EFSA Compendium of Botanicals

Draft - work in progress

Actaea racemosa L. // Cimicifuga racemosa (L.) Nutt.

Family:: Ranunculaceae
Approval state:: Approved
Number of articles retrieved:: 1551
Number of processed references:: 8

Compositions

#1: triterpene glycosides (saponins) #2: alkaloids #3: tannins #4: protocatechuic acid #5: isoimperatorin and cimiside E (steroidal triterpene saponins)( #6: 23-O-acetylschengmanlo (coumarin)

Endpoint Studies

#1: Intragastric administration of doses of 2g/Kg from day 7 to 17 of gestation resulted to be teratogenic #2: autoimmune hepatitis #3: autoimmune hepatitis #4: myopathy with severe asthenia and rhabdomyolysis #5: reversible complete heart block with bradycardia #6: cutaneous pseudolymphoma, cutaneous vasculitis #7: carcinogenic (lungs) #8: liver damage

Genotoxicity

#1: Mouse lymphoma mutagencity #2: An alcoholic extract (40%) resulted to be mutagenic in S. typhimurium TA 98 an TA 100.

Composition #1: Abdualmjid, R.J., Sergi, C. Hepatotoxic botanicals - An evidence-based systematic review. journal of pharmacy and pharmaceutical sciences, 2013, vol. 16, no. 3, p. 376–404. .

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

unspecified
Substance:

Triterpene saponins Triterpene saponins (RF-00004338-PAR)
Additional substance description:

actein, cimicifugoside and 27-deoxyactein
Analytical method code:

Unspecified (F598A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

triterpene glycosides (saponins)

Composition #2: Abdualmjid, R.J., Sergi, C. Hepatotoxic botanicals - An evidence-based systematic review. journal of pharmacy and pharmaceutical sciences, 2013, vol. 16, no. 3, p. 376–404. .

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

unspecified
Substance:

Alkaloids (RF-00004360-PAR)
Analytical method code:

Unspecified (F598A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

alkaloids

Composition #3: Abdualmjid, R.J., Sergi, C. Hepatotoxic botanicals - An evidence-based systematic review. journal of pharmacy and pharmaceutical sciences, 2013, vol. 16, no. 3, p. 376–404. .

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

unspecified
Substance:

Tannins (RF-00004337-PAR)
Analytical method code:

Unspecified (F598A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

tannins

Composition #4: Wang, Yun-Jan., Dou, Jinhui., Cross, Kevin P., Valerio, Luis G., Jr. Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms . regulatory toxicology and pharmacology, 2011, vol. 59, no. 1, p. 111–124. DOI: 10.1016/j.yrtph.2010.09.012. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

unspecified
Substance:

3,4-Dihydroxybenzoic acid (RF-00008853-PAR)
Analytical method code:

Unspecified (F598A)
Result unit:

Percent (G138A)
Result type:

Numerical Value (VAL)
Value (concentration, content):

0.00088
Internal remarks:

protocatechuic acid

Composition #5: Moon, Lidiya., Ha, Yu Mi., Jang, Hwa Jin., Kim, Hee Sook., Jun, Min Soo., Kim, Young Min., Lee, Young Soo., Lee, Dong Hwa., Son, Kun Ho., Kim, Hye Jung., Seo, Han Geuk., Lee, Jae Heun., Kim, Yeong Shik., Chang, Ki Churl. Isoimperatorin, cimiside E and 23-O-acetylshengmanol-3-xyloside from Cimicifugae Rhizome inhibit TNF-alpha-induced VCAM-1 expression in human endothelial cells: Involvement of PPAR-gamma upregulation and PI3K, ERK1/2, and PKC signal pathways . journal of ethnopharmacology, 2011, vol. 133, no. 2, p. 336–344. DOI: 10.1016/j.jep.2010.10.004. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts used as staple food (as part-nature) (A0F5F)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

MeOH, CH2Cl2
Substance:

steroidal triterpene saponins steroidal triterpene saponins (RF-00004374-PAR)
Additional substance description:

isoimperatorin and cimiside E
Analytical method code:

Standard Chromatographic tests (paper- thin layer- and column chromatography) (F016A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

isoimperatorin and cimiside E (steroidal triterpene saponins)(

Composition #6: Moon, Lidiya., Ha, Yu Mi., Jang, Hwa Jin., Kim, Hee Sook., Jun, Min Soo., Kim, Young Min., Lee, Young Soo., Lee, Dong Hwa., Son, Kun Ho., Kim, Hye Jung., Seo, Han Geuk., Lee, Jae Heun., Kim, Yeong Shik., Chang, Ki Churl. Isoimperatorin, cimiside E and 23-O-acetylshengmanol-3-xyloside from Cimicifugae Rhizome inhibit TNF-alpha-induced VCAM-1 expression in human endothelial cells: Involvement of PPAR-gamma upregulation and PI3K, ERK1/2, and PKC signal pathways . journal of ethnopharmacology, 2011, vol. 133, no. 2, p. 336–344. DOI: 10.1016/j.jep.2010.10.004. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts used as staple food (as part-nature) (A0F5F)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

MeOH , CH2CL2
Substance:

Coumarin (RF-00000370-TOX)
Additional substance description:

23-O-acetylschengmanolo 3-xyloside
Analytical method code:

Standard Chromatographic tests (paper- thin layer- and column chromatography) (F016A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

23-O-acetylschengmanlo (coumarin)

Endpoint study #1: Dos Reis Turolla, M.S., De Souza Nascimento, E. Toxicological information of some herbal medicines used in Brazil Informações toxicológicas de alguns fitoterápicos utilizados no Brasil . revista brasileira de ciencias farmaceuticas/brazilian journal of pharmaceutical sciences, 2006, vol. 42, no. 2, p. 289–306. .

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Type of toxicological test:

reproduction toxicity (CHD009TT)
Tested organism:

Rat (as animal) (A0CNV)
Sex:

Female
Route of exposure:

ORAL: FEED (OECD2230PL)
Exposure duration:

10.0
Unit of exposure duration:

Day (G134A)
Control groups used:

yes
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Grams per kilogram body weight (G226A)
Effect concentration:

2.0
Critical effect:

REPRODUCTIVE (TOX05A)
Target tissue:

urogenital: Uterus (TT052A)
Effect description:

teratogenic
Effect or parameter linked to the endpoint:

mortality (CHD010BE)
Internal remarks:

Intragastric administration of doses of 2g/Kg from day 7 to 17 of gestation resulted to be teratogenic

Endpoint study #2: Seeff, L.B. Herbal Hepatotoxicity. clinics in liver disease, 2007, vol. 11, no. 3, p. 577–596. DOI: 10.1016/j.cld.2007.06.005. [DOI link]

Study relevance:

Human health
Type of toxicological test:

not reported (CHD015TT)
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

autoimmune hepatitis
Effect or parameter linked to the endpoint:

immunology (CHD026BE)
Internal remarks:

autoimmune hepatitis

Endpoint study #3: Abdualmjid, R.J., Sergi, C. Hepatotoxic botanicals - An evidence-based systematic review. journal of pharmacy and pharmaceutical sciences, 2013, vol. 16, no. 3, p. 376–404. .

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Type of toxicological test:

case report (CHD060TT)
Sex:

Female
Route of exposure:

ORAL: UNSPECIFIED (OECD2234PL)
Number of organisms dosed:

3
Control groups used:

no data
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

autoimmune hepatitis, severe hepatitis and jaundice leading to liver transplant, fulminant hepatitis with diffuse cell necrosis and cholestasis
Effect or parameter linked to the endpoint:

immunology (CHD026BE)
Internal remarks:

autoimmune hepatitis

Endpoint study #4: Di Lorenzo, C., Ceschi, A., Kupferschmidt, H., Lüde, S., De Souza Nascimento, E., Dos Santos, A., Colombo, F., Frigerio, G., Nørby, K., Plumb, J., Finglas, P., Restani, P. Adverse effects of plant food supplements and botanical preparations: A systematic review with critical evaluation of causality. british journal of clinical pharmacology, 2015, vol. 79, no. 4, p. 578–592. DOI: 10.1111/bcp.12519. [DOI link]

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

Plant food supplement containing A. rasemosa but maybe also other plants. unclear
Type of toxicological test:

chronic/long term toxicity (CHD004TT)
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

MUSCLO-SKELETAL (TOX13A)
Target tissue:

Muscle, Skeletal (TT055A)
Effect description:

myopathy with severe asthenia and rhabdomyolysis
Effect or parameter linked to the endpoint:

mobility (CHD011BE)
Internal remarks:

myopathy with severe asthenia and rhabdomyolysis

Endpoint study #5: Di Lorenzo, C., Ceschi, A., Kupferschmidt, H., Lüde, S., De Souza Nascimento, E., Dos Santos, A., Colombo, F., Frigerio, G., Nørby, K., Plumb, J., Finglas, P., Restani, P. Adverse effects of plant food supplements and botanical preparations: A systematic review with critical evaluation of causality. british journal of clinical pharmacology, 2015, vol. 79, no. 4, p. 578–592. DOI: 10.1111/bcp.12519. [DOI link]

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

Plant food supplement containing A. rasemosa but maybe also other plants. unclear
Type of toxicological test:

short-term toxicity (CHD017TT)
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

PULMONARY AND CARDIAC (TOX08A)
Target tissue:

cardiovascular / haematological: Heart (TT011A)
Effect description:

reversible complete heart block with bradycardia
Effect or parameter linked to the endpoint:

not reported (CHD030BE)
Internal remarks:

reversible complete heart block with bradycardia

Endpoint study #6: Di Lorenzo, C., Ceschi, A., Kupferschmidt, H., Lüde, S., De Souza Nascimento, E., Dos Santos, A., Colombo, F., Frigerio, G., Nørby, K., Plumb, J., Finglas, P., Restani, P. Adverse effects of plant food supplements and botanical preparations: A systematic review with critical evaluation of causality. british journal of clinical pharmacology, 2015, vol. 79, no. 4, p. 578–592. DOI: 10.1111/bcp.12519. [DOI link]

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

Plant food supplement containing A. rasemosa but maybe also other plants. unclear
Type of toxicological test:

not reported (CHD015TT)
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

Other toxicities (TOX19A)
Target tissue:

Skin/subcutis (TT056A)
Effect description:

cutaneous pseudolymphoma, cutaneous vasculitis
Effect or parameter linked to the endpoint:

not reported (CHD030BE)
Internal remarks:

cutaneous pseudolymphoma, cutaneous vasculitis

Endpoint study #7: Davis, Vicki L., Jayo, Manuel J., Ho, Arline., Kotlarczyk, Mary P., Hardy, Mary L., Foster, Warren G., Hughes, Claude L. Black Cohosh Increases Metastatic Mammary Cancer in Transgenic Mice Expressing c-erbB2 . cancer research, 2008, vol. 68, no. 20, p. 8377–8383. DOI: 10.1158/0008-5472.CAN-08-1812. [DOI link]

Study relevance:

Human health
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

ethanol, methanol, or 2-propanol (isopropanol)
Type of toxicological test:

chronic/long term toxicity (CHD004TT)
Limit test:

Yes
Guideline used:

No guideline available
Tested organism:

House mouse (as animal) (A0CNT)
Sex:

Female
Route of exposure:

ORAL: FEED (OECD2230PL)
Exposure duration:

16.0
Unit of exposure duration:

Month (G206A)
Number of organisms dosed:

300
Control groups used:

yes, plain diet
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Milligrams per day (G209A)
Effect concentration:

40
Critical effect:

Other toxicities (TOX19A)
Target tissue:

respiratory: Lung (TT041A)
Effect description:

lung metastases, increased number of lung lesions
Effect or parameter linked to the endpoint:

Carcinogenic (CHD036BE)
Internal remarks:

carcinogenic (lungs)

Endpoint study #8: Wang, Yun-Jan., Dou, Jinhui., Cross, Kevin P., Valerio, Luis G., Jr. Computational analysis for hepatic safety signals of constituents present in botanical extracts widely used by women in the United States for treatment of menopausal symptoms . regulatory toxicology and pharmacology, 2011, vol. 59, no. 1, p. 111–124. DOI: 10.1016/j.yrtph.2010.09.012. [DOI link]

Study relevance:

Human health
Substance:

3,4-Dihydroxybenzoic acid (RF-00008853-PAR)
Type of toxicological test:

subchronic (CHD013TT)
Tested organism:

House mouse (as animal) (A0CNT)
Sex:

No data
Route of exposure:

ORAL: DRINKING WATER (OECD2229PL)
Exposure duration:

60.0
Unit of exposure duration:

Day (G134A)
Control groups used:

no data
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Percent (G138A)
Effect concentration:

0.01-1
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

Mild increase in liver enzymes after 60 day 0.01, 0.1% in drinking water
Effect or parameter linked to the endpoint:

other (CHD003BE)
Internal remarks:

liver damage

Genotox #1: Seifried, H.E., Seifried, R.M., Clarke, J.J., Junghans, T.B., San, R.H.C. A compilation of two decades of mutagenicity test results with the ames Salmonella typhimurium and L5178Y mouse lymphoma cell mutation assays. chemical research in toxicology, 2006, vol. 19, no. 5, p. 627–644. DOI: 10.1021/tx0503552. [DOI link]

Study category:

Mutagenicity
Type of toxicological test:

mammalian cell gene mutation assay (CHD030TT)
Method type:

in vitro
Guideline used:

No guideline followed
Tested organism:

House mouse (as animal) (A0CNT)
Strain of test organism:

lymphoma L5178Y cells (CHD035ST)
Sex:

No data
Exogenous metabolic activation applied:

with
Route of exposure:

OTHER (OECD0PL)
Endpoint measured:

gene mutation
Is genotoxic:

Ambiguous
Remarks on genotox study:

Activity is seen only at high dose levels
Internal remarks:

Mouse lymphoma mutagencity
Internal ID:

eid=2-s2.0-33744493100

Genotox #2: Dos Reis Turolla, M.S., De Souza Nascimento, E. Toxicological information of some herbal medicines used in Brazil Informações toxicológicas de alguns fitoterápicos utilizados no Brasil . revista brasileira de ciencias farmaceuticas/brazilian journal of pharmaceutical sciences, 2006, vol. 42, no. 2, p. 289–306. .

Study category:

Mutagenicity
Type of toxicological test:

bacterial gene mutation assay (CHD027TT)
Method type:

in vitro
Tested organism:

Salmonella typhimurium (as organism) (A0CPZ)
Strain of test organism:

TA 100 (CHD024ST)
Is genotoxic:

Positive
Remarks on genotox study:

S.typhimurium positive test
Internal remarks:

An alcoholic extract (40%) resulted to be mutagenic in S. typhimurium TA 98 an TA 100.
Internal ID:

eid=2-s2.0-33748286692