IA #54-10, REVISION 2/23/07, IMPORT ALERT #54-10, "DETENTION WITHOUT PHYSICAL
EXAMINATION OF BULK OR FINISHED DIETARY SUPPLEMENTS AND OTHER PRODUCTS THAT
MAY CONTAIN ARISTOLOCHIC ACID"
TO: IMPORT PROGRAM MANAGERS
NOTE: This revision was issued to remove certain botanical species from
coverage under this alert and revise the information regarding
the herbs and products covered. Attachment D has been
eliminated. Changes are bracketed by asterisks.
TYPE OF ALERT: Detention Without Physical Examination (DWPE)
(Note: This import alert represents the Agency's current
guidance to FDA field personnel regarding the
manufacturer(s) and/or products(s) at issue. It does not
create or confer any rights for or on any person, and does
not operate to bind FDA or the public).
PRODUCT: *** Dietary Supplements or Drugs, Bulk or Finished, labeled
as containing Aristolochia spp., certain Asarum spp.,
certain Cocculus spp., and certain Thottea spp. ***
PRODUCT
CODE: 54E[][]31 Aristolochia (Herbal & Botanical teas)
54F[][]31 Aristolochia (Fang chi)
54F[][]75 Cocculus
54F[][]76 Asarum
54F[][]99 Thottea
54F[][]99 Herbals & Botanicals (not Teas), N.E.C.
66V[][]99 Miscellaneous patent medicines, etc.
PROBLEM: Poisonous and Unapproved drug
PAF: APP Approvals
*** BIO Naturally occurring toxins ***
HAZ - Hazardous Conditions
*** NAR Only lab analysis should be reported under this
code ***
PAC FOR
COLLECTION: *** 21008 ***
56008H
COUNTRY: All countries (ZZ)
MANUFACTURER/
SHIPPER FEI#: All
IMPORTER'S
ID#: N/A
CHARGE: "The product is subject to refusal of admission pursuant to
Section 801(a)(3) in that it appears to be a dietary
supplement or contain a dietary ingredient that presents a
significant or unreasonable risk of illness or injury under
the conditions of use set out in the labeling or, if none
are set out in the labeling, under customary conditions of
use [Adulteration, Section 402(f)(1)(A)."
(OASIS Charge Code - UNSFDIETLB)
and/or
"The product is subject to refusal of admission pursuant to
Section 801(a)(3) in that it appears to bear or contain a
poisonous or deleterious substance which may render it
injurious to health [Adulteration, Section 402(a)(1)]."
(OASIS Charge Code - POISONOUS)
and/or
"The product is subject to refusal of admission pursuant to
Section 801(a)(3) in that it appears to contain or bear a
poisonous or deleterious substance which renders it
adulterated under section (a)(1) under conditions of use
recommended in or suggested in the labeling [Adulteration,
Section 402(f)(1)(D)."
(OASIS Charge Code - UNSFDIETUS)
and/or
"The article is subject to refusal of admission pursuant to
801(a)(3) in that it appears to be a new drug without an
approved new drug application [Unapproved new drug, Section
505(a)]."
(OASIS Charge Code - UNAPPROVED)
and/or
"The article is subject to refusal of admission pursuant to
801(a)(3) in that it appears to lack adequate directions
for use [Misbranded drug, Section 502(f)(1)]."
(OASIS Charge Code - DIRECTIONS)
OASIS CHARGE
CODE: UNSFDIETLB
POISONOUS
UNSFDIETUS
UNAPPROVED
DIRECTIONS
RECOMMENDING
OFFICE: CFSAN, Office of Nutritional Products, Labeling, and
Dietary Supplements, Division of Compliance and Enforcement
(HFS-810)
REASON FOR
ALERT: The botanical Aristolochia spp. and other plants in the
Aristolochiaceae family are widely used as ingredients in
traditional Chinese herbal medicines and other traditional
medicines. These products may often be labeled for drug use
(e.g., claims that they are intended for use in the
diagnosis, cure, mitigation, treatment, or prevention of
diseases), although there are no approved new drug
applications (NDAs). Some products containing botanicals
in this family may also be labeled as dietary supplements
or may not be labeled in accordance with the requirements
for any specific FDA-regulated product.
Plants in the Aristolochiaceae family contain aristolochic
acid, which is a substance known to result in serious
adverse health effects when taken orally by humans or
animals. Several outbreaks of renal failure in recent
years have been attributed to the use of Chinese herbal
medicines that were later shown to contain aristolochic
acid. In each instance, the source of aristolochic acid
was determined to be an Aristolochia spp. plant that was
used in the product for one of two reasons: (1) the plant
ingredient that was listed on the label was mis-identified;
or (2) the identity of the plant ingredient or product was
confused with an aristolchia-containing ingredient or
product because the traditional Chinese names were
misinterpreted or similar.
*** Aristolochic acid is a potent carcinogen and
nephrotoxin. Its nephrotoxic potential has been
demonstrated in animals and humans in case reports and in
at least one human clinical study. *** Products that
contain a large amount of aristolochic acid have been
documented to result in the rapid onset of acute toxicity
symptoms. However, a product containing a small amount of
aristolochic acid could be used for years with no apparent
adverse effects until serious, irreversible effects, such
as renal damage, has occurred. In sum, products containing
aristolochic acid cause renal damage and can cause or
contribute to renal failure.
There are analytical methods available to examine suspect
raw material and finished product for the presence of
aristolochic acid. *** Products that contain Aristolochia
spp. or other botanicals that contain aristolochic acid
should be evaluated in order to establish that the product
is free of aristolochic acid. ***
GUIDANCE: *** Districts may detain without physical examination bulk
or finished dietary supplements or drugs, or bulk or
finished products of other commodity types that are
identified as being composed, in whole or in part, of any
Aristolochia spp. And those species of Asarum, Cocculus,
and Thottea listed in Attachment A. ***
*** Products identified using the traditional Chinese
Herbal Medicine names of "fang ji," "guang fang ji," "guang
mu tong," or other names noted in Attachment B, may also be
detained without physical examination. ***
Products from the firms identified in *** Attachment C ***
may also be detained without physical examination.
If product labeling includes claims for the diagnosis,
cure, mitigation, treatment, or prevention of disease, use
the new drug charge and the misbranding drug charge. If the
product labeling does not include disease claims but the
district has determined through other means (e.g.,
conversation with the importer, letter from the importer,
etc.) that the product is intended for disease use, then
use the drug misbranding charge. In this instance please
contact the Deputy Chief Counsel For Litigation, (301) 827-
1138, to further discuss the circumstances and evidence of
the importation and whether or not a new drug charge would
also be appropriate. In addition, the appropriate food
charges (see below) should be included.
If the product does not appear to be a drug, only food
adulteration charges should be used. If the products
appear to be finished products labeled as dietary
supplements, charges under section 402(a)(1), section
402(f)(1)(A), and section 402(f)(1)(D) should be used. If
the product is a bulk dietary ingredient (e.g., root,
powder, extract) charges under section 402(a)(1) and
section 402(f)(1)(A) should be used.
A product labeled as a dietary supplement may be released
when a firm is able to provide analytical evidence that it
is free of aristolochic acid. Only certificates of
analysis or other evidentiary documents that rely on liquid
chromatography-mass spectrometry analytical determination
of aristolochic acid content should be accepted as a basis
to release detained product.
For questions or issues concerning science, science policy,
sample collection, analysis, preparation, or analytical
methodology, contact the Division of Field Science at (301)
827-7605.
For questions or issues concerning declared ingredient
names, please contact Sal Evola, Office of Compliance,
Division of Enforcement, Imports Branch at
Salvatore.Evola@fda.hhs.gov or by phone at (301) 436-2164.
PRIORITIZATION
GUIDANCE: I
FOI: No purging is required
KEYWORDS: Aristolochic acid, toxin, carcinogen, nephrotoxin, herbs,
herbals, drugs
PREPARED
BY: Ted Poplawski, DIOP, (301) 443-6553
DATE LOADED
INTO FIARS: February 23, 2007
Attachment A for Import Alert #54-10 1/24/2007
Botanicals Known or Suspected to Contain Aristolochic Acid
Botanical Name* Common or Other Names**
Aristolochia spp. Aristolochia
Guan mu tong
Guang mu tong
*** Aristolochiae ***
Aristolochia acuminata Lam. Oval leaf
Syn. Aristolochia tagala Champ. Dutchman's pipe
Aristolochia argentina Griseb. **
Aristolochia baetica Linn. **
Syn. Aristolochia bracteolata Lam.
Aristolochia bracteata Retz. Ukulwe
Aristolochia chilensis Bridges in Lindl. **
Aristolochia cinnabarina C.Y. Cheng & J.L. Wu **
Aristolochia clematitis L. Birthwort
***Aristoloche
clematite Asarabacca ***
Aristolochia contorta Bunge Ma dou ling
*** Madolin ***
Tian xian teng
***Bei ma dou ling ***
*** Aristolochia cucurbitifolia Hayata Gua ye ma dou ling ***
Aristolochia cymbifera Mart. & Zucc. Mil homens
Aristolochia debilis Siebold & Zucc. Ma dou ling
Syn. Aristolochia longa Thunb. *** Madolin ***
Syn. Aristolochia recurvilabra Hance Tian xian teng
Syn. Aristolochia sinarum Lindl. Qing mu xiang
Sei-mokkou (Japanese)
Birthwort
Long birthwort
Aristolochia elegans Mast. **
Syn. Aristolochia hassleriana Chodat
Aristolochia esperanzae Kuntze **
Aristolochia fangchi Y.C. Wu ex L.D. Chow Guang fang ji
& S.M. Hwang Fang ji
Mokuboi (Japanese)
Kwangbanggi (Korean)
Fang chi
Kou-boui (Japanese)
Aristolochia fimbriata Cham. **
*** Aristolochia foveolata Merr. Feng wo ma dou ling ***
Aristolochia indica L. Indian birthwort
Aristolochia kaempferi Willd. ***Yi ye ma dou ling***
Syn. Aristolochia chrysops (Stapf) E.H. Wilson Yellowmouth
ex Rehder Dutchman's pipe
*** Syn. Aristolochia dabieshanensis C.Y. Cheng & W. Yu ***
Syn. Aristolochia feddei H. Lev.
Syn. Aristolochia heterophylla Hemsl.
*** Syn. Aristolochia kaempferi Willd. F. heterophylla (Hemsl.)
S.M. Hwang
Syn. Aristolochia kaempferi Willd. F. mirabilis Hemsl.)
S.M. Hwang ***
Syn. Aristolochia mollis Dunn
*** Syn. Aristolochia neolongifolia J.L. Wu & Z.L. Yamg ***
Syn. Aristolochia setchuenensis Franch.
Syn. Aristolochia shimadai Hayata
Syn. Aristolochia thibetica Franch.
Syn. Isotrema chryspos Stapf
Syn. Isotrema heterophylla (Hemsl.) Stapf
Syn. Isotrema lasiops Stapf
Aristolochia kwangsiensis Chun & F.C. How **
Syn. Aristolochia austroszechuanica C.B. Chien
& C.Y. Cheng
Aristolochia macrophylla Lam. Dutchman's pipe
Syn. Aristolochia sipho L'Her.
Aristolochia manschuriensis Kom. Manchurian birthwort
Syn. Hocquartia manschuriensis (Kom.) Nakai Manchurian Dutchman's
Syn. Isotrema manschuriensis (Kom.) H. Huber pipe
*** Mu tong ma dou ling ***
Guang mu tong
Kan-Mokutsu (Japanese)
Mokuboi (Japanese)
Kwangbanggi (Korean)
Aristolochia maurorum L. **
Aristolochia maxima Jacq. **
Syn. Aristolochia maxima var. angustifolia
Duchartre in DC.
Syn. Howardia hoffmannii Klotzsch
Aristolochia mollissima Hance **
*** Aristolochia odoratissima L. ** ***
Aristolochia pistolochia L. **
*** Aristolochia pubescens Hort. Ex K. Koch ** ***
Aristolochia rigida Duch. **
Aristolochia rotunda Linn. **
Aristolochia serpentaria L. Virginia snakeroot
*** Syn. Aristolochia convolvulacea Small *** Serpentaria
*** Syn. Aristolochia hastata Nutt. *** Virginia serpentary
*** Syn. Aristolochia nashii Kearney ***
Syn. Aristolochia serpentaria var. hastata
(Nutt.) Duchatre
*** Aristolochia trilobata L. ** ***
Aristolochia watsoni Wooton & Standley or **
Aristolochia watsonii Wooton & Standley
Syn. Aristolochia porphyrophylla Pfeifer
Aristolochia westlandii Hemsl. or **
Aristolochia westlandi Hemsl.
Aristolochia zollingerana Miquel **
Syn. Aristolochia kankauensis Sasaki
Syn. Aristolochia roxburghiana subsp. kankauensis
(Sasaki) Kitam.
Syn. Hocquartia kankausensis (Sasaki) Nakai ex Masam
Syn. Aristolochia tagala var. kankauensis
(Sasaki) T. Yamaz.
*** Asarum arifolium Michx **
Syn. Hexastylis arifolia Small var. ruthii (Ashe) H.L. ***
Asarum canadense Linn. Wild ginger
Syn. Asarum acuminatum (Ashe) E.P. Bicknell Indian ginger
Syn. Asarum ambiguum (E.P. Bicknell) Daniels Canada snakeroot
Syn. Asarum canadense var. ambiguum False coltsfoot
(E.P. Bicknell) Farw. Colic root
Syn. Asarum canadense var. reflexum Heart snakeroot
(E.P. Bicknell) B.L. Rob Vermont snakeroot
Syn. Asarum furcatum Raf. Southern snakeroot
Syn. Asarum medium Raf.
Syn. Asarum parvifolium Raf.
Syn. Asarum reflexum E.P. Bicknell
Syn. Asarum rubrocinctum Peattie
*** Asarum caudatum Lindl **
Asarum crispulatum C.Y. Cheng & C.S. Yang **
Asarum debile Franch. **
Asarum forbesii Maximn Batei-saishin
(Japanese)
Asarum fukienense C.Y. Cheng & C.S. Yang **
Asarum heterotropoides F. Schmidt Keirin-saishin
Syn. Asarum heterotropoides F. Schmidt (Japanese)
Syn. Asiasarum heterotropoides (F. Schmidt) Chinese wild ginger
F. Maek Manchurian wild ginger
Bei Xi Xin
Xi xin
His-hsin ***
Asarum himalaicum Hook. f. & Thomson ex Tanyou-saishin
Klotzsch or (Japanese)
*** Asarum ichangense C.Y. Cheng & C.S. Yang **
Asarum maximum Hemsl. **
Asarum sieboldii Miq. Usuba-siashin
(Japanese)
Syn. Asarum sieboldii fo. Seoulense (Nakai) Chinese wild ginger
C.Y. Cheng & C.S. Yang Xi Xin
Syn. Asarum sieboldii var. seoulensis Nakai Hua Xi Xin
Syn. Asarum heterotropoides var. seoulense Manchurian wild ginger
(Nakai) F. Maek. Siebold's wild ginger
Syn. Asiasarum sieboldii (Miq.) F. Maek His-hsin ***
Asarum splendens (F. Maek.) C.Y. Cheng & Do-saishin
C.S. Yang (Japanese)
*** Asarum wagneri K.L.Lu & M.R. Mesler **
Cocculus orbiculatus (L.) DC Moku-boui (Japanese)
Syn. Cocculus cuneatus Benth.
Syn. Cocculus sarmentosus (Lour.) Diels
Syn. Cocculus sarmentosus var. linearis Yamam.
Syn. Cocculus sarmentosus var. pauciflorus Y.C. Wu
Syn. Cocculus sarmentosus var. stenophyllus Merr.
Syn. Cocculus thunbergii DC
Syn. Cocculus trilobus (Thunb.) DC
Syn. Menispermum orbiculatus L.
Syn. Menispermum trilobum Thunb.
Syn. Nephroia sarmentosa Lour.
Thottea siliquosa (Lam.) Apama
Syn. Bragantia Wallichii R. Br. Thottea ***
Syn. Apama siliquosa Lam.
* The Latin binomial name may appear without the author's name.
** Does not indicate the lack of any common name.
Attachment B to Import Alert# 54-10 1/24/2007
*** Chinese products known to contain Aristolochic Acid
Dang Gui Si Ni
Du Hou Ji Sheng Tang (Tuhuo and Loranthus Formula)
Xiao Qing Long Tang (Minor Blue Dragon Formula)
Chuan Xiong Cha Tiao Wan (Cnidium and tea formula)
Da Qin Jiao Tang (Major Gentiana Macrophylla Root formula)
Ling Gan Jiang Wei Xin Xan Ren Tang (Hoelen and Schizandra formula)
Ma Huang Fu Zi Xi Xin Tang (Ephedra and Asarum ofrmula)
San Bi Tang (Tu Huo and Astragalus formula
Jiu Wei Qiang Hou Tang (Notopterygium Nine Herb formula)
Qing Shang Juan Tong Tang (Ophiopogon and Asarum formula)
Ta Huo lo tan (Da hou lo tan)(Chinese old man tea, The Greater Invigorate
Luou Channel Pill)
Tu zhung feng shi wan
Hai long bu wan (Hailung tonic pills)(sea horse, pipe fish nourishing pills)
RESP Blue Dragon Combination *** Attachment C to Import Alert# 54-10 1/24/2007
Products containing an ingredient from the Aristolochiaceae family from
specific firms
Kaiser Pharmaceutical Co. Ltd. (KPC) Xi Xin (dietary supplement)
9 Hwan Kung Road 54F[][]99
Yungkang Industrial Park 5/11/04
Yungkang, Tainan, 710, Taiwan
FEI# 3003639262
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