Safety Class: 1 (internal), 2d (external) Interaction Class: A

Brassica spp.

B

C

ontraindiCations internal use None known. external use

Not for external use with children under 6 y ears of age (Felter and Lloyd 1898; List and Hörhammer 1973; Watt and Breyer-Brandwijk 1962).

Not for use in persons with varicose veins, severe cir- culatory damage, or other venous disorders (Wichtl 2004).

o

ther

P

reCautions

internal use

Mustards may irritate the gastrointestinal tract and should be used with caution in patients with peptic ulcer or gastric hemorrhage (Bensky et al. 2004).

external use

If left on the skin for more than 15 to 30 minutes, plasters made from mustards can cause blistering that may be accompanied by suppurating, poorly healing ulcerations and necrosis (Wichtl 2004).

d

rugand

s

uPPlement

i

nteraCtions

None known.

a

dverse

e

ventsand

s

ide

e

ffeCts

The local skin irritant effect of topically applied mustards lasts for 24 to 48 hours (Wichtl 2004). Blistering, often accompanied by suppurating, poorly healing ulcerations and necrosis, may occur if topical black mustard plasters are applied for more than 15 to 30 minutes (Wichtl 2004).

Large doses (standard dose listed as an aqueous extract of 3–9 g) of mustards can cause enteritis, abdominal pain, and diarrhea (Bensky et al. 2004).

Allergic reactions to mustards have been reported after both internal and topical use. Reactions included anaphylactic shock and urticaria, and were confirmed by patch testing (Bensky et al. 2004; Morisset et al. 2003).

P

harmaCologiCal

C

onsiderations

Several animal studies have demonstrated that black mustard seed may modify glucose regulation. Diabetic persons are advised to discuss the use of this herb with a qualified healthcare practitioner prior to use (Anand et al. 2007, 2009; Yadav et al. 2004).

P

regnanCyand

l

aCtation

No information on the safety of mustards in pregnancy or lactation was identified in the scientific or traditional litera- ture. Although this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established.

R

eview

D

etailS

i. d

rugand

s

uPPlement

i

nteraCtions

Clinical trials of drug or supplement interactions

No clinical trials of drug or supplement interactions were identified.

Case reports of suspected drug or supplement interactions

No case reports of suspected drug or supplement interactions were identified.

animal trials of drug or supplement interactions

No animal trials of drug or supplement interactions were identified.

ii. a

dverse

e

vents

Case reports of adverse events

Toxicosis was reported in cattle that ingested significant amounts of mustard seed (Katamoto et al. 2001; Semalulu and Rousseaux 1989). The compound allyl isothiocyanate, which has an LD50 of 10 mg/kg in cattle (Kingsbury 1964)

and 339 mg/kg in rats (Jenner et al. 1964), is believed to be responsible for the toxicosis.

Topical application of mustard seed as a plaster has been associated with tachypnea, sweating, dizziness, agitation,

and low blood pressure, with symptoms appearing 40 minutes after topical application (Bensky et al. 2004).

iii. P

harmaCologyand

P

harmaCokinetiCs human pharmacological studies

Mustard seed allergy accounts for 1.1% of food allergies in children (Morisset et al. 2003).

In a study of 30 subjects, age 3 to 20, presenting positive prick tests to ground black mustard seed (B. nigra), mustard flour (B. juncea), metabisulfite-free strong mustard season- ing (B. juncea), or a c ommercialized allergenic extract (B.

nigra), 27 subjects were screened for mustard-specific immu- noglobulin E (IgE) and single- or double-blind placebo- controlled food challenges were completed with up to 1340 mg of the metabisulfite-free seasoning. The mean diam- eter of the wheal induced by prick tests with the allergenic extract was lower than that induced by the native mustard products, ground black mustard seed, mustard flour, or the strong mustard seasoning. The mean of mustard specific- IgE values was 8.7 KU/l (Morisset et al. 2003).

animal pharmacological studies

A decease in serum glucose and increase in serum insulin were observed in diabetic rats orally administered 200 mg/kg black mustard seed daily for 2 months (Anand et al.

B

2009). In the oral glucose tolerance test, the effective dose of the aqueous extract of black mustard seed was 200 mg/kg, with the aqueous extract being more effective than chloro- form, acetone, or ethanol extracts (Anand et al. 2007). In rats fed a d iet containing 10% black mustard seed for 30 days, significant decreases in fasting serum glucose and insulin were observed, although the levels were not normalized (Yadav et al. 2004).

in Vitro pharmacological studies

No relevant in vitro pharmacological studies were identified.

iv. P

regnanCyand

l

aCtation

No information on the safety of mustards in pregnancy or lactation was identified.

v. t

oxiCity

s

tudies

acute toxicity

The LD50 of orally administered black mustard seed extract

in rats could not be determined at doses up to 3 g/kg (Anand et al. 2009).

Genotoxicity

Antimutagenic activity of mustard seed was observed in rats exposed to a c hemical mutagen after being fed a d iet containing 1 to 10% mustard seed daily for 30 days (Polasa et al. 1994).

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Anand, P., K.Y. Murali, V. Tandon, R. Chandra, and P .S. Murthy. 2007. Preliminary studies on antihyperglycemic effect of aque- ous extract of Brassica nigra (L.) Koch in streptozotocin induced diabetic rats. Indian J. Exp. Biol. 45(8):696-701.

Anand, P., Y.K. Murali, V. Tandon, P.S. Murthy, and R. Chandra. 2009. Insulinotropic effect of aqueous extract of Brassica nigra improves glucose homeostasis in str eptozotocin induced dia- betic rats. Exp. Clin. Endocrinol. Diabetes 117(6):251-256.

Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine:

Materia medica. 3rd ed. Seattle: Eastland Press.

Felter, H.W., and J.U. Lloyd. 1898. King’s American dispensatory. 18th ed., 3rd rev. 2 vols. Cincinnati: Ohio Valley Co.

Jenner, P.M., E.C. Hagan, J.M. Taylor, E.L. Cook, and O.G. Fitzhugh. 1964. Food flavourings and compounds of related structure. I. Acute oral toxicity. Food Cosmet. Toxicol. 2(3):327-343.

Katamoto, H., S. Nishiguchi, K. Harada, et al. 2001. Suspected Oriental mustard (Brassica juncea) intoxication in cattle. Vet.

Rec. 149(7):215-216.

Kingsbury, J.M. 1964. Poisonous plants of the United States and

Canada. Prentice-Hall biological science series. Englewood Cliffs, NJ: Prentice-Hall.

List, P.H., and H. Hörhammer. 1973. Hagers handbuch der phar-

mazeutischen praxis. Vollst. 4. Neuausg. ed. Berlin: Springer. Morisset, M., D.A. Moner et-Vautrin, F. Maadi, et al. 2003.

Prospective study of mustard allergy: First study with double- blind placebo-controlled food challenge trials (24 cases). Allergy 58(4):295-299.

Polasa, K., P.U. Kumar, and K. Krishnaswamy . 1994. Ef fect of

Brassica nigra on benzo[ a]pyrene mutagenicity. Food Chem.

Toxicol. 32(8):777-781.

Semalulu, S.S., and C.G. Rousseaux. 1989. Saskatchewan. Suspected oriental mustard seed (Brassica juncea) poisoning in cattle. Can. Vet. J. 30(7):595-596.

Watt, J.M., and M.G. Breyer-Brandwijk. 1962. The medicinal and poi-

sonous plants of southern and eastern Africa. 2nd ed. Edinbur gh: E. & S. Livingstone.

Wichtl, M. 2004. Herbal drugs and phytopharmaceuticals: A handbook

for practice on a scientific basis. 3rd ed. Boca Raton, FL: CRC Press. Yadav, S.P., V. Vats, A.C. Ammini, and J.K. Gr over. 2004. Brassica

juncea (Rai) significantly prevented the development of insulin resistance in rats fed fr uctose-enriched diet. J. Ethnopharmacol. 93(1):113-116.

Bupleurum spp. apiaceae

Bupleurum chinense DC. sCn: bupleurum

pn: chai hu (root)

oCn: Chinese thoroughwax

Bupleurum scorzonerifolium Willd.

sCn: bupleurum pn: chai hu (root)

oCn: Chinese thoroughwax part: root

Q

uick

R

efeRence

S

ummaRy

Safety Class: 1

Interaction Class: A

C

ontraindiCations None known.

o

ther

P

reCautions None known.

d

rugand

s

uPPlement

i

nteraCtions

Bupleurum spp.

B

a

dverse

e

ventsand

s

ide

e

ffeCts

An allergic reaction to bupleurum has been reported (Bensky et al. 2004).

P

harmaCologiCal

C

onsiderations

None known.

P

regnanCyand

l

aCtation

No information on the safety of bupleurum in pregnancy or lactation was identified in the scientific or traditional litera- ture. Although this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established.

R

eview

D

etailS

i. d

rugand

s

uPPlement

i

nteraCtions

Clinical trials of drug or supplement interactions

No clinical trials of drug or supplement interactions were identified.

Case reports of suspected drug or supplement interactions

No case reports of suspected drug or supplement interactions were identified.

animal trials of drug or supplement interactions

No animal trials of drug or supplement interactions were identified.

ii. a

dverse

e

vents

Case reports of adverse events

An allergic reaction to bupleurum has been reported (Bensky et al. 2004).

iii. P

harmaCologyand

P

harmaCokinetiCs human pharmacological studies

No relevant human pharmacological studies were identified.

animal pharmacological studies

No relevant animal pharmacological studies were identified.

in Vitro pharmacological studies

The compound saikosaponin inhibited human platelet aggregation induced by ADP, with a potency of inhibition comparable to that of aspirin, and dose-dependently inhibited platelet thromboxane formation from exogenous and endogenous arachidonic acid. Effects were similar to that of epigallocatechin isolated from green tea (Chang and Hsu 1991).

The compounds eugenin and saikochromone inhibited CD28-costimulated activation of human peripheral blood T cells (Chang et al. 2003).

In human G6PD-deficient red blood cells, an aqueous extract of bupleurum demonstrated dose-dependent reduction of reduced glutathione (GSH) and methemoglobin (MetHb) at concentrations of 5–10 mg/ml (Ko et al. 2008).

No estrogenic activity of an ethanol extract of bupleurum was observed in a recombinant yeast system (Kim et al. 2008).

iv. P

regnanCyand

l

aCtation

No information on the use of bupleurum during pregnancy or lactation was identified.

v. t

oxiCity

s

tudies

acute toxicity

The LD50 of intraperitoneally administered bupleurum

essential oil in mice is 1.19 g/kg, while that of intraperitoneally administered saikosaponin is 1.9 g/kg (Chen and Chen 2004).

The LD50 of the crude saponin fraction of bupleurum in

mice is 4700 mg/kg after oral administration, 1800 mg/kg after subcutaneous administration, 112 mg/kg after intraperitoneal administration, and 70 mg/kg after intravenous administration. In guinea pigs, the LD50 of the same fraction

is 58.3 mg/kg after intraperitoneal administration (Takagi and Shibata 1969).

No adverse effects were observed in rats 14 days after intranasal administration of bupleurum essential oil made from 10 g of bupleurum root (50 times the human clinical dose) (Xie et al. 2006).

Cytotoxicity

The compound saikosaponin d induced apoptosis in human hepatocellular carcinoma cells (HepG2) through the activation of caspases 3 and 7, resulting in poly(ADP-ribose)-poly- merase (PARP) cleavage. DNA fragmentation was clearly noted at more than 6 hours after exposure to saikosaponin d (Chiang et al. 2003).

l

iteRatuRe

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iteD

Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine:

Materia medica. 3rd ed. Seattle: Eastland Press.

Chang, W.C., and F.L. Hsu. 1991. Inhibition of platelet activation and endothelial cell injury by flavan-3-ol and saikosaponin com- pounds. Prostaglandins Leukotrienes Essent. Fatty Acids 44(1):51-56.

Chang, W.L., L.W. Chiu, J.H. Lai, and H.C. Lin. 2003. Immunosuppressive flavones and lignans from Bupleurum scor-

zonerifolium. Phytochemistry 64(8):1375-1379.

Chen, J.K., and T.T. Chen. 2004. Chinese medical herbology and phar-

B

Chiang, L.C., L.T. Ng, L.T. Liu, D.E. Shieh, and C.C. Lin. 2003. Cytotoxicity and anti-hepatitis B virus activities of saikosapo- nins from Bupleurum species. Planta Med. 69(8):705-709. Kim, I.G., S.C. Kang, K.C. Kim, E.S. Choung, and O.P. Zee. 2008.

Screening of estr ogenic and antiestr ogenic activities fr om medicinal plants. Env. Toxicol. Pharmacol. 25(1):75-82.

Ko, C.H., K. Li, P .C. Ng, et al. 2008. Pr o-oxidative effects of Chinese herbal medicine on G6PD-deficient erythrocytes in vitro. Toxicol. in Vitro 22(5):1222-1227.

Takagi, K., and M. Shibata. 1969. Pharmacological studies on

Bupleurum falcatum L. I. Acute toxicity and central depressant action of crude saikosides. Yakugaku Zasshi 89(5):712-720. Xie, Y., W. Lu, S. Cao, et al. 2006. Preparation of bupleurum nasal

spray and evaluation on its safety and ef ficacy. Chem. Pharm.

Bull. (Tokyo) 54(1):48-53.

Buxus sempervirens L. Buxaceae

sCn: boxwood part: leaf

Q

uick

R

efeRence

S

ummaRy

Safety Class: 3

Interaction Class: A

C

ontraindiCations

Not for use except under the supervision of an expert qualified in the appropriate use of this substance (Kingsbury 1964; List and Hörhammer 1973).

o

ther

P

reCautions

None known.

d

rugand

s

uPPlement

i

nteraCtions

None known.

a

dverse

e

ventsand

s

ide

e

ffeCts

None known.

P

harmaCologiCal

C

onsiderations

None known.

P

regnanCyand

l

aCtation

No information on the safety of boxwood during pregnancy or lactation was identified. While this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established, and this substance is not recommended for use except under the supervision of an expert qualified in its appropriate use.

R

eview

D

etailS

i. d

rugand

s

uPPlement

i

nteraCtions

Clinical trials of drug or supplement interactions

No clinical trials of drug or supplement interactions were identified.

Case reports of suspected drug or supplement interactions

No case reports of suspected drug or supplement interactions were identified.

animal trials of drug or supplement interactions

No animal trials of drug or supplement interactions were identified.

ii. a

dverse

e

vents

Case reports of adverse events

After ingestion of an unknown amount of boxwood leaf, a 1-year-old was reported to be apathetic then overexcited (Frohne and Pfänder 2000).

Poisoning has been reported in livestock that have eaten boxwood. A horse died after consuming 1.5 pounds

of boxwood (0.15% of the animal’s body weight) (Frohne and Pfänder 2000; Kingsbury 1964).

iii. P

harmaCologyand

P

harmaCokinetiCs human pharmacological studies

No relevant human pharmacological studies were identified.

animal pharmacological studies

In anesthetized cats administered 1.25 µmol/kg of the compound buxaminol-E, a small short-lasting increase in blood pressure followed by marked hypotension was observed. Atropine inhibited the hypotensive effect almost com- pletely and methylatropine partially inhibited the effect (Kvaltínová et al. 1991).

in Vitro pharmacological studies

No relevant in vitro pharmacological studies were identified.

iv. P

regnanCyand

l

aCtation

No information on the use of boxwood during pregnancy or lactation was identified.

Buxus sempervirens

B

v. t

oxiCity

s

tudies

No toxicity studies were identified.

l

iteRatuRe

c

iteD

Frohne, D., and H.J. Pfänder. 2000. A colour atlas of poisonous

plants: A handbook for pharmacists, doctors, toxicologists, biologists and veterinarians. 2nd ed. London: Manson.

Kingsbury, J.M. 1964. Poisonous plants of the United States and

Canada. Prentice-Hall biological science series. Englewood Cliffs, NJ: Prentice-Hall.

Kvaltínová, Z., L. Lukovic, J. Machová, and M. Fatranská. 1991. Effect of the ster oidal alkaloid buxaminol-E on blood pr es- sure, acetylcholinesterase activity and [$1_{H]quinuclidinyl ben-} zilate binding in cerebral cortex. Pharmacology 43:20-25. List, P.H., and H. Hör hammer. 1973. Hagers handbuch der phar-

C

Calendula officinalis L. asteraceae

sCn: calendula

oCn: marigold; pot marigold part: flower

Q

uick

R

efeRence

S

ummaRy

Safety Class:

Interaction Class: A

C

ontraindiCations

None known.

o

ther

P

reCautions

Persons with allergies to other members of the Asteraceae family (such as feverfew, chamomile, or Echinacea species) should exercise caution with calendula, as allergic cross- reactivity to Asteraceae plants is common (Paulsen 2002).

d

rugand

s

uPPlement

i

nteraCtions

None known.

e

ditors

’ n

ote

The Cosmetic Ingredient Review deemed calendula “safe as used” as a topical cosmetic product (CIR 2009).

a

dverse

e

ventsand

s

ide

e

ffeCts

Allergic reaction to calendula, including anaphylactic reaction, is rare but has been reported (Fiume 2001; Goldman 1974). Irritation and sensitization studies in animals have indicated that calendula is nonirritating and nonsensitizing (Fiume 2001).

P

harmaCologiCal

C

onsiderations

None known.

P

regnanCyand

l

aCtation

An animal study on a water-ethanol extract of calendula at doses up to 1.0 g/kg indicated no adverse effects on fetal development (Silva et al 2009).

No information on the safety of calendula during lactation was identified. While this review did not identify any concerns for use while nursing, safety has not been conclusively established.

R

eview

D

etailS

i. d

rugand

s

uPPlement

i

nteraCtions

Clinical trials of drug or supplement interactions

No clinical trials of drug or supplement interactions were identified.

Case reports of suspected drug or supplement interactions

No case reports of suspected drug or supplement interactions were identified.

animal trials of drug or supplement interactions

Calendula has been shown to increase the hexobarbital- induced sleeping time in rats (Samochowiec 1983).

ii. a

dverse

e

vents

Case reports of adverse events

Patch testing with calendula preparations has indicated a 0–2% incidence of reaction to such testing with ointments containing 10% calendula (Bruynzeel et al. 1992), an ether extract of calendula (Reider et al. 2001), an ethanol extract of calendula (de Groot et al. 1988), and calendula absolute (Rodriquez and Mitchell 1977). In one set of patch tests,

patients sensitive to calendula were also sensitive to nickel, propolis, fragrance mix, and balsam of Peru (Myroxylon

balsamum var. pereirae). Sensitization to calendula can be assessed only by use of an Asteraceae mix or a s esquiter- pene mix (Reider et al. 2001).

Anaphylactic reaction to a c alendula infusion has been reported (Goldman 1974). Contact dermatitis from contact with a calendula plant has been reported (Wrangsjö et al. 1990).

iii. P

harmaCologyand

P

harmaCokinetiCs human pharmacological studies

No relevant human pharmacological studies were identified.

animal pharmacological studies

Little to no irritation was observed in animal dermal and ocular irritation studies of a v ariety of calendula extracts (Fiume 2001). Similarly, in animal sensitization studies, calendula did not produce sensitization reactions (Fiume 2001).

in Vitro pharmacological studies

No relevant in vitro pharmacological studies were identified.

Calendula officinalis

C

iv. P

regnanCyand

l

aCtation

In a r eproductive toxicity assessment of a hydroalcoholic extract of calendula, female rats were orally administered (by gavage) 0, 0.25, 0.5, or 1.0 g/kg of the extract on days 1 to 6, 7 to 14, or 15 to 19 of gestation. On day 20 of gestation, rats were killed for evaluation of maternal and fetal parameters. The treatment did not cause any changes in the number of corpora lutea, implantation sites, or resorption sites and no significant differences were found in the preimplantation and postimplantation loss rates in the treated groups as compared to the control. The number of live fetuses and the fetal weight was similar in the treatment and control groups. A d ose-dependent reduction in maternal weight gain was observed in the group administered calendula on gestational days 15 to 19, although fetal weight was not affected (Silva et al. 2009).

In isolated rabbit and guinea pig uteruses, an aqueous extract of calendula exhibited uterotonic activity (Shipochliev 1981). The relevance of that finding to human use is unknown.

Older studies and references report emmenagogic activity of calendula (Palma 1964; Puri 1971; Saha et al. 1961).

No information on the safety of calendula during lactation was identified.

v. t

oxiCity

s

tudies

acute toxicity

The LD50 of orally administered hydroalcoholic extract in

rats and mice could not be determined at doses up to 5 g/ kg (CTFA 1980; Silva et al. 2007). The LD50 of intraperitone-

ally administered calendula extract in mice is 300 mg/kg (Dhar et al. 1968).

short-term toxicity

In rats and mice administered a hydroalcoholic extract of calendula at doses up to 1 g/kg daily for 30 days, no hema- tological alterations were observed at doses up to 1 g/kg, and no morphological changes in the brain, kidney, and

heart were seen. An increase in blood urea nitrogen and in alanine transaminase levels was observed, and inflam- matory sites were found in the lung (associated with oral gavage) and liver (Silva et al. 2007).

Genotoxicity

No mutagenic activity of saponins isolated from calendula was seen in the Ames test using Salmonella typhimurium TA98 without and with metabolic activation (Elias et al. 1990). No mutagenic activity of an aqueous extract of calendula was seen in a s omatic mutation and recombination test using Drosophila melanogaster. Two flavonols, quercetin and rutin, had weak genotoxic activity (Graf et al. 1994).

No chromosomal damage was observed in the bone marrow micronucleus test after mice were orally administered up to 1 g/kg calendula aqueous-ethanolic extract daily for 2 days (Ramos et al. 1998). An aqueous-ethanolic extract of calendula exhibited dose-dependent toxicity and genotoxicity (both mitotic crossing-over and chromosome malsegre- gation) to Aspergillus at concentrations of 0.1 to 1.0 mg solids/ ml (Ramos et al. 1998). No mutagenic activity of an aqueous- ethanolic calendula extract at concentrations ranging from 50 to 5000 µg/plate was seen in several Salmonella strains with or without S9 activation (Ramos et al. 1998).

At low doses, aqueous and aqueous-ethanolic extracts of calendula provided effects against unscheduled DNA synthesis induced by diethylnitrosamine, whereas at high concentrations without diethylnitrosamine, the same extracts produced some genotoxic effects (Perez-Carreon et al. 2002).

Cytotoxicity

In vitro cytotoxic activity of calendula extracts was observed in MRC5, Hep2, and Ehrlich cell lines. When the same extracts were tested in mice, one was inactive and three were poorly active, whereas the most saponin-rich extract did not produce development of ascites (Boucaud- Maitre et al. 1988).

l

iteRatuRe

c

iteD

Boucaud-Maitre, Y., O. Algernon, and J. Raynaud. 1988. Cytotoxic and antitumoral activity of Calendula officinalis extracts.

Pharmazie 43(3):220-221.

Bruynzeel, D.P., W.G. van Ketel, E. Young, T. van Joost, and G. Smeenk. 1992. Contact sensitization by alternative topical medicaments containing plant extracts. The Dutch Contact Dermatoses Group. Contact Dermat. 27(4):278-279.

CIR. 2009. Cosmetic ingr edients found safe as used. December 2009. Washington D.C.: Cosmetic Ingredient Review. CTFA. 1980. Acute oral toxicity of Calendula officinalis extract. de Groot, A.C., D.P. Bruynzeel, J.D. Bos, et al. 1988. The allergens

in cosmetics. Arch. Dermatol. 124(10):1525-1529.

Dhar, M.L., M.M. Dhar , B.N. Dhawan, B.N. Mehr otra, and C. Ray. 1968. Screening of Indian plants for biological activity: I.

In document American Herbal Products Association's Botanical Safety Handbook (2nd Ed)(Gnv64) (Page 176-184)