`
`
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`Downloaded from on March 4, 2020Downloaded from on March 4, 2020
`
`A Compilation of Safety Impact Information for Extractables
`Associated with Materials Used in Pharmaceutical Packaging,
`Delivery, Administration, and Manufacturing Systems
`Dennis Jenke and Tage Carlson
`
`2014
` PDA J Pharm Sci and Tech
`68,
` 407-455
`
`
`Access the most recent version at doi: 10.5731/pdajpst.2014.00995
`
`
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 1
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`RESEARCH
`
`A Compilation of Safety Impact Information for Extractables
`Associated with Materials Used in Pharmaceutical Packaging,
`Delivery, Administration, and Manufacturing Systems
`
`DENNIS JENKE* and TAGE CARLSON
`
`Baxter Healthcare Corporation, Round Lake, IL ©PDA, Inc. 2014
`
`ABSTRACT: Demonstrating suitability for intended use is necessary to register packaging, delivery/administration,
`or manufacturing systems for pharmaceutical products. During their use, such systems may interact with the
`pharmaceutical product, potentially adding extraneous entities to those products. These extraneous entities, termed
`leachables, have the potential to affect the product’s performance and/or safety. To establish the potential safety
`impact, drug products and their packaging, delivery, or manufacturing systems are tested for leachables or extract-
`ables, respectively. This generally involves testing a sample (either the extract or the drug product) by a means that
`produces a test method response and then correlating the test method response with the identity and concentration of
`the entity causing the response. Oftentimes, analytical tests produce responses that cannot readily establish the
`associated entity’s identity. Entities associated with un-interpretable responses are termed unknowns. Scientifically
`justifiable thresholds are used to establish those individual unknowns that represent an acceptable patient safety risk
`and thus which do not require further identification and, conversely, those unknowns whose potential safety impact
`require that they be identified. Such thresholds are typically based on the statistical analysis of datasets containing
`toxicological information for more or less relevant compounds.
`This article documents toxicological information for over 540 extractables identified in laboratory testing of polymeric
`materials used in pharmaceutical applications. Relevant toxicological endpoints, such as NOELs (no observed effects),
`NOAELs (no adverse effects), TDLOs (lowest published toxic dose), and others were collated for these extractables or their
`structurally similar surrogates and were systematically assessed to produce a risk index, which represents a daily intake
`value for life-long intravenous administration. This systematic approach uses four uncertainty factors, each assigned a
`factor of 10, which consider the quality and relevance of the data, differences in route of administration, non-human species
`to human extrapolations, and inter-individual variation among humans. In addition to the risk index values, all extractables
`and most of their surrogates were classified for structural safety alerts using Cramer rules and for mutagenicity alerts using
`an in silico approach (Benigni/Bossa rule base for mutagenicity via Toxtree). Lastly, in vitro mutagenicity data (Ames
`Salmonella typimurium and Mouse Lymphoma tests) were collected from available databases (Chemical Carcinogenesis
`Research Information and Carcinogenic Potency Database).
`The frequency distributions of the resulting data were established; in general risk index values were normally
`distributed around a band ranging from 5 to 20 mg/day. The risk index associated with 95% level of the cumulative
`distribution plot was approximately 0.1 mg/day. Thirteen extractables in the dataset had individual risk index values
`less than 0.1 mg/day, although four of these had additional risk indices, based on multiple different toxicological
`endpoints, above 0.1 mg/day. Additionally, approximately 50% of the extractables were classified in Cramer Class 1 (low
`risk of toxicity) and approximately 35% were in Cramer Class 3 (no basis to assume safety). Lastly, roughly 20% of the
`extractables triggered either an in vitro or in silico alert for mutagenicity. When Cramer classifications and the mutagenicity
`alerts were compared to the risk indices, extractables with safety alerts generally had lower risk index values, although the
`differences in the risk index data distributions, extractables with or without alerts, were small and subtle.
`
`*Corresponding Author: 25212 West Illinois Route 120, Baxter Healthcare Corporation, Round Lake, IL 60073.
`Telephone: (224) 270-5821; e-mail: dennis_jenke@baxter.com
`doi: 10.5731/pdajpst.2014.00995
`
`Vol. 68, No. 5, September–October 2014
`
`407
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 2
`
`

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`
`KEYWORDS: Extractables, Leachables, Safety assessment, Thresholds, Risk index (RI), Toxicological risk
`assessment.
`
`LAY ABSTRACT: Leachables from packaging systems, manufacturing systems, or delivery devices can accu-
`mulate in drug products and potentially affect the drug product. Although drug products can be analyzed for
`leachables (and material extracts can be analyzed for extractables), not all leachables or extractables can be fully
`identified. Safety thresholds can be used to establish whether the unidentified substances can be deemed to be
`safe or whether additional analytical efforts need to be made to secure the identities. These thresholds are
`typically based on the statistical analysis of datasets containing toxicological information for more or less
`relevant compounds.
`This article contains safety data for over 500 extractables that were identified in laboratory characterizations of
`polymers used in pharmaceutical applications. The safety data consists of structural toxicity classifications of the
`extractables as well as calculated risk indices, where the risk indices were obtained by subjecting toxicological safety
`data, such as NOELs (no observed effects), NOAELs (no adverse effects), TDLOs (lowest published toxic dose), and
`others to a systematic evaluation process using appropriate uncertainty factors. Thus the risk index values represent
`daily exposures for the lifetime intravenous administration of drugs. The frequency distributions of the risk indices
`and Cramer classifications were examined. The risk index values were normally distributed around a range of 5 to 20
`mg/day, and the risk index associated with the 95% level of the cumulative frequency plot was 0.1 mg/day.
`Approximately 50% of the extractables were in Cramer Class 1 (low risk of toxicity) and approximately 35% were
`in Cramer Class 3 (high risk of toxicity). Approximately 20% of the extractables produced an in vitro or in silico
`mutagenicity alert. In general, the distribution of risk index values was not strongly correlated with the either
`extractables’ Cramer classification or by mutagenicity alerts. However, extractables with either in vitro or in silico
`alerts were somewhat more likely to have low risk index values.
`
`Introduction
`
`Packaging, delivery, administration, and manufactur-
`ing systems used with pharmaceutical products may be
`constructed from plastic materials. Such systems are
`demonstrated to be suited for their intended use by
`establishing their ability to
`
`●
`
`●
`
`●
`
`●
`
`the pharmaceutical product (such as a
`protect
`drug product or solution) that is either stored in
`the packaging system, delivered, or administered
`through or via the medical device, or manufac-
`tured with a manufacturing system,
`
`be compatible with the pharmaceutical product,
`
`be safe when used with the pharmaceutical prod-
`uct, and
`
`function properly when used with the pharma-
`ceutical product under the relevant clinical con-
`ditions.
`
`Demonstrating suitability for intended use is a pre-
`requisite for the registration of a pharmaceutical prod-
`uct and/or its packaging, delivery/administration, or
`manufacturing systems.
`
`Chemical entities present in these systems can migrate
`(or leach) into the drug product during that time during
`which the drug product and these systems are in contact.
`These extraneous system-derived entities have the poten-
`tial to affect product performance and/or safety. Exper-
`imentally assessing the extent of migration can be ac-
`complished by characterizing the systems for extractable
`substances (establishing the potential effect) or the pack-
`aged drug product for system-related leachables (estab-
`lishing the actual effect). In either circumstance, the
`analytical process is the same and typically involves
`testing a sample (either the extract or the drug product)
`by a means that produces a response and then correlating
`the response with the identity and concentration of the
`entity causing the response. With this information (iden-
`tity and concentration), the potential safety risk associ-
`ated with individual extractables (or leachables) can be
`assessed.
`
`It is often the case that analytical test methods can
`produce responses more readily than those re-
`sponses can be used to establish the associated
`entity’s identity and concentration. In the case that
`an entity’s identity cannot be established, the entity
`is labeled as an unknown and the unknown cannot
`be toxicologically assessed to directly establish its
`safety. Nevertheless, it is reasonable to hypothesize
`
`408
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 3
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`TABLE I
`Compiled Information for the Group 1 Extractables
`
`Compound
`
`CAS
`Registry
`No.
`
`Value,
`mg/kg
`
`Type
`
`Route Model
`
`Ref.
`
`Toxicological Information
`
`Toxicological Uncertainty Factors
`(UFs)
`
`T1,
`Inter-
`species
`
`T2,
`Intra-
`species
`
`T3,
`Route
`
`T4,
`Type
`
`2,4-Dichlorobenzoic acid
`
`50-84-0
`
`830
`
`Glycerine
`
`56-81-5
`
`4250
`
`oral
`
`i.v.
`
`mouse
`
`mouse
`
`4
`
`5
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`Risk
`Index
`(RI),
`mg/day
`
`5.81
`
`298
`
`Cramer
`Class
`
`3
`
`1
`
`1
`
`Carcinogenicity
`Alerts
`
`In Silicoe
`
`A
`
`B
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`In
`Vitrod
`
`Neg1
`Neg1a
`
`Neg1
`
`Palmitic Acid
`
`Stearic acid
`
`Urea
`
`Propylene glycol
`
`57-10-3
`
`57-11-4
`
`57
`
`21.5
`
`57-13-6
`
`3000
`
`57-55-6
`
`4200
`
`i.v.
`
`i.v.
`
`i.v.
`
`i.v.
`
`mouse
`
`rats
`
`dog
`
`rabbit
`
`6
`
`7
`
`8
`
`9
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`1
`
`1
`
`10
`
`10
`
`10
`
`10
`
`3.99
`
`1.51
`
`210
`
`294
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg1
`Pos1a
`Neg1a
`
`LD50
`LD50
`LD50
`LD50
`LDLO
`LDLO
`LD50
`PDE
`
`PDE
`
`Linoleic acid
`
`Formic acid
`
`Acetic acid
`
`Benzoic acid
`
`60-33-3
`
`280
`
`64-18-6
`
`64-19-7
`
`2.57
`
`45.7
`
`65-85-0
`
`500
`
`i.p.
`
`i.v.
`
`i.v.
`
`mouse
`
`human
`
`human
`
`10
`
`11
`
`11
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`1
`
`1
`
`10
`
`10
`
`1
`
`1
`
`10
`
`1.96
`
`18.0
`
`320
`
`35.0
`
`1
`
`1
`
`1
`
`1
`
`Neg2
`
`Neg1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`LDLO
`LD50
`EPA RfD
`
`1700
`
`4.4
`
`Hexanal
`
`Isopropanol
`
`66-25-1
`
`4890
`
`67-63-0
`
`1024
`
`oral
`
`i.v.
`
`oral
`
`oral
`
`i.v.
`
`human
`
`rats
`
`human
`
`rats
`
`dog
`
`12
`
`12
`
`13
`
`14
`
`15
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`1
`
`10
`
`1
`
`10
`
`10
`
`119
`
`3.08
`
`34.2
`
`71.9
`
`Neg1
`Neg1a
`
`N/A
`Neg1b
`
`1
`
`1
`
`Pose Neg
`
`Neg
`
`Neg
`
`Neg
`
`Acetone
`
`Dimethylformamide
`
`p-Toluenesulfonamide
`
`67-64-1
`
`68-12-2
`
`70-55-3
`
`LD50
`LDLO
`PDE
`
`LD50
`LD50
`NOEL
`
`3
`
`470
`
`250
`
`50
`
`310
`
`N/A
`
`i.v.
`
`i.p.
`
`oral
`
`human
`
`dog
`
`mouse
`
`rats
`
`11
`
`16
`
`17
`
`18
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`1
`
`21.0
`
`32.9
`
`1.75
`
`3.50
`
`1
`
`3
`
`3
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg1
`Neg2b
`
`N/A
`
`1-Butanol
`
`1-Pentanol
`
`71-36-3
`
`71-41-0
`
`15
`
`4-Chlorobenzoic acid
`
`74-11-3
`
`1000
`
`Ethyl aldehyde
`
`75-07-0
`
`10.6
`
`i.v.
`
`i.v.
`
`i.p.
`
`i.v.
`
`rats
`
`cats
`
`rats
`
`human
`
`19
`
`20
`
`21
`
`22
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`1
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`21.7
`
`1.05
`
`7.00
`
`7.42
`
`1
`
`1
`
`3
`
`1
`
`Neg
`
`Neg
`
`Neg1
`
`Neg
`
`Neg
`Posf
`Neg
`Pose Neg
`
`N/A
`
`Neg1
`Neg1c
`
`Carbon disulfide
`
`75-15-0
`
`7.6
`
`2,2-Dimethylpropanoic acid
`
`75-98-9
`
`900
`
`Tributyl acetylcitrate
`
`77-90-7
`
`4000
`
`Diethoxydimethylsilane
`
`78-62-6
`
`9280
`
`i.p.
`
`oral
`
`i.p.
`
`rats
`
`rats
`
`mouse
`
`23
`
`24
`
`25
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`0.053
`
`6.30
`
`28.0
`
`65.0
`
`3
`
`1
`
`1
`
`3
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`N/A
`
`N/A
`Neg
`Posg Neg2
`
`Neg
`
`Neg2
`
`2-Butanone
`
`Propionic acid
`
`Hydroxyacetic acid
`
`78-93-3
`
`79-09-4
`
`361
`
`625
`
`79-14-1
`
`1000
`
`oral
`
`i.p.
`
`i.v.
`
`i.v.
`
`rats
`
`rats
`
`mouse
`
`cat
`
`26
`
`27
`
`28
`
`29
`
`LD50
`LDLO
`LD50
`TDLO
`TDLO
`LD50
`LD50
`LD50
`TDLO
`LD50
`LD50
`2-Hydroxypropanoic acid
`79-33-4
`3194
`LD50
`i.p.
`mouse
`30
`10
`10
`10
`10
`22.4
`1
`Neg
`Neg
`N/A
`aNo genotoxocity indicated based on studies in rats, obtained from the Carcinogenic Potency Database (CPDB, 287).
`bNo genotoxicity indicated based on studies in rats and mice, obtained from CPDB (287).
`⫽ 153 mg/kg/day in rats, 565 mg/kg/day in hamster.
`cTD50
`dFrom CCRIS database (287). Neg1 ⫽ negative Ames Salmonella typimurium test. Neg2 ⫽ negative Ames and
`Mouse Lymphoma tests. Pos1 ⫽ positive Ames or Mouse Lymphoma test. Pos2 ⫽ positive Ames and Mouse
`Lymphoma test. N/A ⫽ No test data available for that compound.
`eFrom Toxtree (3, 285) using Benigni/Biossa rulebase. A ⫽ considering genotoxic effects, B ⫽ considering
`non-genotoxic effects.
`eQSA11 rule triggered, simple aldehyde.
`fQSA31a rule triggered, halogenated benzene.
`gQSA41 rule triggered, substituted n-alkylcarboxylic acids.
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`2.53
`
`43.8
`
`70.0
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg2
`
`Neg1
`
`Pos1
`
`that “scientifically justifiable thresholds based on
`the best available data and industry practices can be
`developed for the reporting and safety qualification
`of leachables . . . and the reporting of extractables
`from . . . container/closure systems” (1). These sci-
`entifically justifiable thresholds would establish
`those amounts of individual leachables and extract-
`ables that could be viewed as representing an ac-
`
`ceptable patient safety risk regardless of their actual
`identity and toxicology
`
`Hypothesis and Purpose
`Over the years, a significant quantity of extractables
`and leachables data, especially their identities, has
`been published in the chemical literature. For many
`extractables and leachables,
`relevant
`toxicological
`
`Vol. 68, No. 5, September–October 2014
`
`409
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 4
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`TABLE I
`(continued)
`
`Compound
`
`1,1,2,2-Tetrachloroethane
`
`Bisphenol A
`
`4-tert-Amylphenol
`
`CAS
`Registry
`No.
`
`79-34-5
`
`80-05-7
`
`80-46-6
`
`Methacrylic acid, methyl ester
`
`80-62-6
`
`Toxicological Information
`
`Type
`
`Route
`
`Model
`
`Ref.
`
`Toxicological Uncertainty Factors
`(UFs)
`
`T1,
`Inter-
`species
`
`T2,
`Intra-
`species
`
`T3,
`Route
`
`T4,
`Type
`
`LDLO
`NOEL
`
`i.v.
`
`oral
`
`oral
`
`i.p.
`
`dog
`
`mouse
`
`rats
`
`mouse
`
`31
`
`32
`
`33
`
`34
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`Value,
`mg/kg
`
`50
`
`5
`
`1830
`
`945
`
`Carcinogenicity
`Alerts
`
`Cramer
`Class
`
`In Silicoi
`
`A
`
`B
`
`In
`Vitroh
`
`3
`
`3
`
`1
`
`1
`
`Posj Neg
`
`Pos1c
`
`Neg Neg Neg1
`
`Neg Neg Neg1
`Pos1b
`
`Neg Neg
`
`Risk
`Index
`(RI),
`mg/day
`
`3.50
`
`0.35
`
`12.8
`
`6.62
`
`7.91
`
`LD50
`LD50
`LDLO
`LD50
`LD50
`LD50
`LD50
`NOAEL
`
`113
`
`100
`
`3990
`
`720
`
`100
`
`159
`
`84-66-2
`
`84-69-5
`
`84-74-2
`
`85-44-9
`
`85-68-7
`
`Diethyl phthalate
`
`Diisobutyl phthalate
`
`Dibutyl phthalate
`
`Phthalic anhydride
`
`Benzyl butyl phthalate
`
`i.v.
`
`i.v.
`
`i.p.
`
`i.v.
`
`i.p.
`
`dog
`
`rabbit
`
`mouse
`
`mouse
`
`guinea pig
`
`oral
`
`rats
`
`35
`
`36
`
`37
`
`38
`
`39
`
`40
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`7.00
`
`27.9
`
`50.4
`
`0.700
`
`11.1
`
`0.700
`
`1
`
`1
`
`1
`
`3
`
`1
`
`3
`
`Neg
`
`Posl Neg1
`Posl Neg1
`Posl Neg1
`Pos1b
`Neg Neg
`Posl Neg1d
`
`Neg
`
`Neg
`
`Neg
`
`2-Furancarboxylic acid
`
`o-Toluenesulfonamide
`
`3,5-Di-tert-butyl-4-
`hydroxybenzyl alcohol
`
`Phthalic acid
`
`88-14-2
`
`88-19-7
`
`88-26-6
`
`88-99-3
`
`100
`
`4870
`
`7000
`
`175
`
`250
`
`102
`
`100
`
`i.p.
`
`oral
`
`oral
`
`oral
`
`i.p.
`
`oral
`
`oral
`
`mouse
`
`rats
`
`rats
`
`rats
`
`mouse
`
`rats
`
`rats
`
`41
`
`42
`
`43
`
`43
`
`44
`
`44
`
`45
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`34.1
`
`49.0
`
`1.23
`
`1.75
`
`0.714
`
`7.00
`
`3
`
`2
`
`1
`
`3
`
`Neg Neg Neg1
`Neg Neg Neg1e
`Neg Neg N/Aa
`
`Neg
`
`Posl Neg1
`
`Neg
`
`Posk
`
`LD50
`LD50
`LDLO
`TDLO
`LD50
`TDLO
`NOAEL
`
`LD50
`LD50
`
`o-Hydroxybiphenyl
`␣-Phenylbenzenemethanol
`
`Hexanoic acid, 2-ethyl-, diester
`with triethylene glycol
`
`90-43-7
`
`91-01-0
`
`5000
`
`94-28-0
`
`13677
`
`oral
`
`rats
`
`dermal
`
`rabbit
`
`46
`
`47
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`35.0
`
`95.7
`
`3
`
`1
`
`Neg Neg N/A
`Posm N/A
`
`Neg
`
`Pos2f
`
`2-Ethyl-1,3-hexanediol
`
`Benzothiazole
`
`o-Xylene
`
`94-96-2
`
`95-16-9
`
`95-47-6
`
`131
`
`95
`
`1500
`
`i.v.
`
`i.v.
`
`i.p.
`
`rats
`
`mouse
`
`mammal
`
`48
`
`49
`
`50
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`10
`
`9.17
`
`6.65
`
`10.5
`
`12.3
`
`1
`
`3
`
`1
`
`1
`
`Neg
`
`Posm Neg2
`
`Neg Neg Neg1
`
`Neg Neg Neg1
`Neg Neg Neg1g
`
`LD50
`LD50
`LDLO
`1,2,4-Trimethylbenzene
`95-63-6
`1752
`LDLO
`i.p.
`rat
`51
`10
`10
`10
`10
`aNo genotoxocity indicated based on studies in rats, obtained from the CPDB (287).
`bNo genotoxicity indicated based on studies in rats and mice, obtained from the CPDB (287).
`⫽ 38.3 mg/kg/day in mice.
`cTD50
`⫽ 1040 mg/kg/day in rats, no effect reported in mice.
`dTD50
`⫽ 3960 mg/kg/day in rats.
`eTD50
`⫽ 232 mg/kg/day in rats, no effect reported in mice.
`fTD50
`⫽ 4350 mg/kg/day in rats.
`gTD50
`hFrom CCRIS database (287). Neg1 ⫽ negative Ames Salmonella typimurium test. Neg2 ⫽ negative Ames and
`Mouse Lymphoma tests. Pos1 ⫽ positive Ames or Mouse Lymphoma test. Pos2 ⫽ positive Ames and Mouse
`Lymphoma test. N/A ⫽ No test data available for that compound.
`iFrom Toxtree (3, 286) using Benigni/Biossa rulebase. A ⫽ considering genotoxic effects, B ⫽ considering
`non-genotoxic effects.
`jQSA8 rule triggered, Aliphatic halogens.
`kQSA47 rule triggered, o-phenyl phenol.
`lQSA42 rule triggered, phthalate diesters and monoesters.
`mQSA41 rule triggered, substituted n-alkyl carboxylic acid.
`
`safety information is also available from the literature.
`Such a database of toxicological safety information
`may be relevant to published safety thresholds, such as
`the safety concern threshold (SCT) and qualification
`threshold (QT). These scientifically justifiable thresh-
`olds establish those amounts of individual leachables
`and extractables that could be viewed as representing
`an acceptable patient safety risk regardless of their
`actual identity and toxicology.
`
`This article documents a large number of largely
`organic, chemically diverse extractables that have
`been discovered in extraction studies performed on
`representative materials that could be used in phar-
`maceutical applications. Toxicological data have been
`collected for these extractables, and the toxicological
`data have been subjected to a systematic process of
`extrapolating the data to the case of long-term, parenter-
`ally administered drug products in humans. The extrap-
`
`410
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 5
`
`

`

`TABLE I
`(continued)
`
`Compound
`
`2,4-Di-t-butyl phenol
`
`CAS
`Registry
`No.
`
`96-76-4
`
`1-Methylethylbenzene
`
`98-82-8
`
`100
`
`25
`
`LD50
`LD50
`0.01 PDE
`
`Acetophenone
`
`98-86-2
`
`200
`
`0.1
`
`LD50
`EPA RfD
`
`Downloaded from
`
`on March 4, 2020
`
`Toxicological Information
`
`Value,
`mg/kg
`
`Type
`
`Route
`
`Model
`
`Ref.
`
`Toxicological Uncertainty Factors
`(UFs)
`
`T1, Inter-
`species
`
`T2,
`Intra-
`species
`
`T3,
`Route
`
`T4,
`Type
`
`i.v.
`
`i.p.
`
`N/A
`
`i.p.
`
`oral
`
`mouse
`
`mouse
`
`human
`
`mouse
`
`human
`
`52
`
`52
`
`53
`
`54
`
`55
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`1
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`Carcinogenicity
`Alerts
`
`Cramer
`Class
`
`In Silicoi
`
`A
`
`B
`
`In
`Vitroh
`
`1
`
`1
`
`1
`
`Neg Neg N/A
`
`Neg Neg Neg1
`
`Neg Neg Neg1
`
`Risk
`Index
`(RI),
`mg/day
`
`7.00
`
`0.175
`
`0.07
`
`1.40
`
`0.07
`
`29.6
`
`2-Propyl valeric acid
`
`Terephthalic acid
`
`Ethyl benzene
`
`Styrene
`
`4-Cyanocyclohexene
`
`Benzyl alcohol
`
`423
`
`NOAEL
`
`20
`
`767
`
`TDLO
`TDLO
`TDLO
`0.28 EPA RfC
`
`99-66-1
`
`100-21-0
`
`100-41-4 1062
`
`100-42-5
`
`100-45-8
`
`460
`
`100-51-6
`
`50
`
`oral
`
`i.v.
`
`i.v.
`
`i.p.
`
`rats
`
`human
`
`dogs
`
`rats
`
`inhaled
`
`human
`
`oral
`
`rats
`
`dog
`
`55
`
`56
`
`57
`
`58
`
`59
`
`60
`
`61
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`1
`
`10
`
`1
`
`1
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`14.0
`
`53.7
`
`7.43
`
`1.96
`
`3.22
`
`3.50
`
`1
`
`1
`
`1
`
`1
`
`3
`
`1
`
`Neg Posl N/A
`
`Neg Neg Neg1
`Neg Neg Pos1c
`Neg Neg Neg2d
`
`Benzaldehyde
`
`100-52-7
`
`9
`
`0.1
`
`Diphenylmethane diisocyanate
`
`101-68-8 2200
`
`Diphenyl ether
`
`101-84-8 2450
`
`2-Ethylhexyl acrylate
`
`Bis(2-ethylhexyl)adipate
`
`301
`
`103-11-7 1326
`
`103-23-1
`
`540
`
`LD50
`LDLO
`LD50
`EPA RfD
`
`LD50
`LD50
`NOAEL
`
`i.v.
`
`i.p.
`
`oral
`
`oral
`
`oral
`
`oral
`
`i.p.
`
`i.v.
`
`mouse
`
`human
`
`mouse
`
`rats
`
`rats
`
`mouse
`
`rabbit
`
`62
`
`63
`
`64
`
`65
`
`66
`
`67
`
`68
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`0.063
`
`0.07
`
`15.4
`
`17.2
`
`21.1
`
`9.28
`
`37.8
`
`1
`
`3
`
`3
`
`1
`
`1
`
`Neg Neg N/A
`Neg Neg Pos1b
`Posj Neg Pos1e
`
`Posk Neg Pos1
`
`Neg Neg Neg1
`
`Dibenzyl amine
`
`103-49-1
`
`395
`
`Dihydro-5-pentyl-2(3H)-furanone
`
`104-61-0 3440
`
`2-Ethyl-1-hexanol
`
`104-76-7
`
`500
`
`50
`
`LD50
`LD50
`LD50
`LD50
`LD50
`NOAEL
`
`oral
`
`oral
`
`i.p.
`
`oral
`
`rats
`
`guinea pig
`
`rats
`
`rats
`
`69
`
`70
`
`71
`
`72,73
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`2.77
`
`24.1
`
`3.50
`
`3.50
`
`3
`
`2
`
`1
`
`Neg Posl Neg1
`Neg Posl Neg1f
`
`Neg Neg N/A
`
`Neg Neg N/A
`Neg Posl Neg1g
`
`i.p.
`
`i.p.
`
`mouse
`
`rats
`
`74
`
`75
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`2.80
`
`5.60
`
`1
`
`1
`
`Posj Neg Neg1
`
`Neg Neg N/A
`
`p-Methylbenzaldehyde
`
`1,4-Cyclohexanedimethanol
`
`104-87-0
`
`105-08-8
`
`400
`
`800
`
`LD50
`LDLO
`1,1-Diethoxyethane
`105-57-7
`500
`LD50
`i.p.
`mouse
`76
`10
`10
`10
`10
`3.50
`1
`Neg Neg Pos1
`aNo genotoxocity indicated based on studies in either rats, mice or hamsters, obtained from the CPDB (287).
`bNo genotoxicity indicated based on studies in rats and mice, obtained from the CPDB (287).
`⫽ 73 mg/kg/day in rats, 1600 mg/kg/day in mice.
`cTD50
`⫽ 23 mg/kg/day in rats, 210 mg/kg/day in mice.
`dTD50
`⫽ 1490 mg/kg/day in mice, no effect reported in rats.
`eTD50
`⫽ 3880 mg/kg/day in mice, no effect reported in rats.
`fTD50
`⫽ 1680 mg/kg/day in mice, no effect reported rats.
`gTD50
`hFrom the CCRIS database (287). Neg1 ⫽ negative Ames Salmonella typimurium test. Neg2 ⫽ negative Ames and
`Mouse Lymphoma tests. Pos1 ⫽ positive Ames or Mouse Lymphoma test. Pos2 ⫽ positive Ames and Mouse
`Lymphoma test. N/A ⫽ No test data available for that compound.
`iFrom Toxtree (3, 285) using Benigni/Biossa rulebase. A ⫽ considering genotoxic effects, B ⫽ considering
`non-genotoxic effects.
`jQSA11 rule triggered, simple aldehyde.
`kPotential S. triphimurium TA 100 mutagen; QAA 15 and QSA 27 rules triggered, isocyanate and isothiocyanate
`groups, primary aromatic amine, hydroxyl amine and its derived esters.
`lQSA41 rule triggered, substituted n-alkyl carboxylic acid.
`
`olated data are presented and certain trends or character-
`istics of
`the data are discussed. Additionally,
`the
`extractables have been considered in the context of in
`silico and in vitro methods for assessing their mutagenic
`potential.
`
`Experimental
`
`General
`
`The extractables considered within this document
`were obtained from analysis of components of pack-
`
`Vol. 68, No. 5, September–October 2014
`
`411
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 6
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`TABLE I
`(continued)
`
`Toxicological Information
`
`Compound
`
`Caprolactam
`
`3-Heptanone
`
`p-Xylene
`
`Acrylonitrile
`
`Ethylene glycol
`
`CAS
`Registry
`No.
`
`105-60-2
`
`106-35-4
`
`106-42-3
`
`107-13-1
`
`107-21-1
`
`Value, mg/kg
`
`Type
`
`Route
`
`Model
`
`Ref.
`
`300
`
`2760
`
`2000
`
`0.00004
`
`LD
`
`LD50
`LDLO
`EPA RfC
`
`i.v.
`
`oral
`
`i.p.
`
`rabbit
`
`rats
`
`mammal
`
`inhaled
`
`human
`
`0.09
`
`PDE
`
`N/A
`
`human
`
`77
`
`78
`
`79
`
`80
`
`81
`
`Toxicological Uncertainty Factors
`(UFs)
`
`T1,
`Inter-
`species
`
`T2,
`Intra-
`species
`
`T3,
`Route
`
`T4,
`Type
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`1
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`Risk
`Index
`(RI),
`mg/day
`
`21.0
`
`19.3
`
`14.0
`
`0.001
`
`0.63
`
`2.65
`
`Carcinogenicity
`Alerts
`
`Cramer
`Class
`
`In Silicog
`
`A
`
`B
`
`In
`Vitrof
`
`Neg Neg Neg2b
`
`Neg Neg N/A
`
`3
`
`2
`
`1
`
`3
`
`1
`
`1
`
`3-Methyl-2-butenal
`
`Butyric acid
`
`107-86-8
`
`107-92-6
`
`378
`
`500
`
`Methyisobutylketone
`
`108-10-1
`
`1.43
`
`3,5-Dimethylphenol
`
`Toluene
`
`108-68-9
`
`108-88-3
`
`156
`
`0.08
`
`0.127
`
`Cyclohexanol
`
`108-93-0
`
`272
`
`LD50
`LDLO
`PDE
`
`LD50
`EPA RfD
`
`PDE
`
`i.p.
`
`oral
`
`N/A
`
`i.p.
`
`oral
`
`N/A
`
`i.v.
`
`mouse
`
`mouse
`
`human
`
`mouse
`
`human
`
`human
`
`mouse
`
`rats
`
`82
`
`83
`
`11
`
`84
`
`85
`
`81
`
`86
`
`87
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`1
`
`1
`
`1
`
`10
`
`1
`
`10
`
`1
`
`1
`
`10
`
`1
`
`3.50
`
`10.0
`
`1.09
`
`0.056
`
`0.89
`
`19.0
`
`70.0
`
`1
`
`1
`
`1
`
`1
`
`2
`
`2
`
`Neg Neg Neg1
`Pos1c
`Neg Neg
`Neg Neg Neg2b
`Posi Neg N/A
`
`Neg Neg Neg1
`
`Neg Neg
`
`Pos1
`
`Neg Neg Neg1
`
`Neg Neg Neg1
`
`Neg Neg
`
`Cyclohexanone
`
`Phenol
`
`108-94-1
`
`108-95-2
`
`100
`
`112
`
`0.3
`
`3-Hydroxypyridine
`
`109-00-2
`
`200
`
`Butanoic acid, butyl
`ester
`
`109-21-7
`
`2300
`
`Pentanoic acid
`
`109-52-4
`
`1290
`
`Tetrahydrofuran
`
`109-99-9
`
`7.2
`
`LD50
`NOEL
`
`LD50
`EPA RfD
`
`TDLO
`
`LD50
`
`LD50
`PDE
`
`i.v.
`
`i.v.
`
`oral
`
`i.p.
`
`i.p.
`
`i.v.
`
`N/A
`
`oral
`
`mouse
`
`human
`
`mouse
`
`rats
`
`mouse
`
`human
`
`mouse
`
`88
`
`89
`
`90
`
`91
`
`92
`
`93
`
`94
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`10
`
`7.84
`
`0.21
`
`1.40
`
`16.1
`
`90.3
`
`50.4
`
`0.011
`
`1
`
`3
`
`1
`
`1
`
`3
`
`1
`
`Neg Neg Neg1
`Pos1b
`Pos1b
`
`Neg Neg
`
`Neg Neg N/A
`
`Neg Neg Neg1
`
`Neg Neg N/A
`Neg Neg Neg1e
`
`Neg Neg N/A
`
`Succinic acid
`
`110-15-6
`
`1.5
`
`1400
`
`Pentanal
`
`110-62-3
`
`5.66
`
`Tetramethylene glycol
`
`110-63-4
`
`2-Ethoxyethanol
`
`110-80-5
`
`10
`
`143
`
`900
`
`Pyridine
`
`110-86-1
`
`1.0
`
`TDLO
`LD50
`LD50
`TDLO
`TDLO
`LD50
`NOAEL
`
`i.v.
`
`oral
`
`oral
`
`oral
`
`i.v.
`
`oral
`
`mouse
`
`rats
`
`human
`
`human
`
`rabbit
`
`rats
`
`94
`
`95
`
`96
`
`97
`
`97
`
`98
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`98.0
`
`0.040
`
`0.70
`
`10.0
`
`63.0
`
`0.07
`
`1
`
`1
`
`1
`
`3
`
`i.v.
`
`rabbit
`
`99
`
`10
`
`10
`
`1
`
`10
`
`11.2
`
`3
`
`Posh Neg
`
`Pos1
`
`Neg Neg Neg1
`
`Neg Neg Neg1
`
`Neg Neg Neg2j
`Pos1b
`
`Neg Neg
`
`Piperidine
`
`110-89-4
`
`160
`
`TDLO
`300
`i.v.
`rabbit
`99
`10
`10
`1
`10
`21.0
`TDLO
`aNo genotoxocity indicated based on studies in either rats, mice or hamsters, obtained from the CPDB (286).
`bNo genotoxicity indicated based on studies in rats and mice, obtained from the CPDB (286).
`⫽ 17 mg/kg/day in rats, 6.3 mg/kg/day in mice.
`cTD50
`⫽ 3060 mg/kg/day in rats, no effect reported in mice.
`dTD50
`⫽ 407 mg/kg/day in rats, 1300 mg/kg/day in mice.
`eTD50
`fFrom CCRIS database (287). Neg1 ⫽ negative Ames Salmonella typimurium test. Neg2 ⫽ negative Ames and Mouse
`Lymphoma tests. Pos1 ⫽ positive Ames or Mouse Lymphoma test. Pos2 ⫽ positive Ames and Mouse Lymphoma test.
`N/A ⫽ No test data available for that compound.
`gFrom Toxtree (3, 285) using Benigni/Biossa rulebase. A ⫽ considering genotoxic effects, B ⫽ considering
`non-genotoxic effects.
`hQSA11 rule triggered, simple aldehyde.
`iQSA10 rule triggered, ␣, ␤-unsaturated carbonyls.
`⫽ 67 mg/kg/day in rats, 24 mg/kg/day in mice.
`jTD50
`
`aging systems, medical devices, and manufacturing
`systems and their associated materials of construc-
`tion. The extractables were revealed during the lab-
`oratory characterization of many and varied types of
`materials; thus, this list of extractables is a compi-
`lation of test results and is a fair representation of
`materials used throughout the pharmaceutical indus-
`
`try, especially the case of parenteral drug products.
`Therefore, any conclusions drawn from the data are
`considered to be applicable to, and relevant for,
`many plastics and polymeric materials used within
`the pharmaceutical industry, especially in the case
`of parenteral drug products. The database contained
`in this article reflects extractables for which rele-
`
`412
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 7
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`TABLE I
`(continued)
`
`Compound
`
`Pentanedioic acid
`
`Squalene
`
`CAS
`Registry
`No.
`
`110-94-1
`
`111-02-4
`
`Value,
`mg/kg
`
`2750
`
`1800
`
`Toxicological Information
`
`Type
`
`Route
`
`Model
`
`Ref.
`
`Toxicological Uncertainty Factors
`(UFs)
`
`T1,
`Inter-
`species
`
`T2,
`Intra-
`species
`
`T3,
`Route
`
`T4,
`Type
`
`oral
`
`i.v.
`
`rats
`
`mouse
`
`100
`
`101
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`Carcinogenicity
`Alerts
`
`Cramer
`Class
`
`In Silicog
`
`A
`
`B
`
`In
`Vitrof
`
`1
`
`1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`N/A
`
`Neg1
`
`Risk
`Index
`(RI),
`mg/day
`
`19.3
`
`126
`
`2-Octanone
`
`Heptanoic acid
`
`Sebacic acid
`
`1-Hexanol
`
`111-13-7
`
`111-14-8
`
`111-20-6
`
`111-27-3
`
`800
`
`1200
`
`500
`
`103
`
`i.p.
`
`i.v.
`
`i.p.
`
`mouse
`
`mouse
`
`mouse
`
`102
`
`103
`
`104
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`5.60
`
`84.0
`
`3.50
`
`7.21
`
`2
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`N/A
`
`Neg1
`
`Neg1
`
`LD50
`LD50
`LD50
`LD50
`LD50
`LD50
`TDLO
`
`Diethylene glycol
`
`111-46-6
`
`2236
`
`Octdecanoic acid, 2-
`hydroethyl ester
`
`111-60-4
`
`200
`
`LD50
`
`i.v.
`
`i.v.
`
`i.p.
`
`mouse
`
`rabbit
`
`mouse
`
`111-61-5
`
`5000
`
`LD50
`
`oral
`
`rats
`
`105
`
`106
`
`107
`
`108
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`157
`
`1.40
`
`35.0
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`N/A
`Neg1d
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`N/A
`
`Octadecanoic acid, ethyl
`ester
`
`Octadecenoic acid, ethyl
`ester
`
`1-Heptanol
`
`2-(1-Butoxy) ethanol
`
`111-62-6
`
`5000
`
`LD50
`
`111-70-6
`
`111-76-2
`
`256
`
`252
`
`oral
`
`i.p.
`
`i.v.
`
`rats
`
`rats
`
`rabbit
`
`109
`
`110
`
`111
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`35.0
`
`1.79
`
`17.6
`
`4.83
`
`1
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`N/A
`Neg1e
`
`Neg1
`
`Octanol
`
`111-87-5
`
`69
`
`Ethylethoxyethanol
`
`111-90-0
`
`1000
`
`Dibutyl amine
`
`Nonanoic acid
`
`111-92-2
`
`112-05-0
`
`167
`
`110
`
`224
`
`TDLO
`LD50
`LD50
`LDLO
`NOEL
`
`i.v.
`
`i.v.
`
`oral
`
`i.p.
`
`mouse
`
`cat
`
`pigs
`
`rats
`
`112
`
`113
`
`114
`
`115
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`1
`
`10
`
`70.0
`
`11.7
`
`0.77
`
`1
`
`3
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`N/A
`
`N/A
`
`2-(2-Ethoxyethoxy) ethyl
`acetate
`
`Triethylene glycol
`
`112-15-2
`
`112-27-6
`
`4400
`
`1900
`
`LD50
`LD50
`
`LD50
`
`i.v.
`
`oral
`
`i.v.
`
`mouse
`
`rabbit
`
`rabbit
`
`116
`
`117
`
`118
`
`119
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`10
`
`15.7
`
`30.8
`
`133
`
`5.95
`
`1
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`Neg
`
`Neg
`
`Neg1b
`
`Pos1
`
`2-(2-Butoxyethoxy)ethanol
`
`112-34-5
`
`Undecanoic acid
`
`Hexadecanoic acid, methyl
`ester
`
`112-37-8
`
`112-39-0
`
`LD50
`LD50
`LD50
`
`TDLO
`
`850
`
`140
`
`750
`
`i.p.
`
`i.v.
`
`i.v.
`
`mouse
`
`mouse
`
`mouse
`
`1-Dodecene
`
`112-41-4
`
`10000
`
`oral
`
`mouse
`
`390
`
`120
`
`121
`
`122
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`1
`
`10
`
`10
`
`10
`
`10
`
`9.80
`
`52.5
`
`70.0
`
`1
`
`1
`
`1
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`N/A
`
`Neg
`
`Neg
`
`N/A
`
`Dodecanol
`
`112-53-8
`
`TDLO
`LD50
`TDLO
`NOAEL
`
`8000
`
`100
`
`i.v.
`
`subq
`
`oral
`
`rats
`
`guinea pig
`
`rats
`
`123
`
`123
`
`124
`
`10
`
`10
`
`10
`
`10
`
`10
`
`10
`
`1
`
`10
`
`10
`
`10
`
`10
`
`1
`
`27.3
`
`56.0
`
`7.00
`
`1
`
`Neg
`
`Neg
`
`Neg1
`
`Dodecanal
`
`112-54-9
`
`23000
`
`oral
`
`rats
`
`125
`
`10
`
`10
`
`10
`
`10
`
`161
`
`1
`
`Posh Neg
`
`N/A
`
`LD50
`Tetraethylene glycol
`112-60-7
`200
`TDLO
`oral
`rats
`126
`10
`10
`10
`10
`1.40
`1
`Neg
`Neg
`N/A
`aNo genotoxocity indicated based on studies in either rats, mice or hamsters, obtained from the CPDB (286).
`bNo genotoxicity indicated based on studies in rats and mice, obtained from the CPDB (286).
`⫽ 1660 mg/kg/day in rats, no effect reported in mice.
`dTD50
`⫽ 1710 mg/kg/day in mice, 1300 mg/kg/day in rats.
`eTD50
`fFrom CCRIS database (287). Neg1 ⫽ negative Ames Salmonella typimurium test. Neg2 ⫽ negative Ames and Mouse
`Lymphoma tests. Pos1 ⫽ positive Ames or Mouse Lymphoma test. Pos2 ⫽ positive Ames and Mouse Lymphoma test.
`N/A ⫽ No test data available for that compound.
`gFrom Toxtree (3, 285) using Benigni/Biossa rulebase. A ⫽ considering genotoxic effects, B ⫽ considering
`non-genotoxic effects.
`hQSA11 rule triggered, simple aldehyde.
`
`vant toxicological data existed or could be inferred.
`Generally, extractables can be classified into two
`groups: (a) those extractables for which there is
`sufficient useful and credible published toxicologi-
`cal data to perform a rigorous safety assessment,
`and (b) those extractables for which there is insuf-
`ficient useful and credible toxicological data to per-
`form a rigorous safety assessment. In the case of the
`
`second group, the toxicology of some these extract-
`ables can be inferred through the use of surrogate
`compounds (e.g., compounds that are chemically
`and structurally similar to the extractable). This
`second group can be further subdivided into two
`sub-groups depending on the nature of the surro-
`gate. One sub-group consists of those extractables
`whose surrogates are themselves extractables from
`
`Vol. 68, No. 5, September–October 2014
`
`413
`
`Opiant Exhibit 2318
`Nalox-1 Pharmaceuticals, LLC v. Opiant Pharmaceuticals, Inc.
`IPR2019-00685, IPR2019-00688, IPR2019-00694
`Page 8
`
`

`

`Downloaded from
`
`on March 4, 2020
`
`TABLE I
`(continued)
`
`Compound
`
`Octadecenoic acid, methyl
`ester
`
`Tetradecanol
`
`Oleic acid
`
`Erucamide
`
`Toxicological Information
`
`CAS
`Registry
`No.
`
`Value, mg/kg
`
`Type
`
`Route
`
`Model
`
`Ref.
`
`Toxicological Unce