31066 Federal Register / Vol. 87, No. 98 / Friday, May 20, 2022 / Proposed Rules 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Parts 175, 176, 177, and 178 

[Docket No. FDA–2016–F–1253] 

Natural Resources Defense Council, et 

al.; Denial of Food Additive Petition; 

Denial Without Prejudice of Food 

Additive Petition 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Notification; denial of petition. 

SUMMARY: The Food and Drug 

Administration (FDA or we) is denying 

a food additive petition (FAP 6B4815) 

submitted by Natural Resources Defense 

Council, et al., requesting that we 

amend or revoke specified regulations to 

no longer provide for the food contact 

use of 28 ortho-phthalates. (We use the 

terms ‘‘phthalates’’ and ‘‘orthophthalates’’ interchangeably in this 

notification to refer to the subset of 

phthalates substituted in the ‘‘ortho’’ 

position). 

DATES: This notification is applicable 

May 20, 2022, except as to any 

provisions that may be stayed by the 

filing of proper objections. Submit 

either electronic or written objections 

and requests for a hearing on the 

document June 21, 2022. See Section V 

for further information on the filing of 

objections. 

ADDRESSES: You may submit objections 

and requests for a hearing as follows. 

Please note that late, untimely filed 

objections will not be considered. 

Electronic objections must be submitted 

on or before June 21, 2022. The https:// 

www.regulations.gov electronic filing 

system will accept objections until 

11:59 p.m. Eastern Time at the end of 

June 21, 2022. Objections received by 

mail/hand delivery/courier (for written/ 

paper submissions) will be considered 

timely if they are postmarked or the 

delivery service acceptance receipt is on 

or before that date. 

Electronic Submissions 

Submit electronic objections in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Objections submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

objection will be made public, you are 

solely responsible for ensuring that your 

objection does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

objection, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit an objection 

with confidential information that you 

do not wish to be made available to the 

public, submit the objection as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand Delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper objections 

submitted to the Dockets Management 

Staff, FDA will post your objection, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2016–F–1253 for ‘‘Natural Resources 

Defense Council, et al.; Denial of Food 

Additive Petition; Denial Without 

Prejudice of Food Additive Petition.’’ 

Received objections, those filed in a 

timely manner (see ADDRESSES), will be 

placed in the docket and, except for 

those submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 

a.m. and 4 p.m., Monday through 

Friday, 240–402–7500. 

• Confidential Submissions—To 

submit an objection with confidential 

information that you do not wish to be 

made publicly available, submit your 

objections only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ We 

will review this copy, including the 

claimed confidential information, in our 

consideration of comments. The second 

copy, which will have the claimed 

confidential information redacted/ 

blacked out, will be available for public 

viewing and posted on https://

www.regulations.gov. Submit both 

copies to the Dockets Management Staff. 

If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://

www.govinfo.gov/content/pkg/FR-2015- 

09-18/pdf/2015-23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Jessica Urbelis, Center for Food Safety 

and Applied Nutrition (HFS–275), Food 

and Drug Administration, 5001 Campus 

Dr., College Park, MD 20740, 240–402– 

5187; or Meadow Platt, Office of 

Regulations and Policy (HFS–024), 

Center for Food Safety and Applied 

Nutrition, Food and Drug 

Administration, 5001 Campus Dr., 

College Park, MD 20740, 240–402–2378. 

SUPPLEMENTARY INFORMATION: 

I. Introduction 

In a notice published in the Federal 

Register on May 20, 2016 (81 FR 31877), 

we announced that we filed a food 

additive petition (FAP 6B4815) 

(petition) submitted by Breast Cancer 

Fund (now Breast Cancer Prevention 

Partners), Center for Environmental 

Health, Center for Food Safety, Center 

for Science in the Public Interest, Clean 

Water Action, Consumer Federation of 

America, Earthjustice, Environmental 

Defense Fund, Improving Kids’ 

Environment, Learning Disabilities 

Association of America, and Natural 

Resources Defense Council, c/o Mr. 

Thomas Neltner, 1875 Connecticut Ave. 

NW, Suite 600, Washington, DC 20009. 

In the May 2016 notice, FDA requested 

comments on the petition. 

The petitioners initially requested 

that we amend or revoke specified food 

additive regulations under 21 CFR parts 

175, 176, 177, and 178, to no longer 

provide for the food contact uses of 30 

substances that the petition identified as 

ortho-phthalates. We filed this portion 

of the submission as a food additive 


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petition (81 FR 31877 at 31878). In 

addition, the petitioners requested that 

FDA amend regulations in 21 CFR part 

181 related to prior-sanctioned uses of 

five ortho-phthalates and issue a new 

regulation in 21 CFR part 189 

prohibiting the use of eight specific 

ortho-phthalates in food contact articles. 

We declined to file these portions of the 

submission as a food additive petition 

because those requests were not within 

the scope of a food additive petition (81 

FR 31877 at 31878). Consequently, those 

portions of the petition are not the 

subject of this notice. 

Following our May 20, 2016, 

announcement that we had filed the 

food additive petition, the petitioners 

provided supplementary information on 

October 8, 2016, and August 24, 2017 

(Supp., October 8, 2016, and Supp., 

August 24, 2017, respectively). Included 

in the October 8, 2016, response, the 

petitioners also requested that FDA 

remove two substances 

(diphenylguanidine phthalate (CAS Reg 

No. 17573–13–6) and di(2-ethylhexyl) 

hexahydrophthalate (CAS Reg No. 84– 

71–9)) from the petitioners’ original list 

of 30 substances, stating that they are 

not ortho-phthalates (Supp., October 8, 

2016). Consequently, the subject of the 

petition is limited to food additive 

regulations for 28 ortho-phthalates. 

The 28 subject ortho-phthalates are 

regulated as food additives under the 

Federal Food, Drug, and Cosmetic Act 

(FD&C Act). The FD&C Act authorizes 

us to regulate ‘‘food additives’’ (see 

section 409(a) of the FD&C Act (21 

U.S.C. 348(a))). The FD&C Act defines 

‘‘food additive,’’ in relevant part, as any 

substance the intended use of which 

results or may reasonably be expected to 

result, directly or indirectly, in its 

becoming a component of food or 

otherwise affecting the characteristics of 

any food (see section 201(s) of the FD&C 

Act (21 U.S.C. 321(s))). Food additives 

can include both substances added 

directly to food and indirectly and can 

also include ‘‘food contact substances.’’ 

‘‘Food contact substances’’ are 

substances intended for use in materials 

that come into contact with food, for 

instance in food packaging or 

manufacturing, but which are not 

intended to have any technical effect in 

the food (see § 170.3(e)(3) (21 CFR 

170.3(e)(3))). Food additives are deemed 

unsafe and prohibited except to the 

extent that we permit their use (see, e.g., 

sections 301(a), 301(k), and 409(a) of the 

FD&C Act (21 U.S.C. 331(a), 331(k), and 

348(a))). The FD&C Act provides a 

process through which persons who 

wish to use a food additive may submit 

a petition proposing the issuance of a 

regulation prescribing the conditions 

under which the additive may be safely 

used (see section 409(b)(1) of the FD&C 

Act). Such a petition is referred to as a 

‘‘food additive petition.’’ 

Under section 409(c)(3) of the FD&C 

Act, we will not establish a regulation 

for the use of a food additive if a fair 

evaluation of the data fails to establish 

that the proposed use of the food 

additive, under the conditions of use to 

be specified in the regulation, will be 

safe. Any food additive regulation that 

we issue authorizes a specific use of the 

substance. Our regulations, at § 170.3(i), 

define safety as a reasonable certainty in 

the minds of competent scientists that 

the substance is not harmful under the 

intended conditions of use. 

The FD&C Act provides that we must, 

by regulation, prescribe the procedure 

by which a food additive regulation may 

be amended or repealed (see section 

409(i) of the FD&C Act). Our regulation 

specific to the administrative actions for 

food additives provides that the 

Commissioner of Food and Drugs, on 

his own initiative or on the petition of 

any interested person, may propose the 

issuance of a regulation amending or 

repealing a regulation pertaining to a 

food additive (see § 171.130(a) (21 CFR 

171.130(a))). ‘‘When a food additive 

petition seeks to amend an existing 

regulation, the petitioner must include 

‘full information on each proposed 

change’ ’’ (In re Natural Resources 

Defense Council, 645 F.3d 400, 403 

(D.C. Cir. 2011) (quoting § 171.1 (21 CFR 

171.1))). Our regulation, at § 171.130(b), 

further provides that any such petition 

must include an assertion of facts, 

supported by data, showing that new 

information exists with respect to the 

food additive or that new uses have 

been developed or old uses abandoned, 

that new data are available as to toxicity 

of the chemical, or that experience with 

the existing regulation or exemption 

may justify its amendment or repeal. 

Under § 171.1(c), a petition must 

include full reports of investigations 

made with respect to the safety of the 

food additive. With respect to the 

showing that is required, a petition that 

seeks to amend or repeal existing 

regulations based on safety must contain 

sufficient data to establish the existence 

of safety questions significant enough to 

support a finding that there is no longer 

a reasonable certainty of no harm from 

the currently approved uses (see 

generally section 409(c) of the FD&C 

Act) (describing the data requirements) 

and §§ 171.1 through 171.130 (food 

additive petition regulations)). Should 

FDA determine that there is sufficient 

data to raise safety concerns, FDA 

ensures that these concerns are 

addressed or that substances are no 

longer used as food additives. The FD&C 

Act makes clear that food additives 

introduced into commerce must be 

shown to be safe (see generally sections 

402 (21 U.S.C. 342) and 409 of the FD&C 

Act). If FDA determines that a food 

additive is no longer safe, FDA will 

revoke the approval or otherwise ensure 

that the food additive is no longer in 

use. 

The petitioners requested that FDA 

amend parts 175, 176, 177, and 178 to 

no longer provide for the food contact 

use of 28 specified ortho-phthalates. 

The ortho-phthalates and corresponding 

regulations in parts 175, 176, 177, and 

178 are as follows: 

21 CFR 175.105 Adhesives 

Butyl benzyl phthalate (Chemical 

Abstract Service (CAS) No. 85–68–7), 

Butyl decyl phthalate (CAS No. 89–19– 

0), Butyl octyl phthalate (CAS No. 84– 

78–6), Butyl phthalyl butyl glycolate 

(CAS No. 85–70–1), Di(butoxyethyl) 

phthalate (CAS No. 117–83–9), Dibutyl 

phthalate (CAS No. 84–74–2), 

Dicyclohexyl phthalate (CAS No. 84– 

61–7), Di(2-ethylhexyl) phthalate (CAS 

No. 117–81–7), Diethyl phthalate (CAS 

No. 84–66–2), Dihexyl phthalate (CAS 

No. 84–75–3), Dihydroabietyl phthalate 

(CAS No. 26760–71–4), Diisobutyl 

phthalate (CAS No. 84–69–5), 

Diisodecyl phthalate (CAS No. 26761– 

40–0), Diisooctyl phthalate (CAS No. 

27554–26–3), Dimethyl phthalate (CAS 

No. 131–11–3), Dioctyl phthalate (CAS 

No. 117–84–0), Diphenyl phthalate 

(CAS No. 84–62–8), Ethyl phthalyl ethyl 

glycolate (CAS No. 84–72–0), Methyl 

phthalyl ethyl glycolate (CAS No. 85– 

71–2), Octyl decyl phthalate (CAS No. 

119–07–3), and Diallyl phthalate (CAS 

No. 131–17–9). 

21 CFR 175.300 Resinous and 

Polymeric Coatings 

Dibutyl phthalate (CAS No. 84–74–2), 

Diethyl phthalate (CAS No. 84–66–2), 

Diisooctyl phthalate (CAS No. 27554– 

26–3), Di(2-ethylhexyl) phthalate (CAS 

No. 117–81–7), Diisodecyl phthalate 

(CAS No. 26761–40–0), Butyl phthalyl 

butyl glycolate (CAS No. 85–70–1), and 

Ethyl phthalyl ethyl glycolate (CAS No. 

84–72–0). 

21 CFR 175.320 Resinous and 

Polymeric Coatings for Polyolefin Films 

Butyl phthalyl butyl glycolate (CAS 

No. 85–70–1), Diethyl phthalate (CAS 

No. 84–66–2), and Ethyl phthalyl ethyl 

glycolate (CAS No. 84–72–0). 


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21 CFR 176.170 Components of Paper 

and Paperboard in Contact With 

Aqueous and Fatty Foods 

Butyl benzyl phthalate (CAS No. 85– 

68–7), Dibutyl phthalate (CAS No. 84– 

74–2), Dicyclohexyl phthalate (CAS No. 

84–61–7), and Diallyl phthalate (CAS 

No. 131–17–9). 

21 CFR 176.180 Components of Paper 

and Paperboard in Contact With Dry 

Food 

Butyl benzyl phthalate (CAS No. 85– 

68–7) and Diallyl phthalate (CAS No. 

131–17–9). 

21 CFR 176.210 Defoaming Agents 

Used in the Manufacture of Paper and 

Paperboard 

Di(2-ethylhexyl) phthalate (CAS No. 

117–81–7). 

21 CFR 176.300 Slimicides 

Dibutyl phthalate (CAS No. 84–74–2), 

Didecyl phthalate (CAS No. 84–77–5), 

and Dodecyl phthalate (CAS No. 21577– 

80–0). 

21 CFR 177.1010 Acrylic and Modified 

Acrylic Plastics, Semirigid and Rigid 

Di(2-ethylhexyl) phthalate (CAS No. 

117–81–7) and Dimethyl phthalate (CAS 

No. 131–11–3). 

21 CFR 177.1200 Cellophane 

Castor oil phthalate with adipic acid 

and fumaric acid diethylene glycol 

polyester (CAS No. 68650–73–7), Castor 

oil phthalate, hydrogenated (FDA No. 

977037–59–4), Dibutyl phthalate (CAS 

No. 84–74–2), Dicyclohexyl phthalate 

(CAS No. 84–61–7), Di(2-ethylhexyl) 

phthalate (CAS No. 117–81–7), 

Diisobutyl phthalate (CAS No. 84–69– 

5), and Dimethylcyclohexyl phthalate 

(CAS No. 1322–94–7). 

21 CFR 177.1210 Closures With 

Sealing Gaskets for Food Containers 

Diisodecyl phthalate (CAS No. 26761– 

40–0). 

21 CFR 177.1460 MelamineFormaldehyde Resins In Molded 

Articles 

Dioctyl phthalate (CAS No. 117–84– 

0). 

21 CFR 177.1590 Polyester Elastomers 

Dimethyl phthalate (CAS No. 131–11– 

3). 

21 CFR 177.2420 Polyester Resins, 

Cross-Linked 

Butyl benzyl phthalate (CAS No. 85– 

68–7), Dibutyl phthalate (CAS No. 84– 

74–2), and Dimethyl phthalate (CAS No. 

131–11–3). 

21 CFR 177.2600 Rubber Articles 

Intended for Repeated Use 

Amyl decyl phthalate (CAS No. 7493– 

81–4), Dibutyl phthalate (CAS No. 84– 

74–2), Didecyl phthalate (CAS No. 84– 

77–5), Diisodecyl phthalate (CAS No. 

26761–40–0), Dioctyl phthalate (CAS 

No. 117–84–0), and Octyl decyl 

phthalate (CAS No. 119–07–3). 

21 CFR 178.3740 Plasticizers in 

Polymeric Substances 

Butyl benzyl phthalate (CAS No. 85– 

68–7), Dicyclohexyl phthalate (CAS No. 

84–61–7), Diisononyl phthalate (CAS 

No. 28553–12–0), Dihexyl phthalate 

(CAS No. 84–75–3), and Diphenyl 

phthalate (CAS No. 84–62–8). 

21 CFR 178.3910 Surface Lubricants 

Used in the Manufacture of Metallic 

Articles 

Diisodecyl phthalate (CAS No. 26761– 

40–0), Di(2-ethylhexyl) phthalate (CAS 

No. 117–81–7), and Diethyl phthalate 

(CAS No. 84–66–2). 

II. Evaluation of the Information 

Contained in the Petition 

The petition concludes that the 

authorized food contact uses for the 28 

specified ortho-phthalates no longer 

meet the safety standard of ‘‘reasonable 

certainty of no harm’’ and, therefore, the 

ortho-phthalates should no longer be 

authorized under the existing 

regulations. 

The petition is premised on three 

distinct assertions (which for ease of 

reference we refer to as Assertions A, B, 

and C). Assertion A claims that the 28 

subject ortho-phthalates are chemically 

and pharmacologically related and 

should therefore be treated as a class for 

purposes of evaluating their safety. 

Under Assertion B, the petition 

proposes applying a purported 

acceptable daily intake (ADI) for di(2- 

ethylhexyl) phthalate (DEHP) to all 28 

ortho-phthalates that are the subject of 

the petition (i.e., the petition proposes 

applying the proposed ADI to the entire 

purported class). Assertion C states that 

the estimated daily intake (EDI) for the 

asserted class of ortho-phthalates 

significantly exceeds the proposed ADI, 

thus rendering the purported class 

unsafe for their use as food contact 

substances. 

We address each assertion in turn. 

A. Assertion A: Ortho-Phthalates Are a 

Class of Chemically and 

Pharmacologically Related Substances 

for Purposes of Determining Safety 

Pursuant to Section 409 of the FD&C 

Act and § 170.18 (21 CFR 170.18) 

The petition asserts that all 28 

phthalates have similar chemical 

structures and similar or related 

pharmacological effects sufficient to be 

treated as one class of compounds for 

the purposes of evaluating the safety of 

these compounds. The petition states 

that such an approach would be 

consistent with section 409(c)(5)(B) of 

the FD&C Act, which directs FDA to 

consider, among other factors, the 

cumulative effect of an additive in the 

diet of man or animals, taking into 

account any chemically or 

pharmacologically related substance or 

substances in such diet, and § 170.18(a), 

which states that food additives that 

cause similar or related pharmacological 

effects will be regarded as a class, and 

in the absence of evidence to the 

contrary, as having additive toxic effects 

and will be considered as related food 

additives. 

1. Information Provided in the Petition 

To Support the 28 Ortho-Phthalates as 

Chemically Related Substances 

The primary document the petition 

relies on to support the proposed 

grouping of the 28 ortho-phthalates as 

chemically related substances is the 

Organization for Economic Co-operation 

and Development (OECD) guidance on 

Grouping Chemicals (Ref. 1). The 

petition states that the OECD guidance 

lists five underpinning rationales in the 

category approach and asserts that the 

28 ortho-phthalates ‘‘meet’’ two of the 

five rationales: (i) The common 

functional group rationale, and (iv) the 

likelihood of common precursors and/or 

breakdown products via physical or 

biological processes that result in 

structurally similar chemicals rationale. 

While we note that the OECD 

guidance does not establish criteria for 

chemical grouping (rather, it provides 

guidance on how to ensure that any 

chemical categories selected are 

sufficiently robust), in the discussion 

that follows we nevertheless address 

each of the OECD rationales adopted by 

the petition. 

2. FDA’s Evaluation of the Information 

Provided To Support the 28 OrthoPhthalates as Chemically Related 

Substances 

In support of the assertion that the 28 

ortho-phthalates ‘‘meet’’ rationale (i) of 

the OECD guidance (i.e., share a 

common functional group), the petition 

states that all 28 phthalates share a 

general 1,2-benzene diester chemical 

structural framework comprised of a 

benzene ring with two ester functional 

groups attached at adjacent carbons 

(referred to as ortho positions). A 

functional group is a part of an organic 

molecule that gives the molecule its 

characteristic physical and chemical 


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properties. The physical-chemical 

properties are one of many factors that 

may determine the toxicity of a 

substance for one or more given 

endpoints. Contrary to the petition’s 

assertion that there is a similar 

structural framework shared by all 28 

ortho-phthalates, we reviewed the 

chemical structures of the phthalates 

provided by the petitioner and 

determined that four of the 28 

phthalates do not contain the framework 

described by the petition (i.e., do not 

contain the framework of sharing a 

general 1,2-benzene diester chemical 

structural framework comprised of a 

benzene ring with two ester functional 

groups attached at adjacent carbons). 

Specifically, two compounds, 

dimethylcyclohexyl phthalate and 

dodecyl phthalate, contain only one 

ester side chain and are, therefore, 

considered mono- (not di-) esters of 1,2- 

benzenedicarboxylic acid and cannot be 

classified as ortho-phthalates. Two other 

phthalates (castor oil phthalate, 

hydrogenated and castor oil phthalate 

with adipic acid and fumaric aciddiethylene glycol) are polymeric in 

nature and, therefore, have many 

possible chemical structures (Ref. 3). 

Thus, the shared structural framework 

described in the petition is not, in fact, 

shared by these four ortho-phthalates. 

In addition, the petition does not 

address the structural differences in the 

ester side chains across the 28 

phthalates. Structural differences across 

substances may impact whether they 

share characteristic physical and 

chemical properties (i.e., whether they 

possess a ‘‘common functional group’’ 

for the purposes of risk assessment). It 

is not appropriate to group substances 

into a class for the purposes of risk 

assessment based merely on the 

assertion that they have a common 

functional group. Rather, the common 

functional group rationale should be 

supported with a discussion of any 

structural variations within that 

common functional group definition 

and an explanation of why the 

chemical-structural differences between 

members would not impact the 

suitability of the category for risk 

assessment. Notably, OECD guidelines 

state that when structural variations 

across a category impact functionality, 

inclusion of such variances in a category 

should be limited (Ref. 1). Across the 28 

phthalates, the number of carbon atoms 

in the ester side chains vary from one 

carbon atom (e.g., dimethyl phthalate 

(DMP)) to as many as 10 carbon atoms 

(e.g., diisodecyl phthalate (DIDP)). The 

ester side chains also differ by 

consisting of either branched or linear 

carbon chains, and varying degrees of 

saturation and oxidation (Ref. 3). 

Indeed, the chemical-structural 

differences of the side chains among the 

ortho-phthalates are associated with 

differences in physical-chemical 

properties (e.g., volatility). For example, 

phthalates with ester side chains with 

more than eight carbon atoms are 

generally less volatile than phthalates 

with ester side chains with eight or 

fewer carbon atoms. Also, phthalates 

that contain straight ester side chains 

are generally less volatile than their 

branched-chain counterparts. The 

petition does not discuss these 

structural differences nor does the 

petition discuss whether structural 

variances across substances would still 

allow for those substances to be grouped 

with a ‘‘common functional group’’ for 

the purposes of a risk assessment. The 

petition, therefore, does not provide 

adequate evidence to demonstrate that 

the asserted shared structural similarity 

(i.e., a benzene ring attached to two ester 

functional groups) is sufficient to group 

the 28 substances into a single class. 

The petition also cites FDA’s previous 

evaluation of long-chain perfluorinated 

compounds (PFCs) in support of 

utilizing the rationale of a common 

functional group to constitute the 28 

phthalates as a class of chemically 

related substances. FDA’s evaluation of 

long-chain PFCs was limited to a set of 

compounds with very specific structural 

similarities in their designated common 

functional group. Due to the structural 

similarity, and in the absence of 

contrary data, FDA determined that data 

demonstrating reproductive 

developmental toxicity for some longchain PFCs was applicable to the three 

long-chain PFCs under evaluation (81 

FR 5 at 7, January 4, 2016). Across the 

three compounds at issue in FDA’s 

action on long-chain PFCs, the only 

variance in the common functional 

group was the number of carbons in the 

linear perfluorinated alkyl chain. This 

contrasts with the 28 ortho-phthalates 

that are the subject of the current 

petition, where there are significant 

structural differences, and these 

differences result in large differences in 

chemical-structural properties (Refs. 3 

and 4). The classification of the subject 

ortho-phthalates as chemically related 

would not be akin to FDA’s previous 

evaluation of long-chain PFCs. 

With respect to the petition’s 

assertion that the ortho-phthalates 

subject to the petition ‘‘meet’’ rationale 

(iv) of the OECD guidance (i.e., share 

common precursors and/or breakdown 

products via physical or biological 

processes that result in structurally 

similar chemicals), the petition asserts 

that the ortho-phthalates share common 

metabolites and a common metabolic 

pathway (petition at 4). 

We address the assertion of common 

metabolites first. The petition provides 

a list of 10 ortho-phthalates and their 

metabolites to support the claim that 

there are common metabolites (Supp., 

August 24, 2017, at 3–4). However, the 

data provided in the petition only 

demonstrate one common metabolite 

shared by only two parent phthalates 

(Ref. 4). As the petitioners were only 

able to provide metabolic data 

pertaining to 10 of the 28 phthalates, 

and that data does not support that 

these 10 ortho-phthalates share common 

metabolites, this information does not 

support common metabolites for the 

other 18 phthalates or the group of 28 

phthalates as a whole. 

In addition, the petition discusses a 

common metabolic pathway as support 

for the assertion that the subject 28 

ortho-phthalates ‘‘meet’’ rationale (iv) of 

the OECD guidance. We note that 

rationale (iv) is not based on 

identification of shared steps in a 

metabolic pathway as described in the 

petition. Rather, the OECD guidance 

explains that this rationale is based on 

the applicability of data from a parent 

chemical to identify the hazards of its 

metabolites (or vice versa). The data 

between parent chemical and metabolite 

may be related because the toxicity 

induced by treatment with the parent 

chemical is likely due to the exposure 

to the metabolite(s). Likewise, under 

OECD rationale (iv), several different 

parent chemicals and their metabolite(s) 

could be considered as one class if a 

common metabolite is formed from 

these parent chemicals. Therefore, the 

assertion of a common metabolic 

pathway, without supporting 

information indicating that this pathway 

results in common metabolites, is not 

consistent with the approach to 

grouping in rationale (iv) of the OECD 

guidance. 

Furthermore, FDA does not agree that 

the petition has demonstrated that the 

subject ortho-phthalates share a 

common metabolic pathway. While the 

petition purports to identify three 

common steps associated with the 

metabolism of all 28 phthalates, it also 

acknowledges that not all 28 phthalates 

follow the purported metabolic pathway 

(see Supp., August 24, 2017). The 

petition notes that phthalates that lack 

longer alkyl side chains either do not or 

might not follow steps two (oxidation) 

or three (glucuronidation) of the 

purported common metabolic pathway 

(id. at 2). The data cited to support the 

list of 10 ortho-phthalates and their 

metabolites provided in the petition also 


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demonstrate that for four phthalates 

(dimethyl phthalate (DMP), diethyl 

phthalate (DEP), butyl benzyl phthalate 

(BBP), and dicyclohexyl phthalate 

(DCHP)), only primary (hydrolytic) 

metabolites and no secondary (oxidized) 

metabolites were identified (see Supp., 

August 24, 2017, at 3–4). These four 

phthalates therefore differ from other 

phthalates in both the metabolic 

pathway (only undergoing step one of 

three) and the resulting metabolites 

from that pathway. Similar trends 

between chain length and metabolism 

were also observed in the three 

biomonitoring articles cited in the 

petition, which identified excreted 

metabolites that may result from 

phthalate exposure. The phthalates with 

shorter side chain length (e.g., DMP, 

DEP, and BBP) exhibit hydrolytic 

monoesters as the major urinary 

metabolites; however, for phthalates 

with longer side chain length (e.g., 

DEHP, di-isononyl phthalate (DINP), 

and DIDP)), the hydrolytic monoesters 

are predominantly further metabolized 

before excretion in urine (Ref. 4). The 

existence of different metabolic 

pathways among phthalates is also 

demonstrated by a 2008 National 

Academy of Science (NAS) report (Ref. 

5). The NAS report notes that 

monoesters are the main detected 

metabolites of the low molecular weight 

phthalates, such as DEP and dibutyl 

phthalate (DBP). However, phthalate 

monoesters with five or more carbons in 

the ester side chain (i.e., not low 

molecular weight phthalates) are 

efficiently transformed further to 

oxidized metabolites arising mainly 

from oxidation at the terminal or 

penultimate carbon of the alkyl ester 

side chain. All of these examples 

demonstrate how the differences in 

chemical structure among phthalates 

studied give rise to differences in 

metabolism and resulting metabolites. 

In addition to side chain length and 

molecular weight, the other structural 

differences among the 28 orthophthalates described earlier in this 

subsection suggest that it is unlikely 

common metabolites and/or breakdown 

products exist for the purported class. 

Phthalates with ester side chains 

containing different structural elements 

(e.g., double bonds, bulky side chain, 

and extra ester linkage) can be expected 

to metabolize differently than phthalates 

with saturated ester side chains. For 

example, available information suggests 

steric hindrance of the bulky side chain 

of dihydroabietyl phthalate may prevent 

hydrolysis (which is usually the first 

step in the metabolic pathway for 

phthalates with straight/branched side 

chains). The bulky side chain may 

prevent hydrolysis by blocking the 

access of the esterases (which are the 

enzymes that perform this reaction) to 

the ester linkage, therefore reducing the 

likelihood of this reaction occurring 

(Ref. 1). Alternatively, methyl phthalyl 

ethyl glycolate (MPEG), ethyl phthalyl 

ethyl glycolate (EPEG), and butyl 

phthalyl butyl glycolate (BPBG) have 

extra ester linkages in their side chains 

that could subject them to an additional 

hydrolysis step and produce glycolyl 

phthalate (GP) that is not expected to 

generate from ortho-phthalates without 

the extra ester bond (e.g., DEHP) (Ref. 4). 

These examples further demonstrate 

how the chemical structure differences 

across these phthalates impact their 

metabolic pathway, and therefore result 

in different metabolites and/or 

breakdown products. 

As discussed earlier in this section, 

the petition does not support the 

assertion of a common metabolic 

pathway for the subject orthophthalates. Furthermore, data cited in 

the petition as well as other available 

information contradict the claim of a 

common metabolite or group of 

metabolites for all 28 ortho-phthalates. 

The petition therefore does not justify 

the applicability of rationale (iv) of 

OECD’s guidance for grouping 

chemicals to all 28 ortho-phthalates. 

3. Information Provided in the Petition 

To Support the 28 Ortho-Phthalates as 

Pharmacologically Related Substances 

In support of the proposed grouping 

of the 28 ortho-phthalates as 

pharmacologically related substances, 

the petition discusses the 2014 report 

from the Chronic Hazard Advisory 

Panel on Phthalates and Phthalate 

Alternatives (the CHAP report) (Ref. 6) 

and the results of a literature search for 

toxicological information that yielded 

information on health effects for 12 of 

the 28 phthalates. The petition asserts 

that these data demonstrate that 

‘‘[w]hen ortho-phthalates have been 

studied, similar or related 

pharmacological effects have been 

identified affecting children’s health’’ 

(petition at 5). The petition also states 

that ‘‘[r]eproductive, developmental, 

and endocrine toxicity effects were 

among the health endpoints identified 

for multiple compounds’’ (petition at 5). 

The petition asserts that ‘‘while the 

specific effects associated with orthophthalate exposure may vary among 

some studies, these effects nonetheless 

are pharmacologically related because 

they result from the effects of orthophthalates on the endocrine system’’ 

(Supp., August 24, 2017, at 6). The 

petition also asserts that the 12 

phthalates with available data have ‘‘at 

least some evidence of endocrine 

disruption’’ (id.) and that this 

information supports the conclusion 

that the 28 phthalates are therefore 

‘‘pharmacologically related by 

endocrine disrupting effects’’ (id. at 13). 

4. FDA’s Evaluation of the Information 

Provided To Support the 28 OrthoPhthalates as Pharmacologically Related 

Substances 

In asserting that the 28 orthophthalates constitute a class of 

pharmacologically related substances 

for purposes of determining safety, the 

petition states that ‘‘eleven orthophthalate have reproductive, 

developmental and endocrine health 

effects.’’ The petition further points to 

‘‘adverse effects on endpoints relevant 

to children’s health,’’ as summarized in 

table 1, that the petition characterizes as 

showing ‘‘similar toxic effects.’’ 

However, reproductive, developmental, 

and endocrine effects are broad 

categorizations that cover a wide range 

of toxicological effects that are not 

necessarily similar and can be caused by 

a variety of different mechanisms. The 

petition’s generalized assertion that all 

of the cited effects are 

pharmacologically related because they 

‘‘result from the effects of orthophthalates on the endocrine system’’ 

(Supp., August 24, 2017, at 6) does not 

acknowledge that the endocrine system 

is a generic term that encompasses 

multiple organs and multiple hormonal 

pathways. A substance that exhibits 

activity in one hormonal pathway may 

not have any effect on a different 

hormonal pathway, and disruption of 

different hormonal pathways may not 

result in common health outcomes (Ref. 

4). 

The petition’s assertion that all 

studied ortho-phthalates demonstrate 

similar effects on the endocrine system 

is also directly contradicted by data 

cited in the petition (see Supp., August 

24, 2017). One of the most commonly 

studied pharmacological effects for 

phthalates is antiandrogenicity; 

antiandrogens affect the endocrine 

system by modulating the production of 

testicular testosterone pertaining to the 

development of the male reproductive 

system. The data cited in the 

petitioners’ literature search indicates 

that, among the 12 phthalates with 

available toxicological information, 7 

phthalates exhibit antiandrogenic effects 

(i.e., butyl benzyl phthalate (BBP), 

diisobutyl phthalate (DiBP), DBP, 

dicyclohexyl phthalate (DCHP), dihexyl 

phthalate (DHP), DEHP, and diisononyl 

phthalate (DINP)) (see Supp., August 24, 

2017, Appendix B). Importantly, four of 


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the phthalates (i.e., dimethyl phthalate 

(DMP), diethyl phthalate (DEP), di-noctyl phthalate (DnOP), and DiDP) have 

been shown to not exhibit 

antiandrogenic effects. As the 

petitioners provide data for only 12 of 

the 28 ortho-phthalates, and those data 

do not support the 12 ortho-phthalates 

as having similar pharmacologicaleffects on the endocrine system, this 

information does not support that the 

remaining 16 ortho-phthalates also 

exhibit similar pharmacological effects 

(see Supp., August 24, 2017). Similarly, 

the data do not support the notion that 

the group of 28 ortho-phthalates as a 

whole consists of phthalates with 

similar pharmacological effects (see Ref. 

4). 

Furthermore, the petition’s approach 

to class grouping is not consistent with 

the approach taken by other regulatory 

and scientific bodies. Other regulatory 

and scientific bodies have not grouped 

phthalates based on broad criteria such 

as non-specific effects on the endocrine 

system. Instead, other regulatory and 

scientific bodies have focused on 

common health outcomes that result 

from a discrete mechanism of action. 

Specifically, reports from regulatory or 

scientific bodies cited in the petition 

(i.e., the 2014 CHAP report and the NAS 

report) as well as other reviews 

conducted by OECD (Ref. 7), the 

European Food Safety Authority (EFSA) 

(Ref. 8), and the Government of Canada 

(Ref. 9), grouped small subsets of orthophthalates for cumulative risk 

assessment based on specific related 

health (i.e., pharmacological) effects. 

These assessments relied on defined 

toxicological endpoints with a common 

mechanism of action to conduct 

grouping, and also relied on specific 

and well-defined similarities in 

chemical structure. For example, the 

CHAP report concluded that phthalates 

with three to eight carbon atoms in the 

backbone of the alkyl side chain have 

the same endpoint of antiandrogenicity, 

while phthalates with alkyl side chains 

having carbon atoms outside of this 

range are not antiandrogenic and 

therefore should not be considered in 

the same class for a safety assessment 

(Ref. 6). The CHAP report did not group 

together these different categories of 

phthalates. Similarly, the NAS report 

noted that phthalates with ester chains 

of four to six carbon atoms are most 

potent in causing effects on the 

development of the male reproductive 

system (i.e., antiandrogenicity), but 

phthalates with shorter or longer chains 

typically exhibit less severe or no effects 

(see Ref. 5). While the petition states 

that the NAS report ‘‘recommends that 

effects of ortho-phthalates should be 

considered additive’’ (petition at 6), the 

relevant point in the NAS report only 

pertains to those ortho-phthalates that 

cause common adverse outcomes of 

antiandrogenicity (Ref. 5). The NAS 

report similarly did not group together 

the different categories of phthalates. 

Additionally, a 2004 OECD report 

grouped phthalates for the purpose of 

assessing human health and ecotoxicity 

endpoints but only did so with respect 

to seven high molecular weight 

phthalates consisting of esters with an 

alkyl carbon backbone with seven 

carbon atoms or greater. OECD noted 

that the seven phthalates in the group 

produce little (if any) effects of 

developmental or reproductive toxicity, 

and only phthalates with alkyl carbon 

backbones of four to six carbon atoms 

cause adverse effects in development 

and reproduction (Ref. 4). 

Since the petition was filed, EFSA 

and the Government of Canada also 

conducted their own assessments of 

phthalates. Both regulatory bodies 

grouped phthalates using defined 

toxicological endpoints. EFSA 

considered five ortho-phthalates 

commonly used in food contact 

materials, but only grouped four based 

on the common mechanism of fetal 

testosterone reduction and excluded the 

fifth (i.e., DIDP) due to not sharing this 

effect (Ref. 8 at 1). The Government of 

Canada conducted a ‘‘screening 

assessment’’ of 28 ortho-phthalates but 

only grouped those with ester sidechains of three to seven carbons for the 

purposes of cumulative risk assessment 

based on the observation of 

antiandrogenic effects for this group 

(Ref. 9 at 7). Thus, the approach 

proposed in the petition (i.e., grouping 

a large number of phthalates together 

despite data showing that those 

phthalates do not share the same toxic 

endpoints), is not consistent with the 

approach taken in the scientific 

literature, including reports cited in the 

petition. The petition also cites FDA’s 

previous decision on PFCs as support 

for grouping the 28 ortho-phthalates as 

pharmacologically related substances. 

As discussed previously in section 

II.A.2, our grouping of long-chain PFCs 

was limited to a strict subset of 

structurally similar compounds, 

distinguishable from the wide structural 

differences in the 28 ortho-phthalates 

that are the subject of the current 

petition. 

The petition also specifically invokes 

§ 170.18 as support for its proposed 

class grouping approach. In accordance 

with § 170.18(a), food additives that 

cause similar or related pharmacological 

effects will be regarded as a class, and 

in the absence of evidence to the 

contrary, as having additive toxic effects 

and will be considered as related food 

additives. Our regulation, at § 170.18(b), 

states that tolerances established for 

such related food additives may limit 

the amount of a common component 

that may be present or may limit the 

amount of biological activity that may 

be present, or may limit the total 

amount of related food additives that 

may be present. Section 170.18(c) 

provides that where food additives from 

two or more chemicals in the same class 

are present in or on a food, the tolerance 

for the total of such additives shall be 

the same as that for the additive having 

the lowest numerical tolerance in this 

class, unless there are available methods 

that permit quantitative determination 

of the amount of each food additive 

present or unless it is shown that a 

higher tolerance is reasonably required 

for the combined additives to 

accomplish the physical or technical 

effect for which such combined 

additives are intended and that the 

higher tolerance will be safe 

(§ 170.18(c)). 

The petition asserts that § 170.18 is 

applicable to the evaluation of the 28 

ortho-phthalates subject to the petition. 

Specifically, the petition asserts that the 

toxicokinetic and toxicodynamic 

properties of the ortho-phthalates ‘‘may 

be comparable’’ and ‘‘similar or related 

pharmacological effects have been 

identified affecting children’s health.’’ 

The petition further states that 

‘‘[r]eproductive, developmental and 

endocrine toxicity effects were among 

the health endpoints identified for 

multiple compounds and at low 

exposure.’’ Based on what the petition 

describes as ‘‘similar toxicity effects’’ 

from 13 ortho-phthalates, the petition 

states that ortho-phthalates are 

‘‘pharmacologically related food 

additives for purposes of 21 CFR 

170.18.’’ (Note that the August 2017 

supplement refers to data only for 12 

ortho-phthalates). Further, the petition 

states that ‘‘we found several 

publications reporting on additive 

mixtures of four and five orthophthalates on developmental and 

reproductive endpoints’’ and that the 

NAS report ‘‘recommends that effects of 

ortho-phthalates should be considered 

additive’’ (petition at 6). 

The petition has not demonstrated 

that § 170.18 is applicable because the 

petition has not shown that the 28 

ortho-phthalates cause similar or related 

pharmacological effects. By its terms, 

§ 170.18 only provides that food 

additives are to be regarded as a class 

if it has been shown that the food 

additives cause similar or related 


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pharmacological effects. However, as 

the petitioners concede, they only have 

submitted data on the effects of 12 of the 

28 ortho-phthalates that are the subject 

of the petition and have not submitted 

data addressing the effects of 16 of the 

28 ortho-phthalates. Furthermore, as 

discussed in the previous paragraphs, 

the data for the 12 phthalates provided 

by the petition do not demonstrate that 

all 12 phthalates have similar or related 

pharmacological effects; therefore, this 

data also does not support that all 28 

ortho-phthalates have similar or related 

pharmacological effects. Thus, the 

petition has not put forward the 

threshold evidence that is necessary to 

apply § 170.18. 

In arguing for grouping all 28 

phthalates into one class, the petition 

also points to section 409(c)(5)(B) of the 

FD&C Act. The FD&C Act provides that 

a food additive cannot be approved for 

use unless the data presented to FDA 

establish that the food additive is safe 

for that use (section 409(c)(3)(A) of the 

FD&C Act). To determine whether a 

food additive is safe, section 409(c)(5) of 

the FD&C Act requires FDA to consider 

among other relevant factors the 

following: (1) Probable consumption of 

the additive; (2) the cumulative effect of 

such additive in the diet of man or 

animals, taking into account any 

chemically or pharmacologically related 

substance or substances in such diet; 

and (3) safety factors recognized by 

experts as appropriate for the use of 

animal experimentation data (section 

409(c)(5) of the FD&C Act). As a 

preliminary matter, the petition has not 

presented evidence to show that section 

409(c)(5)(B) of the FD&C Act is even 

applicable to the proposed class 

grouping. With respect to section 

409(c)(5)(B) of the FD&C Act, we note as 

a preliminary matter that the petition 

has not presented sufficient evidence to 

show that all 28 ortho-phthalates are in 

fact chemically or pharmacologically 

related substances (see discussion in the 

previous paragraphs). As an additional 

matter, we note that section 409(c)(5)(B) 

of the FD&C Act does not direct FDA to 

group food additives in a class in the 

manner proposed in the petition. If it is 

established that substances are 

chemically or pharmacologically related 

to a food additive under consideration, 

FDA is directed to ‘‘tak[e] into account’’ 

such substances in considering the 

cumulative effect of the food additive in 

the diet of man or animals. Chemically 

or pharmacologically related substances 

can be taken into account for this 

purpose in any number of scientifically 

valid ways that are distinct from the 

class grouping approach proposed by 

the petition (e.g., considering 

chemically related substances in an 

exposure analysis or considering 

toxicity data from one 

pharmacologically related substance to 

evaluate possible toxic effects of another 

pharmacologically related substance, as 

appropriate). To the extent that the 

petition interprets section 409(c)(5) of 

the FD&C Act to compel FDA to adopt 

the petition’s approach to class 

grouping, the petition is incorrect. The 

petition proposes grouping a chemically 

diverse group of substances together, 

applying a proposed ADI value for one 

substance to all the substances in the 

purported class, and comparing the 

exposure of all the substances against 

that single proposed ADI. The FD&C Act 

sets forth no requirement to analyze the 

safety of a food additive in this manner. 

5. Conclusion for Assertion A: OrthoPhthalates Are Not a Class of 

Chemically and Pharmacologically 

Related Substances for Purposes of 

Determining Safety Pursuant to Section 

409 of the FD&C Act and § 170.18 

After our review of the relevant 

information, we conclude that the 

petition’s arguments for treating the 28 

ortho-phthalates as a class are not 

supported. The petition points to two 

rationales in the OECD guidance to 

support its argument but fails to 

demonstrate that grouping all 28 

phthalates is in fact consistent with 

those rationales. The 28 phthalates do 

not have a common functional group, do 

not have similar or related 

pharmacological effects, do not share a 

‘‘common metabolic pathway’’ or even a 

common mechanism of action, and do 

not have effects on the same or similar 

target or system (i.e., the reproductive 

system of male rodents). To the extent 

the petition suggests that the proposed 

class grouping is required by section 

409(c)(5)(B) of the FD&C Act and/or 

§ 170.18, the petition is incorrect. 

B. Assertion B: The ADI for DEHP 

Should Be Assigned to All 28 OrthoPhthalates 

To establish with reasonable certainty 

that a food additive is not harmful 

under its intended conditions of use, 

FDA considers the projected human 

dietary exposure to the food additive, 

the additive’s toxicological data, and 

other available relevant information 

(such as published literature). To 

determine safety, one approach FDA 

may utilize is to compare the EDI of the 

food additive to an ADI level 

established by appropriate toxicological 

data. Following the argument contained 

in Assertion A that all 28 phthalates 

should be grouped as a single class, the 

petition asserts that a single ADI should 

be established for the class and also 

asserts that the ADI should be used to 

set the upper exposure limit for 

cumulative exposure to all 28 

phthalates. 

1. Information Provided in the Petition 

To Support Assertion B 

To establish a proposed ADI for all 28 

ortho-phthalates, the petition cites no 

observed adverse effect levels (NOAELs) 

for specific phthalates that are 

published in a variety of sources. The 

petition then picks a NOAEL for DEHP 

as the basis to derive an ADI for the 

purported class because it is the lowest 

of the listed NOAEL values. The 

petition then proposes safety factors to 

be applied to that NOAEL to derive the 

proposed ADI. In the discussion that 

follows, we evaluate the petition’s 

approach for deriving the proposed ADI 

for DEHP, as well as the applicability of 

the proposed ADI to all 28 phthalates. 

2. FDA’s Evaluation of the Information 

Provided To Support Assignment of the 

ADI for DEHP to All 28 OrthoPhthalates 

An ADI is the amount of a substance 

that is considered safe to consume each 

day over the course of a person’s 

lifetime (Ref. 10). The ADI is typically 

based on an evaluation of toxicological 

studies to determine the highest 

appropriate experimental exposure dose 

level in animal studies that was shown 

to cause no adverse effect (also known 

as the no-observed-adverse-effect level, 

or NOAEL), multiplied by an 

appropriate safety factor (Ref. 10). 

Accordingly, the lower the NOAEL for 

a specific substance, the lower the 

resulting ADI for the substance. A 

calculated dietary exposure to the food 

additive (i.e., the estimated daily intake, 

or EDI) at or below the ADI is 

considered consistent with a reasonable 

certainty of no harm (Ref. 10). 

Therefore, a lower ADI requires a lower 

dietary exposure to the food additive to 

meet the burden of safety than a food 

additive with a higher ADI. 

To establish a proposed ADI for all 28 

phthalates, the petition identifies 

NOAELs for nine phthalates that are 

included in the 2014 CHAP report. The 

petition also identifies NOAELS for 15 

phthalates that are included in the 1973 

paper by Shibko, et al. (the 1973 paper, 

Ref. 2). Together, this makes for a total 

of 24 NOAEL values for 17 different 

phthalates. The petition does not 

provide NOAEL values for the 

remaining 11 phthalates that are the 

subject of the petition. The petition 

adopts the NOAEL provided for DEHP 

in the 2014 CHAP report because it was 


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the lowest of the cited values. To 

calculate the ADI, the petition applies a 

total safety factor of 1,000 to the cited 

NOAEL for DEHP, resulting in a 

proposed ADI of 3 micrograms per 

kilogram of body weight per day (mg/kg 

bw/d) (petition at 11). However, the 

petition fails to provide any discussion 

or supplementary information to justify 

why any of these NOAEL values are 

appropriate for assessing risk of dietary 

exposure to ortho-phthalates. 

Our regulation, at § 171.1(c), requires 

that a petition provide full reports of 

investigations made with respect to the 

safety of a food additive and not omit, 

without explanation, any reports of 

investigations that would bias an 

evaluation of the safety of the food 

additive. Such information is necessary 

so that FDA can independently evaluate 

and verify the relevant evidence. 

However, the petition merely lists 

values published in the CHAP report 

and the 1973 paper and does not 

evaluate the underlying evidence 

supporting the NOAEL values listed in 

those publications. Although the CHAP 

report is the result of considerable 

scientific analysis, it was not designed 

to assess the safety of food additive uses 

and does not provide a comprehensive 

discussion of evidence that would be 

sufficient to permit FDA to 

independently evaluate the evidence 

used to determine the NOAELs (Refs. 10 

and 11). Similarly, the 1973 paper 

provides only a truncated summary of 

literature available at the time of 

publication. Furthermore, the NOAELs 

in the 1973 paper were derived from 

either subacute or chronic animal 

studies, which only tested phthalates in 

weanling animals. These studies have 

limitations to assess antiandrogenicity 

as an endpoint (Refs. 4 and 6) and 

therefore are not appropriate to 

determine NOAELs for those phthalates 

that are known antiandrogens. Most 

importantly, the petition does not 

provide additional information that 

would allow FDA to fill the gaps. 

Typically, to determine appropriate 

NOAEL values, FDA considers a wide 

array of information, including the 

results of a comprehensive literature 

search, so that we can evaluate the most 

relevant studies and their methods, 

determine the most appropriate 

endpoint(s), and consider the 

appropriateness of the animal species 

selected for study (Refs. 10 and 11). 

However, the petition provides no such 

wide array of information with respect 

to the NOAEL. Rather, the petition 

merely lists the NOAEL value that is 

included in the CHAP report. The 

petition does not explain why this 

NOAEL for DEHP is appropriate for 

human risk assessment of dietary 

exposure. FDA is aware of the existence 

of studies on DEHP in non-human 

primates that identify NOAELs based on 

testicular effects that are at least two 

orders of magnitude higher than the 

level derived from studies conducted in 

rats cited by the petitioners (Refs. 12 to 

15). Results in primates are generally 

considered more applicable to human 

risk assessment than results in rats, and 

these non-human primate studies were 

not included in the assessment in the 

CHAP report. As the petition does not 

address these studies or others that may 

impact the appropriateness of the cited 

NOAEL for human risk assessment of 

exposure to DEHP itself, the petition has 

not provided an adequate scientific 

rationale to justify the selected NOAEL 

for DEHP. Thus, the information 

submitted in the petition does not 

amount to a full report of investigations 

made with respect to safety, as required 

by § 171.1(c), and the petition has not 

provided adequate scientific 

justification for the proposed NOAEL 

for DEHP. 

In addition to lacking sufficient 

support for the appropriateness of the 

selected NOAEL for evaluation of DEHP 

itself, the petition also lacks scientific 

support to justify applying the cited 

NOAEL for DEHP to all 28 orthophthalates. Although the petition cites 

the 1973 paper in support of applying 

a single substance’s ADI to a group of 

phthalates, that paper discussed this 

approach based on the assumption that 

the toxicity for an ortho-phthalate may 

be related to the toxicity of the alcohol 

moiety (which is not antiandrogenic). 

The paper describes the alcohol moiety 

as a common metabolite for these 

substances, when in fact more current 

scientific information does not support 

that all 28 phthalates share a common 

metabolite. Accordingly, the 

recommendation in the 1973 paper is 

based on a scientific assumption that 

has since been contradicted. The 1973 

paper therefore does not support the 

petition’s requested action. 

Furthermore, the petition’s proposed 

NOAEL for DEHP is based on an 

antiandrogenic endpoint. Recent 

scientific data, including information 

contained in the petition, demonstrate 

that not all phthalates are 

antiandrogenic. Recent data also 

demonstrate that antiandrogenicity may 

not be the most sensitive endpoint for 

all 28 ortho-phthalates, including some 

which also demonstrate 

antiandrogenicity (Ref. 4). NOAELs 

serve to identify the highest dosages of 

a particular substance in which toxic 

effects were not observed, but a NOAEL 

is not useful for determining safe 

exposure levels if it is not in fact based 

on toxic effects that may result from the 

substance. Also, as discussed in our 

response to Assertion A, the petition has 

not provided sufficient information to 

demonstrate that the pharmacological 

effects for all 28 ortho-phthalates are 

similar or related. Therefore, it is not 

appropriate to apply a NOAEL based on 

the effect of antiandrogenicity to 

substances that are not antiandrogenic. 

In addition, with respect to converting 

the NOAEL to an ADI, the petition has 

not sufficiently supported the 

application of additional safety factors 

to the proposed NOAEL. In general, the 

use of a safety factor is intended to 

provide an adequate margin of safety for 

consumers by accounting for variability, 

such as differences between animals 

and humans (i.e., interspecies 

variability) and differences in sensitivity 

among humans (i.e., intraspecies 

variability) (Ref. 10). In accordance with 

§ 170.22, a safety factor of 100 will be 

used as a general rule in applying 

animal test data for the purposes of 

safety assessment for human consumers. 

However, exceptions to a safety factor 

of 100 are permitted in accordance with 

the nature and extent of data available 

and the circumstances of use of the food 

additive. For reproductive and 

developmental endpoints, FDA 

recommends the use of a safety factor of 

1,000 if the observed effects are severe 

or irreversible (e.g., decrease in the 

number of pups born live) (Ref. 10). 

Otherwise, FDA recommends a safety 

factor of 100. Additional adjustments 

may be appropriate when considered on 

a case-by-case basis (Refs. 4 and 11). 

The petition proposes dividing the cited 

NOAEL for DEHP by a safety factor of 

1,000 to derive the proposed ADI. In 

support of the application of an 

additional 10x safety factor for the 

severity of effects, the petition makes a 

general assertion that ‘‘developmental, 

reproductive and endocrine toxicity 

effects observed after prenatal and 

postnatal exposure also represent severe 

findings due to their likely 

irreversibility’’ (Supp., August 24, 2017, 

at 9). Because the petition does not 

provide critical information about the 

studies (e.g., study design, animal 

species, animal numbers, dosing regime, 

dosing duration, examined endpoints, 

and statistical methods) to support the 

selected NOAEL for DEHP, the petition 

fails to adequately justify an exception 

to a safety factor of 100. This absence of 

information means that the proposed 

ADI for DEHP lacks scientific 

justification. 


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3. Conclusion for Assertion B: The ADI 

Proposed in the Petition Should Not Be 

Assigned to All 28 Ortho-Phthalates 

The petition has not provided the 

requisite information for either the 

selected NOAEL or the proposed ADI 

for DEHP. Similarly, the petition has not 

justified the application of the proposed 

ADI for DEHP to all 28 phthalates. To 

the extent that the petition relies on 

§ 170.18 for applying a single ADI to all 

28 phthalates, there is no support for 

such an approach because, as discussed 

in section II.A, the petition has not 

demonstrated that the criteria in 

§ 170.18 for treating food additives as a 

class are met. 

C. Assertion C: The EDI for OrthoPhthalates Exceeds the Proposed ADI 

and, Therefore, the Intentional Use of 

Ortho-Phthalates as Food Contact 

Substances Are Not Safe 

The argument in Assertion C is 

predicated on the underlying premise of 

the petition (i.e., the establishment of a 

single class for all 28 phthalates). The 

petition asserts that certain published 

dietary exposure estimates for several of 

the individual subject phthalates, as 

well as the cumulative exposure to all 

28 phthalates, significantly exceeds the 

ADI proposed in the petition for the 

purported class. From this comparison 

between published dietary exposure 

estimates and the proposed ADI, the 

petition states that ‘‘the intentional use 

of ortho-phthalates as food contact 

substances are not safe as defined by 

FDA’s regulations’’ (petition at 11). 

1. Information Provided in the Petition 

To Support Assertion C 

The petition concedes that it does not 

provide exposure data for all 28 orthophthalates, asserting that a cumulative 

exposure to all 28 phthalates cannot be 

determined based on the limited 

information available (see petition at 

14). Instead, the petition compares 

estimated exposures to individual 

phthalates for specific subpopulations 

(as reported in various published data 

sources) to the proposed ADI for the 

purported class. Specifically, the 

petition asserts that the following 

dietary exposures are all greater than the 

proposed ADI for the purported class: 

The average women’s dietary exposures 

to DINP and DIDP, as estimated in the 

CHAP report; the 95th percentile 

exposure for women to DEHP, as listed 

in the CHAP report; and the infant 

exposure to DEHP, as listed in a 2013 

publication by Schecter et al. (Ref. 16). 

Turning to biomonitoring data, the 

petition also relies on this type of data 

to assert that the following additional 

exposures exceed the proposed ADI: 

The median and 95th percentile 

exposures for pregnant women and 

women of reproductive age to DEHP; 

and the 95th percentile exposures for 

pregnant women and women of 

reproductive age to DBP and DINP. This 

biomonitoring data comes from National 

Health and Nutrition Examination 

Survey (NHANES) survey results 

covering different years. 

We have previously discussed in 

sections II.A and II.B that the petition 

does not demonstrate that all 28 

phthalates should be considered as a 

single class, and that the petition does 

not demonstrate that the proposed ADI 

for DEHP should be applied to the 

purported class. Therefore, our 

discussion below is not focused on 

comparing published exposure 

estimates for members of a purported 

ortho-phthalate class to a proposed ADI 

for that purported class. Rather, our 

discussion below evaluates the 

relevance of the cited data for estimating 

U.S. dietary exposure. 

2. FDA’s Evaluation of the Information 

Provided To Support Assertion C 

Food surveys, total diet studies, and 

human biomonitoring studies can all be 

part of an appropriate postmarket 

approach to determine dietary exposure 

for a substance that is already 

authorized for use as a food contact 

substance. However, many factors 

should be addressed to determine the 

suitability of any given dataset for 

determining dietary exposure. These 

factors can include suitability of sample 

preparation and data analysis, relevance 

of the data to the current market, 

specific population or geographic 

region, and whether it is sufficiently 

robust in both sample breadth (number 

of different types of foods sampled) and 

size (number of samples within a given 

food type) to be representative. In 

determining sample breadth, it may be 

appropriate to consider dietary exposure 

from a number of sources, such as uses 

that are authorized through the food 

contact notification process or food 

additive regulations and uses that are 

determined to be generally recognized 

as safe. Rather than analyze the 

relevance or suitability of the data cited, 

the petition simply lists any reported 

value from any dataset that is higher 

than the proposed ADI for the purported 

class. 

In general, dietary exposure values for 

a substance can be calculated using the 

level of the substance in food (taken 

from food surveys) and the daily food 

consumption rate (taken from food 

categorization systems). Food 

categorization systems divide the daily 

diet into distinct food types. This allows 

for surveying consumption of individual 

foods within those food types to be 

representative of exposure from overall 

consumption of those types of foods by 

the consumer. Food categorization 

systems provide for a tiered grouping of 

foods first based on a broad category 

(i.e., aquatic animals, land animals, 

plants, and other) all the way down to 

differences in processing (e.g., 

pasteurized or not pasteurized). These 

subdivisions allow for assignment of 

foods to a specific category for purposes 

of determining consumption rates of 

individual foods or larger food 

categories (e.g., all forms of dairy). Food 

surveys analyze the foods in the average 

diet of the whole population in a 

country (i.e., Total Diet Study (TDS) 

approach), or by analyzing select foods 

in the diet of a given population within 

a limited geographical area (e.g., the 

data in Schecter et al. (Ref. 16)). When 

determining whether a particular food 

survey is relevant and suitable for 

estimating levels of a substance in the 

total diet of a specific population, 

multiple factors should be considered to 

ensure scientific validity. These 

include, among others, whether the 

types of food, number of samples, and 

location of where food samples were 

obtained represent the diet of the target 

population, the appropriateness of the 

sample preparation and analytical 

methods, and whether a particular food 

categorization system is suitable to 

calculate exposure from the levels in 

food obtained from the survey. 

As previously stated, the petition 

relies on dietary exposure estimates that 

are provided in the CHAP report and 

Schecter et al. study. Although the 

CHAP report described and supported 

its dietary exposures estimates, there are 

still data gaps that raise questions about 

the petition’s reliance on estimated 

dietary exposure values that are derived 

from the CHAP report. Specifically, the 

CHAP report relies on a TDS conducted 

in the United Kingdom (UK). This 

survey may not reflect U.S. dietary 

exposures, as different supply chains in 

different continents may result in 

different exposures. In addition, this 

data was almost 10 years old at the time 

the petition was submitted to FDA (see 

Ref. 6). Further, while the data in 

Schecter et al. is from a segment of the 

U.S. population (i.e., food sampled in 

Albany, NY, in 2011), the dataset is less 

robust than the UK TDS. Schecter et al. 

analyzed for 9 phthalates in 72 

commonly consumed foods, compared 

with the UK TDS that analyzed for 15 

phthalate diesters and 9 phthalate 

esters, as well as phthalic acid in 261 


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retail food items in the UK. The studies 

also differ in the food categorization 

systems used to calculate exposure. An 

appropriate way to utilize the Schecter 

et al. study in the context of the CHAP 

report would be to examine if the results 

from these studies reinforce each other 

while accounting for the different 

parameters used by each. However, the 

petition provides no such examination 

or analysis and instead adopts any 

exposure to any phthalate from either 

analysis that is over the proposed ADI 

for the purported class. As such, the 

petition does not address the results 

from the CHAP report and the Schecter 

et al. study that are contradictory for 

select reported values. For example, the 

average exposure to DEHP for women in 

the CHAP report is 4.8 mg/kg bw/d (over 

the ADI of 3 mg/kg bw/d proposed in the 

petition), while the average exposure to 

DEHP for adults (which should be 

comparable to women) in Schecter et al. 

is only 0.67 mg/kg bw/d (lower than the 

proposed ADI) (Refs. 6 and 16). Further 

analysis is needed to determine which, 

if either, of these contradictory values is 

suitable for the purpose of a safety 

assessment. 

We note that other available dietary 

survey/TDS data that are only briefly 

discussed in the petition (Canadian TDS 

and Australian TDS studies published 

in 2015 and 2014, respectively) could 

potentially address several of the data 

gaps. These data sets are more recent 

than the CHAP report and Schecter et al. 

study. They are also more robust than 

the Schecter et al. study. In addition, the 

Canadian TDS may be more directly 

relevant to the U.S. population than the 

UK TDS used in the CHAP report, in 

that Canadian and U.S. diet and 

packaging and processing supply chains 

may be more similar than UK and U.S. 

diet and packaging and processing 

supply chains. Although exposure 

estimates were not calculated in the 

Canadian and Australian TDS reports, 

the data from these studies could be 

applied to an appropriate food 

categorization system and used to 

calculate exposure estimates. The 

petition provides no such examination 

or analysis. 

With respect to the petition’s reliance 

on biomonitoring data, we note that 

biomonitoring studies are used in 

assessing human exposure to a chemical 

by measuring the level of the biomarker 

(e.g., the chemical itself, its 

metabolite(s), or reaction product(s) in a 

biological matrix such as human blood 

or urine) from individuals and then 

analyzing the data collectively. The 

exposure values calculated from 

biomonitoring data include 

contributions not just from the ingestion 

of food (i.e., diet), but also from 

inhalation and dermal contact. 

However, using exposure values from 

biomonitoring studies without 

discussion and supporting information 

to determine the specific contribution 

from dietary sources is not appropriate 

in the context of a food additive 

petition, as the overall exposure value 

in a biomonitoring study may not be an 

appropriate proxy for the probable 

dietary exposure value (see section 

409(c)(5)(B) of the FD&C Act (directing 

that FDA consider the cumulative effect 

of a food additive ‘‘in the diet of man 

or animals’’) (emphasis added); 21 CFR 

171.3(i)(2) (providing that in 

determining a food additive’s safety 

‘‘the cumulative effect of the substance 

in the diet’’ shall be considered) 

(emphasis added)). 

As to the specific biomonitoring data 

cited in the petition, the NHANES data 

and resultant exposure values are 

relevant in that they reflect relatively 

recent dietary patterns and are 

generated from the U.S. population. 

However, the approach of directly 

comparing biomonitoring-based 

exposure values to a proposed ADI for 

the purpose of assessing the safety of a 

food additive is not scientifically 

appropriate. As discussed in the 

previous paragraph, relying on 

biomonitoring data alone does not 

differentiate the amount of exposure 

that results from the diet compared to 

environmental and other sources. We 

note that NHANES and other 

biomonitoring data do not differentiate 

specific sources or routes of exposure, 

such as exposure from dietary sources. 

Because the petition does not account 

for these limitations by addressing how 

the biomonitoring data accounts for 

dietary exposure, the petition’s direct 

comparison of biomonitoring-based 

exposure values to the purported ADI is 

scientifically flawed. 

3. Conclusion for Assertion C: The EDI 

Approach in the Petition Is Not Valid 

As discussed in sections II.A and II.B, 

the petition does not support the 

establishment of a single class for all 28 

phthalates, nor does it support the 

proposed ADI for DEHP or the 

application of the proposed ADI to the 

purported class. As Assertion C is 

predicated on Assertions A and B, the 

approach in Assertion C of comparing 

published exposure estimates to the 

proposed ADI for the purported class is 

therefore scientifically flawed. In 

addition, the petition does not 

adequately support its proposed 

exposure estimates. The petition does 

not justify its approach of adopting any 

reported single phthalate exposure 

estimate that is over the proposed ADI 

for the purported class. Specifically, the 

petition does not account for: (1) The 

imprecision of relying on exposures 

estimates derived from biomonitoring 

studies to assess dietary exposure; (2) 

the diverse parameters used in the cited 

dietary exposure analyses to determine 

which analysis, if any, most accurately 

reflects true U.S. dietary exposure; and 

(3) the contradiction in reported dietary 

exposure values between those analyses. 

D. Summary Conclusion of FDA’s 

Review of the Petition 

As discussed in section II.A, the 

petition does not support the 

establishment of a proposed class for all 

28 phthalates. In light of the differences 

in the chemical structures and toxicity 

profiles among the 28 phthalates, the 

petition does not provide adequate 

scientific support for grouping 

chemicals for the purpose of assessing 

safety. Section II.B explains that the 

petition’s approach of applying the 

proposed ADI to the purported class is 

also flawed, in that the proposed ADI is 

not adequately supported, and it is not 

scientifically appropriate to apply the 

proposed ADI to the purported class of 

28 ortho-phthalates. Section II.C 

explains that, as it is not valid to group 

all 28 ortho-phthalates as a class of 

chemically or pharmacologically related 

substances for the purpose of assessing 

safety, it is also not valid to compare 

exposures for these ortho-phthalates to 

a proposed ADI for the purported class. 

In addition, the petition’s approach for 

estimating exposure to ortho-phthalates 

is not adequately supported. For all 

these reasons, the petition does not 

contain sufficient data to support a 

finding that there is no longer a 

reasonable certainty of no harm from the 

currently approved uses. 

As an additional matter, based on the 

information currently available to FDA, 

we do not have a basis to conclude that 

dietary exposure levels from approved 

ortho-phthalates exceed a safe level. As 

new information becomes available to 

us, we will continue to examine such 

data as appropriate to assess whether 

there remains a reasonable certainty of 

no harm. 

III. Comments on the Filing Notice 

Overall, we received multiple 

comments in support of the petitioners’ 

request that we amend or revoke the 

specified regulations to no longer 

provide for the food contact use of the 

28 ortho-phthalates. Other comments, 

such as those from a coalition composed 

of trade organizations, materials 

suppliers, compounders, formulators, 

molders, and fabricators, oppose the 


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petition. Additionally, some comments 

addressed matters that are outside the 

scope of the petition, and some 

comments were duplicate submissions. 

In this section, we discuss the issues 

raised in the comments. We preface 

each comment discussion with a 

numbered ‘‘Comment’’ and each 

response by ‘‘Response’’ to make it 

easier to identify comments and our 

responses. We have numbered each 

comment to help distinguish among 

different topics. The number assigned is 

for organizational purposes only and 

does not signify the comment’s value, 

importance, or the order in which it was 

received. 

(Comment 1) Many comments, 

primarily form letters, stated that 

phthalates are hormone disrupting 

chemicals linked to a wide variety of 

adverse health outcomes such as: 

Reduced anogenital distance in male 

infants; reduced sperm quality; 

infertility; genital birth defects in boys; 

impaired mental and/or psychomotor 

development; attention deficit disorder 

and behavioral symptoms; obesity and 

insulin resistance; rhinitis; eczema; 

asthma; endometriosis; and renal, 

hepatic, thyroid, and hormonedependent cancers. The comments 

stated that, given the available research, 

FDA should take quick action to reduce 

exposure to these chemicals in our food 

supply. 

(Response 1) FDA is aware of the 

research that has been conducted with 

respect to phthalates. While FDA 

considered the research in its evaluation 

of the petition, including the research 

identified in the comments, most of the 

research considered individual 

phthalates or mixtures of phthalates. 

The petition is based on the idea that 

the 28 subject phthalates should be 

considered as a class and deemed 

unsafe as a class. For the reasons 

described previously, the petition does 

not provide adequate support for 

grouping the 28 phthalates as a single 

class, and therefore, the research 

pertaining to individual phthalates or 

specific mixtures of phthalates cannot 

be applied to all 28 phthalates that are 

the subject of the petition. 

(Comment 2) Many comments cited 

the CHAP report and pointed to the 

Consumer Product Safety Commission’s 

(CPSC’s) final rule prohibiting 

children’s toys and childcare articles 

that contain more than 0.1 percent of 

five specific ortho-phthalates (82 FR 

49938, October 27, 2017). Other 

comments also cited the CHAP report’s 

finding that the diet (separate from 

exposure from children’s toys and 

childcare articles) is a major route of 

exposure to phthalates as a reason why 

FDA should also address the use of 

phthalates. These comments argued 

that, because maximum use levels of 

certain phthalates in toys have been 

used to assess risk to children during 

early development, FDA should take 

action against uses of phthalates in food 

contact applications that contribute to 

exposure for pregnant women and the 

developing fetus, as well as for nursing 

mothers and babies. 

(Response 2) The CHAP report 

included a risk assessment regarding the 

use of 14 phthalates and 6 phthalate 

alternatives in children’s toys and 

childcare articles. While the report was 

a result of significant scientific analysis, 

the report was conducted primarily for 

the purpose of evaluating the safety of 

certain phthalates and phthalate 

alternatives in children’s toys and 

childcare articles, and the regulatory 

recommendations in that report apply to 

those particular uses of phthalates. 

Notably, the CHAP report was not 

designed to evaluate the safety of 

phthalates for food contact uses, which 

is the subject of this petition. In 

evaluating the safety of substances for 

food contact uses, FDA is required by 

statute to consider the safety of a 

substance for the particular food contact 

use (see sections 409(b) and (h)(1) of the 

FD&C Act (providing that sponsors may 

submit petitions or notifications with 

respect to the ‘‘intended use’’ of the 

substance)). In addition, we are directed 

by statute to consider food-related uses 

in assessing safety (see section 409(c)(5) 

of the FD&C Act) (providing that in 

determining safety, the Secretary shall 

consider among other relevant factors 

‘‘the probable consumption of the 

additive and of any substance formed in 

or on food because of the use of the 

additive’’)). Accordingly, safety 

assessments conducted for purposes 

other than evaluating the safety of food 

contact uses cannot directly determine 

the safety of food contact uses. As 

appropriate, FDA may consider the 

underlying evidence reviewed in such 

assessments. But FDA’s statutory 

responsibility is to evaluate safety in 

accordance with the FD&C Act and in 

consideration of the specific intended 

uses for which we have jurisdiction. 

(Comment 3) Some comments 

discussed actions taken with regard to 

phthalates by other government entities 

(such as CPSC’s final rule prohibiting 

phthalates in children’s toys and 

childcare articles if they contain more 

than 0.1 percent of five ortho-phthalates 

(82 FR 49938) and the European Union’s 

(EU’s) plastic regulation (Commission 

Regulation 10/2011, Plastic Materials 

and Articles Intended to Come into 

Contact with Food, 2011 O.J. (L 12)). 

Some comments referred to the EU 

regulation as an unequivocal ban on the 

use of almost all ortho-phthalates in 

food contact materials intended for fatty 

and infant foods. In addition, the 

comments pointed to FDA’s Center for 

Drug Evaluation and Research’s 

(CDER’s) removal of two phthalates 

from its inactive ingredients database 

(77 FR 72869, December 6, 2012), and 

FDA’s Center for Devices and 

Radiological Health’s (CDRH’s) draft 

guidance on medical devices made with 

polyvinyl chloride (PVC) containing 

DEHP (67 FR 57026, September 6, 

2002). The comments argued that FDA 

should take similar action by banning 

the use of all phthalates in contact with 

food. 

(Response 3) Each of the 

governmental actions described in the 

comments were taken based on different 

applicable legal standards, and the 

safety considerations and assessments 

that supported those actions were not 

conducted in accordance with FDA’s 

food additive safety standards under 

section 409 of the FD&C Act. In this 

action, FDA is responding to the 

specific claims made in the petition 

about the applicability of the safety 

standard in section 409 of the FD&C Act 

to a purported class of 28 orthophthalates, and we have evaluated those 

claims in accordance with the 

requirements for food additive petitions 

and applicable regulations. 

We also note that other regulatory 

actions and government bodies 

identified in the comments have not 

limited or banned the use of all 28 

ortho-phthalates that are the subject of 

the petition. For example, the actions 

taken by Congress and CPSC to limit the 

use of eight phthalates (DEHP, DBP and 

BBzP, DINP, di-n-pentylphthalate 

(DPENP), dihexyl phthalate (DHEXP), 

dicyclohexyl phthalate (DCHP), and 

diisobutyl phthalate (DIBP)) in 

children’s toys and childcare articles 

was not a total ban on the use of these 

substances, but a ban above the specific 

use level of 0.1 percent in the articles. 

While Congress also put an interim ban 

on DINP, DIDP, and DnOP, the CHAP 

report later recommended to lift the 

interim ban for DnOP and DIDP as these 

compounds are not likely to be 

antiandrogenic. The CHAP report also 

recommended that no action be taken 

on dimethyl phthalate (DMP) and 

diethyl phthalate (DEP). 

The EU’s plastic regulation 

(Commission Regulation 10/2011, 2011 

O.J. (L 12)) authorizes six phthalates 

(DBP, BBP, DEHP, DINP, diallyl 

phthalate (DAP), and DIDP) for use in 

food contact plastic materials and 

articles. These phthalates have different 


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use restrictions, specific migration 

limits, and specific type(s) of food the 

articles containing these substances may 

contact. The EU’s regulation authorizes 

certain phthalates and does not ban the 

use of all other phthalates for food 

contact applications. 

The removal of DEHP and DBP from 

CDER’s database of inactive ingredients 

in drug products followed the 

publication of CDER’s guidance 

document, ‘‘Limiting the Use of Certain 

Phthalates as Excipients in Center for 

Drug Evaluation and ResearchRegulated Products’’ (77 FR 72869). 

While CDER’s guidance was informed 

by concerns about the safety of DBP and 

DEHP, the guidance was limited to the 

use of those substances as excipients in 

drug and biologic products, and the 

guidance specifically states that the 

recommendations in the document do 

not address the use of DBP or DEHP in 

other types of FDA-regulated products. 

As an additional matter, the guidance 

document—like all FDA guidance 

documents—is non-binding and sets 

forth policy and regulatory 

recommendations only (see 21 CFR 

10.115). In addition, the CDRH draft 

guidance is not a ban on the use of 

DEHP. Instead, the draft guidance 

(which was never finalized and has 

since been withdrawn) would have 

suggested labeling DEHP content and 

would have recommended that device 

manufacturers consider replacing DEHP 

for a small subset of medical devices 

where PVC containing DEHP may come 

in contact with the tissue of a sensitive 

patient population in a manner and for 

a period of time that may result in 

concerns about aggregate exposure to 

DEHP. The draft guidance did not 

address exposure to DEHP from any 

other use of PVC, such as food contact 

applications. 

(Comment 4) Most comments 

supported banning all 28 orthophthalates even in the absence of 

scientific evidence of harm because of 

concern that banning only some 

phthalates could lead to substitution 

with other phthalates or alternatives 

that may carry unknown risks. 

(Response 4) Consistent with section 

409 of the FD&C Act, FDA evaluates the 

safety of all food additives against the 

same safety standard of reasonable 

certainty of no harm and does not make 

safety determinations based on the 

comparison of one chemical to its 

potential substitute. The 28 orthophthalates that are the subject of the 

petition were approved via the food 

additive petition process and included 

an evaluation using the same safety 

standard as other food contact 

substances. Any ‘‘substitute’’ phthalate 

used as a food contact substance would 

also undergo any required premarket 

safety review and would be required to 

meet FDA’s safety standard. 

In response to the comments arguing 

that FDA should take action even if 

there is uncertainty about the data, FDA 

regulates food additives in accordance 

with the FD&C Act. Under the FD&C 

Act, food additives may not be used 

unless it can be demonstrated that there 

is a reasonable certainty that no harm 

will result from their use. 

(Comment 5) Several comments 

supported the petitioners’ position that 

all 28 phthalates should be considered 

and regulated as a single class because, 

in the commentors’ view, the phthalates 

are chemically and pharmacologically 

related. The comments also stated that 

exposure to phthalates should be 

considered cumulatively based on the 

antiandrogenic effects seen in rats 

treated with certain phthalates and that 

a single ADI should be established for 

the asserted class. The comments agreed 

with the petition’s argument that 

adverse effects and the 3 mg/kg bw/day 

ADI proposed for DEHP should be 

attributed to the entire asserted class, 

and that current exposure levels for 

phthalates exceeds this level. 

Conversely, one comment stated that 

the antiandrogenic effect identified is 

species-specific and that some studies 

have reported that, unlike the 

observations made in studies testing rat 

fetus tissue, antiandrogenicity is not 

observed in human fetus tissue when 

exposed to phthalates in the same way. 

(Response 5) FDA has addressed the 

petitioners’ three assertions in sections 

II (A, B, and C). FDA has also addressed 

the human relevance to the 

antiandrogenicity effect reported from 

rat studies in section II.B and in Ref. 4. 

(Comment 6) Some comments stated 

that FDA should consider purported 

economic costs of human health 

impacts (such as healthcare expenses 

due to illness and lost productivity) 

associated with exposure to chemicals 

generally, including phthalates. 

(Response 6) FDA does not agree that 

it is necessary to evaluate the potential 

economic impact of the regulated uses 

of the 28 ortho-phthalates that are the 

subject of the petition. The economic 

costs for which the comment wants FDA 

to conduct estimates are health related 

(i.e., costs to the healthcare system that 

result from asserted health problems 

caused by phthalates). At the time FDA 

authorized the 28 ortho-phthalates that 

are the subject of the petition, FDA 

found them to be safe. The comments 

did not explain why FDA is under an 

ongoing obligation to develop cost 

estimates for substances that FDA has 

found to be safe. If new data and 

information accrue such that FDA 

determines that any approved additives 

are in fact unsafe, FDA will take 

appropriate action by revoking the 

approvals for such additives or 

otherwise ensuring that the additives 

are not used. 

(Comment 7) Several comments stated 

that if FDA does not grant the petition, 

we should require disclosure of the use 

of phthalates in food packaging directly 

on the label so consumers who wish to 

avoid or limit exposure to phthalates are 

able to make an informed decision. 

(Response 7) The petition did not 

request that FDA establish requirements 

for the labeling of products 

manufactured with phthalates. We note 

that manufacturers may voluntarily 

label their products as phthalate-free, as 

long as such labeling is truthful and not 

misleading. 

For FDA to require labeling on food 

packages regarding the use of 

phthalates, FDA would consider the 

standards in: (1) Section 409(c)(1)(A) of 

the FD&C Act, providing that 

regulations for food additives prescribe 

the conditions necessary to provide for 

the safe use of the ingredient, and (2) 

the standard under section 201(n) of the 

FD&C Act that any such declaration 

constitutes a material fact with respect 

to the consequences that may result 

from the use of the food. The comments 

did not provide evidence to address 

either of these standards, and based on 

the current record, we do not find it 

appropriate to take such action in 

response to these comments. 

(Comment 8) Some comments urged 

FDA to consider the effects phthalates 

have on the environment and wildlife. 

The comments stated that the use of 

these chemicals could result in the 

contamination of soil, air, and drinking 

water. 

(Response 8) The comments did not 

provide any information or relevant data 

to substantiate the asserted 

environmental effects of phthalates from 

their use as food additives. Therefore, 

these comments are unsupported. To 

the extent the comments suggested that 

FDA conduct an environmental 

assessment or impact statement under 

the National Environmental Policy Act 

(NEPA), 42 U.S.C. 4321 et seq., we note 

that NEPA does not require Agencies to 

conduct such assessments or impacts 

unless there is a major Federal action. 

Agency decisions that maintain the 

status quo do not constitute major 

Federal actions (see, e.g., 40 CFR 

1508.1(q); Fund for Animals, Inc. v. 

Thomas, 127 F.3d 80 (D.C. Cir. 1997); 

Defenders of Wildlife v. Andrus, 627 

F.2d 1238, 1243–46 (D.C. Cir. 1980)). 


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31078 Federal Register / Vol. 87, No. 98 / Friday, May 20, 2022 / Proposed Rules 

Our denial of this food additive petition 

maintains the status quo. To the extent 

that the comments suggested that 

environmental effects can be a basis for 

withdrawing a food additive petition, 

we are unaware of any such authority 

under the FD&C Act and the comments 

did not identify any. 

(Comment 9) Some comments agreed 

with the petitioners’ exposure 

estimation that considers cumulative 

exposure using four datasets from 

different sources, while others disagreed 

with the approach used to estimated 

exposure. One comment stated that one 

of petitioners’ sources for estimating 

exposure, the 2014 CHAP report, 

overestimates exposure levels because it 

used outdated NHANES biomonitoring 

data that does not reflect a more recent 

decline in exposure, as evidenced by a 

reduction in urinary metabolite levels 

observed in the most recent NHANES 

data (2009–2010 CDC NHANES data, 

published September 2012). 

(Response 9) As discussed in section 

II.C, the petition does not adequately 

support the proposed exposure values. 

We have addressed the petitioners’ use 

of exposure data in section II.C. 

(Comment 10) Many comments agreed 

with the petitioner regarding the 

additional safety factor applied to the 

NOAEL for DEHP to calculate the ADI. 

The comments stated that a safety factor 

of 1,000 should be used. Conversely, 

one comment stated that the available 

data does not support the use of a safety 

factor of 1,000 because the effects 

identified for DEHP in the reference 

studies are ‘‘mild’’ and do not warrant 

an adjustment for severity. 

(Response 10) As discussed in section 

II.B.2, FDA cannot determine the 

appropriate safety factor without more 

information than what was provided in 

the petition. 

IV. Conclusion 

FAP 6B4815 requested that the food 

additive regulations be amended to 

provide for the removal of 28 authorized 

phthalates listed for use in contact with 

food. After reviewing the petition, as 

well as additional data and information 

relevant to the petitioners’ request, we 

determine that the petition provides 

insufficient information to support a 

finding that there is no longer a 

reasonable certainty of no harm for the 

proposed class of ortho-phthalates. 

Therefore, FDA is denying FAP 6B4815 

in accordance with § 171.100(a). 

V. Objections 

Any persons that may be adversely 

affected by this notice may file with the 

Dockets Management Staff (see 

ADDRESSES) either electronic or written 

objections. You must separately number 

each objection, and within each 

numbered objection you must specify 

with particularity the provision(s) to 

which you object, and the grounds for 

your objection. Within each numbered 

objection, you must specifically state 

whether you are requesting a hearing on 

the particular provision that you specify 

in that numbered objection. If you do 

not request a hearing for any particular 

objection, you waive the right to a 

hearing on that objection. If you request 

a hearing, your objection must include 

a detailed description and analysis of 

the specific factual information you 

intend to present in support of the 

objection in the event that a hearing is 

held. If you do not include such a 

description and analysis for any 

particular objection, you waive the right 

to a hearing on the objection. 

It is only necessary to send one set of 

documents. Identify documents with the 

docket number found in brackets in the 

heading of this document. Any 

objections received in response to the 

regulation may be seen in the Dockets 

Management Staff between 9 a.m. and 4 

p.m., Monday through Friday, and will 

be posted to the docket at http://

www.regulations.gov. We will publish 

notice of the objections that we have 

received or lack thereof in the Federal 

Register. 

VI. References 

The following references marked with 

an asterisk (*) are on display at the 

Dockets Management Staff (see 

ADDRESSES) and are available for 

viewing by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday; they also are available 

electronically at https://

www.regulations.gov. References 

without asterisks are not on public 

display at https://www.regulations.gov 

because they have copyright restriction. 

Some may be available at the website 

address, if listed. References without 

asterisks are available for viewing only 

at the Dockets Management Staff. FDA 

has verified the website addresses, as of 

the date this document publishes in the 

Federal Register, but websites are 

subject to change over time. In addition, 

Reference A is also part of the 

administrative record and is on display 

at the Dockets Management Staff. This 

reference is also available electronically 

at https://www.regulations.gov. 

*1. 2014 Organization for Economic Cooperation and Development (OECD) 

Guidance on Grouping of Chemicals. 

*2. Shibko, S.I. and H. Blumenthal (1973) 

‘‘Toxicology of Phthalic Acid Esters Used in 

Food Packaging Material,’’ Environmental 

Health Perspectives, 3:131–137. 

*3. FDA Memorandum from R. Brin ̃ as to J. 

Urbelis, May 11, 2022. 

*4. FDA Memorandum from T–F. Cheng to 

J. Urbelis, May 11, 2022. 

*5. Phthalates and Cumulative Risk 

Assessment: The Tasks Ahead; National 

Research Council (US) Committee on the 

Health Risks of Phthalates (NAS Report): 

Washington (DC): National Academies Press 

(US); 2008. 

*6. 2014 Chronic Hazard Advisory Panel 

(CHAP) on Phthalates and Phthalate 

Alternatives Final Report. 

*7. OECD: Screening Information Dataset 

(SIDS) Initial Assessment Meeting (SIAM) 

19), 19–22 October 2004. 

*8. European Food Safety Authority 

(EFSA) Panel on Food Contact Materials, 

Enzymes and Processing Aids (2019) 

‘‘Update of the Risk Assessment of 

di-butylphthalate (DBP), 

butyl-benzyl-phthalate (BBP), 

bis(2-ethylhexyl)phthalate (DEHP), 

di-isononylphthalate (DINP) and 

di-isodecylphthalate (DIDP) for Use in Food 

Contact Materials,’’ EFSA Journal, 

17(12):5838. 

*9. Canada: Screening Assessment— 

Phthalate Substance Grouping. Environment 

and Climate Change Canada, Health Canada. 

December 2020. Cat. No.: En14–393/2019E– 

PDF; ISBN 978–0–660–32979–6. 

*10. FDA, Guidance for Industry, 

‘‘Toxicological Principles for the Safety 

Assessment of Food Ingredients: Redbook 

2000,’’ July 2007 (available at: https://

www.fda.gov/media/79074/download). 

*11. FDA, Guidance for Industry, 

‘‘Preparation of Food Contact Notifications 

for Food Contact Substances: Toxicology 

Recommendations,’’ October 2021 (available 

at: https://www.fda.gov/regulatoryinformation/search-fda-guidance-documents/ 

guidance-industry-preparation-food-contactsubstance-notifications-toxicologyrecommendations. 

*12. FDA, (2001) ‘‘Safety Assessment of 

Di(2-ethylhexyl) phthalate (DEHP) Released 

from PVC Medical Devices,’’ (available at: 

https://www.fda.gov/media/114001/ 

download). 

13. Kurata, Y., F. Kidachi, M. Yokoyama, 

et al. (1998) ‘‘Subchronic Toxicity of Di(2- 

ethylhexyl)phthalate in Common Marmosets: 

Lack of Hepatic Peroxisome Proliferation, 

Testicular Atrophy, or Pancreatic Acinar Cell 

Hyperplasia,’’ Toxicological Sciences, 42:49– 

56. 

*14. Rhodes, C., T.C. Orton, S. Pratt, et al. 

(1986) ‘‘Comparative Pharmacokinetics and 

Subacute Toxicity of Di-(2-ethylhexyl) 

Phthalate (DEHP) in Rats and Marmosets: 

Extrapolation of Effects in Rodents to Man,’’ 

Environmental Health Perspectives, 65, 299– 

307. 

15. Pugh, G. Jr., J.S. Isenberg, L.M. 

Kamendulis, et al. (2000) ‘‘Effects of Diisononyl Phthalate, Di-2-ethylhexyl 

Phthalate, and Clofibrate in Cynomolgus 

Monkeys,’’ Toxicological Sciences, 

56(1):181–188. 

*16. Schecter, A., M. Lorber, Y. Guo, et al. 

(2013) ‘‘Phthalate Concentrations and Dietary 

Exposure from Food Purchased in New York 

State,’’ Environmental Health Perspectives, 

121(4): 473–494. 


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*A. FDA Supplementary Memorandum for 

Food Additive Petition (FAP) 6B4815, J. 

Urbelis, May 11, 2022. 

Dated: May 11, 2022. 

Lauren K. Roth, 

Associate Commissioner for Policy. 

[FR Doc. 2022–10530 Filed 5–19–22; 8:45 am] 

BILLING CODE 4164–01–P 


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