EFSA Compendium of Botanicals

Draft - work in progress

Gingko (as plant) // Ginkgo biloba L.

Family:: Ginkgoaceae
Approval state:: Approved
Number of articles retrieved:: 19509
Number of processed references:: 7

Compositions

#1: Ginkgotoxin (MPN) in seeds #2: Proanthocyanidins in seeds and leaves #3: Diterpenes (Ginkgolides A, B, J and Bilabolide) in seeds and leaves

Endpoint Studies

#1: Liver carcinogenicity in mice #2: Hepatotoxicity in male B6C3F1 mice #3: Hepatotoxicity in male and female C3H mice #4: Neurological effects in human (child poisoning case report) #5: Neurologic effects in case report of child consuming seeds

Genotoxicity

#1: Mutagenic effects of G. biloba extract in In the bacterial Ames test #2: genotoxicity of G. biloba extract in the Comet assay #3: In vitro mutagenicity of leaf extract #4: In vitro genotoxicity (DNA double-strand breaks) of leaf extract #5: DNA damage in human hepatic HepG2 cells in vitro

Composition #1: Wada, K., Ishigaki, S., Ueda, K., Take, Y., Sasaki, K., Sakata, M., Haga, M. Studies on the Constitution of Edible and Medicinal Plants. I. Isolation and Identification of 4-0-Methylpyridoxine, Toxic Principle from the Seed of Ginkgo biloba L.. chemical and pharmaceutical bulletin, 1988, vol. 36, no. 5, p. 1779–1782. DOI: 10.1248/cpb.36.1779. [DOI link]

Language:

English (en)
Plant part:

Seed (as part-nature) (A066P)
Extraction/Preparation method:

Solvent extraction (A0BZR)
Additional extraction description:

albumin of seeds, dried, powdered, then extracted with water
Substance:

ginkgotoxin (RF-00003833-PAR)
Analytical method code:

Standard Chromatographic tests (paper- thin layer- and column chromatography) (F016A)
Analytical method - additional description:

Also: MS, NMR
Result unit:

Percent (G138A)
Result expression:

Dry matter (B002A)
Result type:

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

0.01
Internal remarks:

Ginkgotoxin (MPN) in seeds

Composition #2: Zhang, Z., Mei, N., Chen, S., Guo, L., Guo, X. Assessment of Genotoxic Effects of Selected Herbal Dietary Supplements. nutraceuticals: efficacy, safety and toxicity, 2016, p. 883–892. DOI: 10.1016/B978-0-12-802147-7.00062-0. [DOI link]

Language:

English (en)
Plant part:

Aerial part of plants (as part-nature) (A166F)
Additional extraction description:

seeds and leaves, not extraction specifics in Review paper
Substance:

Proanthocyanidins (condensed tannins) Proanthocyanidins (condensed tannins) (RF-00004370-PAR)
Analytical method code:

Unspecified (F598A)
Analytical method - additional description:

Review paper - no details given
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

Proanthocyanidins in seeds and leaves

Composition #3: Zhang, Z., Mei, N., Chen, S., Guo, L., Guo, X. Assessment of Genotoxic Effects of Selected Herbal Dietary Supplements. nutraceuticals: efficacy, safety and toxicity, 2016, p. 883–892. DOI: 10.1016/B978-0-12-802147-7.00062-0. [DOI link]

Language:

English (en)
Plant part:

Aerial part of plants (as part-nature) (A166F)
Additional extraction description:

seeds and leaves, not extraction specifics in Review paper
Substance:

Diterpenes Diterpenes (RF-00004378-PAR)
Additional substance description:

Ginkgolides A, B, C and J and Bilabolide (all diterpenes, group of concern)
Analytical method code:

Unspecified (F598A)
Analytical method - additional description:

Review paper - no details given
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

Diterpenes (Ginkgolides A, B, J and Bilabolide) in seeds and leaves

Endpoint study #1: Zhang, Z., Mei, N., Chen, S., Guo, L., Guo, X. Assessment of Genotoxic Effects of Selected Herbal Dietary Supplements. nutraceuticals: efficacy, safety and toxicity, 2016, p. 883–892. DOI: 10.1016/B978-0-12-802147-7.00062-0. [DOI link]

Study relevance:

Human health
Plant part:

Unspecified (A07XD)
Additional plant/substance description:

Review paper - no details provided
Type of toxicological test:

chronic/long term toxicity (CHD004TT)
Tested organism:

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

B6C3F1 (CHD001ST)
Sex:

No data
Route of exposure:

ORAL: GAVAGE (OECD2231PL)
Exposure duration:

2.0
Unit of exposure duration:

Year (G207A)
Control groups used:

yes
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

Increased incidence of hepatocellular carcinoma and hepatoblastoma.
Effect or parameter linked to the endpoint:

Carcinogenic (CHD036BE)
Internal remarks:

Liver carcinogenicity in mice

Endpoint study #2: Maeda, Jun., Kijima, Aki., Inoue, Kaoru., Ishii, Yuji., Ichimura, Ryohei., Takasu, Shinji., Kuroda, Ken., Matsushita, Kohei., Kodama, Yukio., Saito, Naoaki., Umemura, Takashi., Yoshida, Midori. In Vivo Genotoxicity of Ginkgo Biloba Extract in gpt Delta Mice and Constitutive Androstane Receptor Knockout Mice. toxicological sciences, 2014, vol. 140, no. 2, p. 298–306. DOI: 10.1093/toxsci/kfu090. [DOI link]

Study relevance:

Human health
Plant part:

Leaves (as part-nature) (A0EKT)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

extract solvent not specified...dose in corn oil as vehicle
Type of toxicological test:

subchronic (CHD013TT)
Tested organism:

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

B6C3F1 (CHD001ST)
Sex:

Male
Route of exposure:

ORAL: GAVAGE (OECD2231PL)
Exposure duration:

13.0
Unit of exposure duration:

Week (G205A)
Number of organisms dosed:

10
Control groups used:

yes, concurrent vehicle
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Milligrams per kilogram body weight per day (G211A)
Effect concentration:

2000
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

Increase absolute and relative liver organ weights and liver hypertrophy and necrosis.
Effect or parameter linked to the endpoint:

organ weights (CHD012BE)
Internal remarks:

Hepatotoxicity in male B6C3F1 mice

Endpoint study #3: Maeda, Jun., Kijima, Aki., Inoue, Kaoru., Ishii, Yuji., Ichimura, Ryohei., Takasu, Shinji., Kuroda, Ken., Matsushita, Kohei., Kodama, Yukio., Saito, Naoaki., Umemura, Takashi., Yoshida, Midori. In Vivo Genotoxicity of Ginkgo Biloba Extract in gpt Delta Mice and Constitutive Androstane Receptor Knockout Mice. toxicological sciences, 2014, vol. 140, no. 2, p. 298–306. DOI: 10.1093/toxsci/kfu090. [DOI link]

Study relevance:

Human health
Plant part:

Leaves (as part-nature) (A0EKT)
Preparation/Extraction method:

Solvent extraction (A0BZR)
Additional plant/substance description:

extract solvent not specified (dose in corn oil as vehicle)
Type of toxicological test:

short-term toxicity (CHD017TT)
Tested organism:

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

C3H (CHD086ST)
Sex:

Male/Female
Route of exposure:

ORAL: GAVAGE (OECD2231PL)
Exposure duration:

3.0
Unit of exposure duration:

Day (G134A)
Number of organisms dosed:

5
Control groups used:

yes, concurrent vehicle
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Milligrams per kilogram body weight per day (G211A)
Effect concentration:

500-2000
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

Increase absolute and relative liver organ weights and liver hypertrophy and vaculolation.
Effect or parameter linked to the endpoint:

histopathology non neoplastic (CHD025BE)
Internal remarks:

Hepatotoxicity in male and female C3H mice

Endpoint study #4: Di Lorenzo, Chiara., Ceschi, Alessandro., Colombo, Francesca., Frigerio, Gianfranco., Bianchetti, Mario G., Luede, Saskia., von Dechend, Margot., Valoti, Ermanno., Restani, Patrizia. Identification and quantification of biomarkers to confirm the poisoning by Ginkgo biloba seeds in a 2-year-old boy. toxicology research, 2015, vol. 4, no. 4, p. 922–930. DOI: 10.1039/c5tx00016e. [DOI link]

Study relevance:

Human health
Substance:

ginkgotoxin (RF-00003833-PAR)
Plant part:

Seed (as part-nature) (A066P)
Type of toxicological test:

case report (CHD060TT)
Tested organism:

Human (as organism) (A056J)
Sex:

Male
Route of exposure:

ORAL: UNSPECIFIED (OECD2234PL)
Number of organisms dosed:

1
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

NEUROTOXICITY (TOX04A)
Target tissue:

Digestive (TT002A)
Effect description:

Afebrile tonic-clonic seizures, vomiting, and somnolence in a 2-year-old after ingesting unknown amount of seeds. MPN (ginkgotoxin) biomarkers confirmed in blood/urine.
Effect or parameter linked to the endpoint:

neurology (CHD027BE)
Internal remarks:

Neurological effects in human (child poisoning case report)

Endpoint study #5: Sado, Tomomitsu., Nakata, Setsuko., Tsuno, Takahisa., Sato, Masanori., Misawa, Yuka., Yamauchi, Shoko., Inaba, Yuji., Kobayashi, Daisuke., Wada, Keiji. Concentrations of various forms of vitamin B-6 in ginkgo seed poisoning. brain & development, 2019, vol. 41, no. 3, p. 292–295. DOI: 10.1016/j.braindev.2018.10.007. [DOI link]

Study relevance:

Human health
Plant part:

Seed (as part-nature) (A066P)
Additional plant/substance description:

patient ingested 20-30 seeds two days in a row
Type of toxicological test:

case report (CHD060TT)
Tested organism:

Human (as organism) (A056J)
Sex:

Female
Route of exposure:

ORAL: UNSPECIFIED (OECD2234PL)
Exposure duration:

2.0
Unit of exposure duration:

Day (G134A)
Number of organisms dosed:

1
Control groups used:

no
Endpoint measured:

Dose not reported (CHD066EP)
Critical effect:

NEUROTOXICITY (TOX04A)
Target tissue:

Neurologic (TT004A)
Effect description:

Tonic-clonic convulsions and drowsiness.
Effect or parameter linked to the endpoint:

neurology (CHD027BE)
Internal remarks:

Neurologic effects in case report of child consuming seeds

Genotox #1: Zhang, Z., Mei, N., Chen, S., Guo, L., Guo, X. Assessment of Genotoxic Effects of Selected Herbal Dietary Supplements. nutraceuticals: efficacy, safety and toxicity, 2016, p. 883–892. DOI: 10.1016/B978-0-12-802147-7.00062-0. [DOI link]

Study category:

Mutagenicity
Type of toxicological test:

bacterial reverse mutation assay (CHD028TT)
Method type:

in vitro
Guideline used:

No guideline required
Tested organism:

Salmonella typhimurium (as organism) (A0CPZ)
Endpoint measured:

gene mutation
Is genotoxic:

Positive
Remarks on genotox study:

Review article mentioning In the bacterial Ames test, G. biloba extract at concentrations of 1–10 mg/plate was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101 both in the absence or presence of exogenous S9 metabolic activation
Internal remarks:

Mutagenic effects of G. biloba extract in In the bacterial Ames test
Internal ID:

2-s2.0-84967121161

Genotox #2: Zhang, Z., Mei, N., Chen, S., Guo, L., Guo, X. Assessment of Genotoxic Effects of Selected Herbal Dietary Supplements. nutraceuticals: efficacy, safety and toxicity, 2016, p. 883–892. DOI: 10.1016/B978-0-12-802147-7.00062-0. [DOI link]

Study category:

Genotoxicity
Type of toxicological test:

single cell gel/comet assay in mammalian cells for detection of DNA damage (CHD040TT)
Method type:

in vitro
Guideline used:

No guideline required
Tested organism:

Other (A07XE)
Strain of test organism:

lymphoma L5178Y cells (CHD035ST)
Endpoint measured:

DNA damage and/or repair
Is genotoxic:

Positive
Remarks on genotox study:

Review article mentioning that G. biloba extract at concentrations of 0.2– 1.2 mg/mL induced a dose-dependent increase in the percentage of tail DNA intensity in the Comet assay, with positive responses
Internal remarks:

genotoxicity of G. biloba extract in the Comet assay
Internal ID:

2-s2.0-84967121161

Genotox #3: Lin, Haixia., Guo, Xiaoqing., Zhang, Suhui., Dial, Stacey L., Guo, Lei., Manjanatha, Mugimane G., Moore, Martha M., Mei, Nan. Mechanistic Evaluation of Ginkgo biloba Leaf Extract-Induced Genotoxicity in L5178Y Cells. toxicological sciences, 2014, vol. 139, no. 2, p. 338–349. DOI: 10.1093/toxsci/kfu037. [DOI link]

Study category:

Mutagenicity
Type of toxicological test:

mammalian cell gene mutation assay (CHD030TT)
Method type:

in vitro
Tested organism:

House mouse (as animal) (A0CNT)
Sex:

No data
Exogenous metabolic activation applied:

with and without
Control groups used:

yes
Endpoint measured:

gene mutation
Is genotoxic:

Positive
Remarks on genotox study:

Ginkgo biloba leaf extract was mutagenic in vitro without metabolic activation in Tk mouse lymphoma cell line
Internal remarks:

In vitro mutagenicity of leaf extract
Internal ID:

WOS:000337075900007

Genotox #4: Lin, Haixia., Guo, Xiaoqing., Zhang, Suhui., Dial, Stacey L., Guo, Lei., Manjanatha, Mugimane G., Moore, Martha M., Mei, Nan. Mechanistic Evaluation of Ginkgo biloba Leaf Extract-Induced Genotoxicity in L5178Y Cells. toxicological sciences, 2014, vol. 139, no. 2, p. 338–349. DOI: 10.1093/toxsci/kfu037. [DOI link]

Study category:

Genotoxicity
Type of toxicological test:

single cell gel/comet assay in mammalian cells for detection of DNA damage (CHD040TT)
Method type:

in vitro
Tested organism:

House mouse (as animal) (A0CNT)
Sex:

No data
Control groups used:

yes
Endpoint measured:

DNA damage and/or repair
Is genotoxic:

Positive
Remarks on genotox study:

Ginkgo biloba leaf extract was genotoxic in vitro in Tk mouse lymphoma cell line via Comet assay - DNA double strand breaks
Internal remarks:

In vitro genotoxicity (DNA double-strand breaks) of leaf extract
Internal ID:

WOS:000337075900007

Genotox #5: Zhang, Zhuhong., Chen, Si., Mei, Hu., Xuan, Jiekun., Guo, Xiaoqing., Couch, Letha., Dobrovolsky, Vasily N., Guo, Lei., Mei, Nan. Ginkgo biloba leaf extract induces DNA damage by inhibiting topoisomerase II activity in human hepatic cells. scientific reports, 2015, vol. 5 . DOI: 10.1038/srep14633. [DOI link]

Study category:

Genotoxicity
Type of toxicological test:

single cell gel/comet assay in mammalian cells for detection of DNA damage (CHD040TT)
Method type:

in vitro
Tested organism:

Human (as organism) (A056J)
Sex:

No data
Exogenous metabolic activation applied:

with
Exposure duration for in vivo:

4.0
Unit of exposure duration:

Hour (G099A)
Control groups used:

yes
Endpoint measured:

DNA damage and/or repair
Is genotoxic:

Positive
Remarks on genotox study:

Comet assay with metabolic activation revealed DNA damage of G. biloba extract in human hepatic HepG2 cells at concentrations above 400 ug/ml.
Internal remarks:

DNA damage in human hepatic HepG2 cells in vitro
Internal ID:

WOS:000361945400001