………………………………………….
6.5.2.3. Subchronic exposure ………………………………………………………………….
6.5.2.4. Chronic exposure ……………………………………………………………………….
6
6.5.2.5. Reproductive/developmental endpoints ……………………………………
6.5.2.6. Genotoxicity and related endpoints …………………………………………..
6.5.2.7. Immunological and neurological effects …………………………………….
6.5.3. Effects on humans ……………………………………………………………………………………..
6.5.4. Effects on other organisms in the laboratory and field ………………………………
6.5.4.1. Aquatic organisms ……………………………………………………………………….
6.5.4.2. Terrestrial organisms …………………………………………………………………..
6.5.5. Evaluation of health effects ……………………………………………………………………….
6.5.5.1. Hazard identification and dose-response assessment …………………..
6.5.5.2. Criteria for setting tolerable intakes …………………………………………..
6.5.6. Evaluation of environmental effects ………………………………………………………….
6.6 Cyclodextrins ……………………….……………………………………………………………………………………
6.6.1. Identity and physical/chemical properties ……………………………………………….
6.6.1.1. Nomenclature ……………………………………………………………………………
6.6.1.2. Chemical structures …………………………………………………………………..
6.6.1.3. Chemical properties …………………………………………………………………..
6.6.2. Effects on laboratory mammals and in vitro test systems ………………………….
6.6.2.1. Acute exposure ………………………………………………………………………….
6.6.2.2. Irritation/sensitization ……………………………………………………………….
6.6.2.3. Subchronic exposure ………………………………………………………………….
6.6.2.4. Chronic exposure ……………………………………………………………………….
6.6.2.5. Reproductive/developmental endpoints ……………………………………
6.6.2.6. Genotoxicity and related endpoints …………………………………………..
6.6.2.7. Immunological and neurological effects …………………………………….
6.6.3. Effects on humans ……………………………………………………………………………………..
6.6.4. Effects on other organisms in the laboratory and field ………………………………
6.6.4.1. Aquatic organisms ……………………………………………………………………….
6.6.4.2. Terrestrial organisms …………………………………………………………………..
6.6.5. Evaluation of health effects ……………………………………………………………………….
6.6.5.1. Hazard identification and dose-response assessment …………………..
6.6.5.2. Criteria for setting tolerable intakes …………………………………………..
6.6.6. Evaluation of environmental effects ………………………………………………………….
7. Summary and conclusions ………………………………………………………………………………………………………..
8. References ………………………………………………………………………………………………………………………………
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1. Introduction
Although oral delivery of medications has become a widely accepted route of administration for
therapeutic drugs, the gastrointestinal (GI) tract presents a formidable barrier to drug delivery,
principally due to the degradation of acid-labile compounds. To circumvent this potential problem,
drug manufacturers have identified a variety of excipient compounds that are insoluble in acid media,
but are readily soluble in neutral or alkaline media, to provide an “enteric” coating on the dosage
form, which facilitates its dissolution and absorption in the less hostile environment of the intestines.
This concept of enteric coating has existed for over 140 years, and although well over 100 materials
have been evaluated and used to create enteric coatings over the years, there are relatively few that
have been successfully employed in marketed pharmaceutical products. Although physical/chemical
properties of enteric coated pharmaceutical excipients have been the subject of previous reviews
(Edgar et al., 2001 and Chourasia and Jain 2003), none have dealt specifically with issues related to
health and safety of patients or the environment, due in part to their extensive safe use over many
years.
In the chemical industry, a more recent trend has been an increase in the development of compounds
that can be incorporated in polymers to promote and enhance their plasticity. Among these so-called
plasticizers is a group of compounds that have become known as phthalate plasticizers (or simply
phthalates). Although the structures of the phthalate plasticizers share a specific chemical structure
(ie., an ortho-phthalic acid molecule esterified with two short-chain alcohol molecules), usage of the
colloquial name phthalates has implied a more general structure and hence, a potential for the
phthalate plasticizers to be confused with other classes of chemicals.
As of 2006, phthalate plasticizers are produced in high volume, with annual production exceeding 470
million pounds (EPA 2006 ). Several recent studies have suggested that exposure to specific
phthalate plasticizers can produce adverse human health effects, wherein the development of the
male reproductive system seems to be most affected. As a result of these concerns, the USEPA has
issued the Phthalates Action Plan in December of 2009, in an effort to manage potential risks
associated with exposure to phthalate plasticizers.
Heightened awareness of the potential health effects associated with exposure to phthalate
plasticizers has stimulated diverse research initiatives to identify specific compounds of concern and
to explore potential underlying mechanisms for these effects. With respect to the safety of
pharmaceutical products, the FDA recently has developed and issued draft guidance to limit the use of
two phthalate plasticizers, namely dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP)(Fed
Register _________). In March of 2012, researchers from the National Institute of Environmental
Health Science (NIEHS) have broadened the scope of the FDA’s guidance document to raise concerns
about any compound that has the word “phthalate” in its name, whether or not its physical or
chemical properties are at all comparable to the phthalate plasticizers in question. Since many of the
polymers that are used as excipients to produce enteric coatings also contain phthalic acid
substituents (and whose name also contains the word “phthalate”), it is reasonable to expect that the
8
safety of these polymers may be incriminated by proxy. Recognizing that the safety of excipients for
the enteric coating of pharmaceutical products per se also has not been a topic for review in the
recent literature, a review at this time appears particularly germane.
2. DEFINITIONS
Before presenting data on specific materials, it is particularly valuable to define terminology and
supportive background to facilitate a broad understanding of the excipients used to create enteric
coatings for pharmaceuticals.
1. Cellulose:
2. Cellulose ester:
3. Enteric-coated [product]:
4. Ester:
5. Isophthalate:
6. Phthalate:
7. Phthalate plasticizer:
8. Polymer:
9. Polysaccharide:
10. Sustained-release [product]:
11. Terephthalate:
9
3. CELLULOSE POLYMERS
3.1 CELLULOSE ACETATE PHTHALATE
3.1.1. Identity and physical/chemical properties
3.1.1.1. Nomenclature
3.1.1.2. Chemical structures.
3.1.1.3. Chemical properties.
3.1.2. Effects on laboratory mammals and in vitro test systems.
3.1.2.1. Acute exposure
3.1.2.2. Irritation/sensitization
3.1.2.3. Subchronic exposure
3.1.2.4. Chronic exposure
3.1.2.5. Reproductive/developmental endpoints
3.1.2.6. Genotoxicity and related endpoints
3.1.2.7. Immunological and neurological effects
3.1.3. Effects on humans
3.1.4. Effects on other organisms in the laboratory and field
3.1.4.1. Aquatic organisms
3.1.4.2. Terrestrial organisms
3.1.5. Evaluation of health effects
3.1.5.1. Hazard identification and dose-response assessment
3.1.5.2. Criteria for setting tolerable intakes
3.1.6. Evaluation of environmental effects
10
3.2 CELLULOSE ACETATE TRIMELLIATE
3.2.1. Identity and physical/chemical properties
3.2.1.1. Nomenclature
3.2.1.2. Chemical structures
3.2.1.3. Chemical properties
3.2.2. Effects on laboratory mammals and in vitro test systems
3.2.2.1. Acute exposure
3.2.2.2. Irritation/sensitization
3.2.2.3. Subchronic exposure
3.2.2.4. Chronic exposure
3.2.2.5. Reproductive/developmental endpoints
3.2.2.6. Genotoxicity and related endpoints
3.2.2.7. Immunological and neurological effects
3.2.3. Effects on humans
3.2.4. Effects on other organisms in the laboratory and field
3.2.4.1. Aquatic organisms
3.2.4.2. Terrestrial organisms
3.2.5. Evaluation of health effects
3.2.5.1. Hazard identification and dose-response assessment
3.2.5.2. Criteria for setting tolerable intakes
3.2.6. Evaluation of environmental effects
11
3.3. HYPROMELLOSE PHTHALATE
3.3.1. Identity and physical/chemical properties
3.3.1.1. Nomenclature
3.3.1.2. Chemical structures
3.3.1.3. Chemical properties
3.3.2. Effects on laboratory mammals and in vitro test systems
3.3.2.1. Acute exposure
3.3.2.2. Irritation/sensitization
3.3.2.3. Subchronic exposure
3.3.2.4. Chronic exposure
3.3.2.5. Reproductive/developmental endpoints
3.3.2.6. Genotoxicity and related endpoints
3.3.2.7. Immunological and neurological effects
3.3.3. Effects on humans
3.3.4. Effects on other organisms in the laboratory and field
3.3.4.1. Aquatic organisms
3.3.4.2. Terrestrial organisms
3.3.5. Evaluation of health effects
3.3.5.1. Hazard identification and dose-response assessment
3.3.5.2. Criteria for setting tolerable intakes
3.3.6. Evaluation of environmental effects
12
4. VINYL ACETATE POLYMERS
4.1. VINYL ACETATE PHTHALATE
4.1.1. Identity and physical/chemical properties
3.1.1.1. Nomenclature
3.1.1.2. Chemical structures
3.1.1.3. Chemical properties
4.1.2. Effects on laboratory mammals and in vitro test systems
4.1.2.1. Acute exposure
4.1.2.2. Irritation/sensitization
4.1.2.3. Subchronic exposure
4.1.2.4. Chronic exposure
4.1.2.5. Reproductive/developmental endpoints
4.1.2.6. Genotoxicity and related endpoints
4.1.2.7. Immunological and neurological effects
4.1.3. Effects on humans
4.1.4. Effects on other organisms in the laboratory and field
4.1.4.1. Aquatic organisms
4.1.4.2. Terrestrial organisms
4.1.5. Evaluation of health effects
4.1.5.1. Hazard identification and dose-response assessment
4.1.5.2. Criteria for setting tolerable intakes
4.1.6. Evaluation of environmental effects
13
5. METHACRYLIC ACID COPOLYMERS
5.1. EUDRAGIT®L
5.1.1. Identity and physical/chemical properties
5.1.1.1. Nomenclature
5.1.1.2. Chemical structures
5.1.1.3. Chemical properties
5.1.2. Effects on laboratory mammals and in vitro test systems
5.1.2.1. Acute exposure
5.1.2.2. Irritation/sensitization
5.1.2.3. Subchronic exposure
5.1.2.4. Chronic exposure
5.1.2.5. Reproductive/developmental endpoints
5.1.2.6. Genotoxicity and related endpoints
5.1.2.7. Immunological and neurological effects
5.1.3. Effects on humans
5.1.4. Effects on other organisms in the laboratory and field
5.1.4.1. Aquatic organisms
5.1.4.2. Terrestrial organisms
5.1.5. Evaluation of health effects
5.1.5.1. Hazard identification and dose-response assessment
5.1.5.2. Criteria for setting tolerable intakes
5.1.6. Evaluation of environmental effects
14
5.2. EUDRAGIT® S
5.2.1. Identity and physical/chemical properties
5.2.1.1. Nomenclature
5.2.1.2. Chemical structures
5.2.1.3. Chemical properties
5.2.2. Effects on laboratory mammals and in vitro test systems
5.2.2.1. Acute exposure
5.2.2.2. Irritation/sensitization
5.2.2.3. Subchronic exposure
5.2.2.4. Chronic exposure
5.2.2.5. Reproductive/developmental endpoints
5.2.2.6. Genotoxicity and related endpoints
5.2.2.7. Immunological and neurological effects
5.2.3. Effects on humans
5.2.4. Effects on other organisms in the laboratory and field
5.2.4.1. Aquatic organisms
5.2.4.2. Terrestrial organisms
5.2.5. Evaluation of health effects
5.2.5.1. Hazard identification and dose-response assessment
5.2.5.2. Criteria for setting tolerable intakes
5.2.6. Evaluation of environmental effects
15
5.3. DIVINYLAZOBENZENE CROSSLINKED METHACRYLATES
5.3.1. Identity and physical/chemical properties
5.3.1.1. Nomenclature
5.3.1.2. Chemical structures
5.3.1.3. Chemical properties
5.3.2. Effects on laboratory mammals and in vitro test systems
5.3.2.1. Acute exposure
5.3.2.2. Irritation/sensitization
5.3.2.3. Subchronic exposure
5.3.2.4. Chronic exposure
5.3.2.5. Reproductive/developmental endpoints
5.3.2.6. Genotoxicity and related endpoints
5.3.2.7. Immunological and neurological effects
5.3.3. Effects on humans
5.3.4. Effects on other organisms in the laboratory and field
5.3.4.1. Aquatic organisms
5.3.4.2. Terrestrial organisms
5.3.5. Evaluation of health effects
5.3.5.1. Hazard identification and dose-response assessment
5.3.5.2. Criteria for setting tolerable intakes
5.3.6. Evaluation of environmental effects
16
6. BIODEGRADABLE POLYSACCHARIDES
6.1. CHITOSAN
6.1.1. Identity and physical/chemical properties
6.1.1.1. Nomenclature
6.1.1.2. Chemical structures
6.1.1.3. Chemical properties
6.1.2. Effects on laboratory mammals and in vitro test systems
6.1.2.1. Acute exposure
6.1.2.2. Irritation/sensitization
6.1.2.3. Subchronic exposure
6.1.2.4. Chronic exposure
6.1.2.5. Reproductive/developmental endpoints
6.1.2.6. Genotoxicity and related endpoints
6.1.2.7. Immunological and neurological effects
6.1.3. Effects on humans
6.1.4. Effects on other organisms in the laboratory and field
6.1.4.1. Aquatic organisms
6.1.4.2. Terrestrial organisms
6.1.5. Evaluation of health effects
6.1.5.1. Hazard identification and dose-response assessment
6.1.5.2. Criteria for setting tolerable intakes
6.1.6. Evaluation of environmental effects
17
6.2. PECTIN
6.2.1. Identity and physical/chemical properties
6.2.1.1. Nomenclature
6.2.1.2. Chemical structures
6.2.1.3. Chemical properties
6.2.2. Effects on laboratory mammals and in vitro test systems
6.2.2.1. Acute exposure
6.2.2.2. Irritation/sensitization
6.2.2.3. Subchronic exposure
6.2.2.4. Chronic exposure
6.2.2.5. Reproductive/developmental endpoints
6.2.2.6. Genotoxicity and related endpoints
6.2.2.7. Immunological and neurological effects
6.2.3. Effects on humans
6.2.4. Effects on other organisms in the laboratory and field
6.2.4.1. Aquatic organisms
6.2.4.2. Terrestrial organisms
6.2.5. Evaluation of health effects
6.2.5.1. Hazard identification and dose-response assessment
6.2.5.2. Criteria for setting tolerable intakes
6.2.6. Evaluation of environmental effects
18
6.3 AMYLOSE
6.3.1. Identity and physical/chemical properties
6.3.1.1. Nomenclature
6.3.1.2. Chemical structures
6.3.1.3. Chemical properties
6.3.2. Effects on laboratory mammals and in vitro test systems
6.3.2.1. Acute exposure
6.3.2.2. Irritation/sensitization
6.3.2.3. Subchronic exposure
6.3.2.4. Chronic exposure
6.3.2.5. Reproductive/developmental endpoints
6.3.2.6. Genotoxicity and related endpoints
6.3.2.7. Immunological and neurological effects
6.3.3. Effects on humans
6.3.4. Effects on other organisms in the laboratory and field
6.3.4.1. Aquatic organisms
6.3.4.2. Terrestrial organisms
6.3.5. Evaluation of health effects
6.3.5.1. Hazard identification and dose-response assessment
6.3.5.2. Criteria for setting tolerable intakes
6.3.6. Evaluation of environmental effects
19
6.4 GUAR GUM
6.4.1. Identity and physical/chemical properties
6.4.1.1. Nomenclature
6.4.1.2. Chemical structures
6.4.1.3. Chemical properties
6.4.2. Effects on laboratory mammals and in vitro test systems
6.4.2.1. Acute exposure
6.4.2.2. Irritation/sensitization
6.4.2.3. Subchronic exposure
6.4.2.4. Chronic exposure
6.4.2.5. Reproductive/developmental endpoints
6.4.2.6. Genotoxicity and related endpoints
6.4.2.7. Immunological and neurological effects
6.4.3. Effects on humans
6.4.4. Effects on other organisms in the laboratory and field
6.4.4.1. Aquatic organisms
6.4.4.2. Terrestrial organisms
6.4.5. Evaluation of health effects
6.4.5.1. Hazard identification and dose-response assessment
6.4.5.2. Criteria for setting tolerable intakes
6.4.6. Evaluation of environmental effects
20
6.5 INULIN
6.5.1. Identity and physical/chemical properties
6.5.1.1. Nomenclature
6.5.1.2. Chemical structures
6.5.1.3. Chemical properties
6.5.2. Effects on laboratory mammals and in vitro test systems
6.5.2.1. Acute exposure
6.5.2.2. Irritation/sensitization
6.5.2.3. Subchronic exposure
6.5.2.4. Chronic exposure
6.5.2.5. Reproductive/developmental endpoints
6.5.2.6. Genotoxicity and related endpoints
6.5.2.7. Immunological and neurological effects
6.5.3. Effects on humans
6.5.4. Effects on other organisms in the laboratory and field
6.5.4.1. Aquatic organisms
6.5.4.2. Terrestrial organisms
6.5.5. Evaluation of health effects
6.5.5.1. Hazard identification and dose-response assessment
6.5.5.2. Criteria for setting tolerable intakes
6.5.6. Evaluation of environmental effects
21
6.6 CYCLODEXTRINS
6.6.1. Identity and physical/chemical properties
6.6.1.1. Nomenclature
6.6.1.2. Chemical structures
6.6.1.3. Chemical properties
6.6.2. Effects on laboratory mammals and in vitro test systems
6.6.2.1. Acute exposure
6.6.2.2. Irritation/sensitization
6.6.2.3. Subchronic exposure
6.6.2.4. Chronic exposure
6.6.2.5. Reproductive/developmental endpoints
6.6.2.6. Genotoxicity and related endpoints
6.6.2.7. Immunological and neurological effects
6.6.3. Effects on humans
6.6.4. Effects on other organisms in the laboratory and field
6.6.4.1. Aquatic organisms
6.6.4.2. Terrestrial organisms
6.6.5. Evaluation of health effects
6.6.5.1. Hazard identification and dose-response assessment
6.6.5.2. Criteria for setting tolerable intakes
6.6.6. Evaluation of environmental effects
22
7. SUMMARY AND CONCLUSIONS
23
8. REFERENCES
24