EFSA Compendium of Botanicals

Draft - work in progress

Symphytum officinale L.

Family:: Boraginaceae
Approval state:: Approved
Number of articles retrieved:: 688
Number of processed references:: 7

Compositions

#1: symlandine in roots #2: pyrrolizidine alkaloids in leaves #3: pyrrolizidine alkaloids in root #4: acetyllcopsamine in roots #5: echimidine in roots #6: lycopsamine in roots #7: symphytine in roots #8: 7-acetyllycopsamine in roots #9: lycopsamine in roots #10: symphytine in roots #11: intermedine in roots #12: 7- acetylintermedine in roots #13: lycopsamine in roots #14: intermedine in roots #15: symphytoxide A in roots

Endpoint Studies

#1: hepatic veno-occlusive disease #2: hepatotoxicity effect - body weight, biochemical and histopathological changes #3: hepatoxicity, decrease body weight

Genotoxicity

#1: mutagenic effect on a human cell line #2: in vivo mutagenicity effect of 2% root in the diet #3: positive mutagenicity test in rat lung with 8% root in the diet

Composition #1: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Symlandine (RF-00000303-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

HPLC/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

symlandine in roots

Composition #2: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Pyrrolizidine alkaloids (RF-00000230-TOX)
Analytical method code:

Gaschromatography (GC) (F037A)
Analytical method - additional description:

GC/FID, GC/MS
Result unit:

Microgram/gram (G049A)
Result type:

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

15-55
Internal remarks:

pyrrolizidine alkaloids in leaves

Composition #3: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Pyrrolizidine alkaloids (RF-00000230-TOX)
Analytical method code:

Gaschromatography (GC) (F037A)
Analytical method - additional description:

GC/FID, GC/MS
Result unit:

Microgram/gram (G049A)
Result type:

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

1.38-8.32
Internal remarks:

pyrrolizidine alkaloids in root

Composition #4: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

7-acetyllycopsamine (RF-00000265-TOX)
Additional substance description:

acetyllcopsamine
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

HPLC/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

acetyllcopsamine in roots

Composition #5: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Echimidine (RF-00000276-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

HPLC/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

echimidine in roots

Composition #6: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Lycopsamine (RF-00000228-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

HPLC/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

lycopsamine in roots

Composition #7: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Language:

English (en)
Plant part:

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

Solvent extraction (A0BZR)
Additional extraction description:

methanol
Substance:

Symphytine (RF-00000229-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

HPLC/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

symphytine in roots

Composition #8: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Substance:

7-acetyllycopsamine (RF-00000265-TOX)
Analytical method code:

Mass Spectroscopy and hyphenated methods without chromatography (F063A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

7-acetyllycopsamine in roots

Composition #9: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Substance:

Lycopsamine (RF-00000228-TOX)
Analytical method code:

Mass Spectroscopy and hyphenated methods without chromatography (F063A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

lycopsamine in roots

Composition #10: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Substance:

Symphytine (RF-00000229-TOX)
Analytical method code:

Mass Spectroscopy and hyphenated methods without chromatography (F063A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

symphytine in roots

Composition #11: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Substance:

Intermedine (RF-00000227-TOX)
Analytical method code:

Mass Spectroscopy and hyphenated methods without chromatography (F063A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

intermedine in roots

Composition #12: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Language:

English (en)
Plant part:

Roots and other underground parts (as part-nature) (A067M)
Substance:

7-acetylintermedine (RF-00000264-TOX)
Analytical method code:

Mass Spectroscopy and hyphenated methods without chromatography (F063A)
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

7- acetylintermedine in roots

Composition #13: Brown, Ammon W., Stegelmeier, Bryan L., Colegate, Steven M., Gardner, Dale R., Panter, Kip E., Knoppel, Edward L., Hall, Jeffery O. The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus) . journal of applied toxicology, 2016, vol. 36, no. 5, p. 716–725. DOI: 10.1002/jat.3205. [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:

Lycopsamine (RF-00000228-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

MS-MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

lycopsamine in roots

Composition #14: Brown, Ammon W., Stegelmeier, Bryan L., Colegate, Steven M., Gardner, Dale R., Panter, Kip E., Knoppel, Edward L., Hall, Jeffery O. The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus) . journal of applied toxicology, 2016, vol. 36, no. 5, p. 716–725. DOI: 10.1002/jat.3205. [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:

Intermedine (RF-00000227-TOX)
Analytical method code:

High Performance Liquid Chromatography (HPLC)/Liquid Chromatography (LC) (F018A)
Analytical method - additional description:

MS/MS
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

intermedine in roots

Composition #15: AHMAD, VU., NOORWALA, M., MOHAMMAD, FV., SENER, B., GILANI, AUH., AFTAB, K. SYMPHYTOXIDE-A, A TRITERPENOID SAPONIN FROM THE ROOTS OF SYMPHYTUM-OFFICINALE . phytochemistry, 1993, vol. 32, no. 4, p. 1003–1006. DOI: 10.1016/0031-9422(93)85244-L. [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:

Ethanol
Substance:

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

symphytoxide A
Analytical method code:

Nuclear Magnetic Resonance (NMR) (F061A)
Analytical method - additional description:

ms, uv, ir
Yes/No Qualitative:

Positive/Present (POS)
Result type:

Qualitative Value (Binary) (BIN)
Internal remarks:

symphytoxide A in roots

Endpoint study #1: Stickel, F., Seitz, H K. The efficacy and safety of comfrey.. public health nutrition, 2000, vol. 3, no. 4A, p. 501–8. .

Study relevance:

Human health
Substance:

Pyrrolizidine alkaloids (RF-00000230-TOX)
Plant part:

Unspecified (A07XD)
Preparation/Extraction method:

Drying (dehydration) (A07KG)
Additional plant/substance description:

tea, capsules
Type of toxicological test:

case report (CHD060TT)
Limit test:

Not applicable
Tested organism:

Human (as organism) (A056J)
Sex:

Female
Route of exposure:

ORAL: UNSPECIFIED (OECD2234PL)
Exposure duration:

6.0
Unit of exposure duration:

Month (G206A)
Number of organisms dosed:

1
Control groups used:

no
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Micrograms per kilogram body weight (G224A)
Effect concentration:

15
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

hepatic veno-occlusive disease
Effect or parameter linked to the endpoint:

other (CHD003BE)
Internal remarks:

hepatic veno-occlusive disease

Endpoint study #2: Brown, Ammon W., Stegelmeier, Bryan L., Colegate, Steven M., Gardner, Dale R., Panter, Kip E., Knoppel, Edward L., Hall, Jeffery O. The comparative toxicity of a reduced, crude comfrey (Symphytum officinale) alkaloid extract and the pure, comfrey-derived pyrrolizidine alkaloids, lycopsamine and intermedine in chicks (Gallus gallus domesticus) . journal of applied toxicology, 2016, vol. 36, no. 5, p. 716–725. DOI: 10.1002/jat.3205. [DOI link]

Study relevance:

Human health
Substance:

Pyrrolizidine alkaloids (RF-00000230-TOX)
Plant part:

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

Solvent extraction (A0BZR)
Type of toxicological test:

short-term toxicity (CHD017TT)
Limit test:

Not applicable
Tested organism:

Gallus gallus (chicken) (as animal) (A057Z)
Sex:

Male
Route of exposure:

ORAL: GAVAGE (OECD2231PL)
Exposure duration:

10.0
Unit of exposure duration:

Day (G134A)
Control groups used:

yes
Endpoint measured:

Dose level (CHD014EP)
Concentration unit:

Millimole/kilogram (G070A)
Effect concentration:

0.13
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

chenges in SDH enzyme, bile acids, serum glucose, decrease in average daily gain, lower liver weight, presence hepatic necrosis, angiectasis, capsular serositis
Effect or parameter linked to the endpoint:

histopathology non neoplastic (CHD025BE)
Internal remarks:

hepatotoxicity effect - body weight, biochemical and histopathological changes

Endpoint study #3: GARRETT, BJ., CHEEKE, PR., MIRANDA, CL., GOEGER, DE., BUHLER, DR. CONSUMPTION OF POISONOUS PLANTS (SENECIO-JACOBAEA, SYMPHYTUM-OFFICINALE, PTERIDIUM-AQUILINUM, HYPERICUM-PERFORATUM) BY RATS - CHRONIC TOXICITY, MINERAL METABOLISM, AND HEPATIC DRUG-METABOLIZING-ENZYMES . toxicology letters, 1982, vol. 10, no. 2-3, p. 183–188. DOI: 10.1016/0378-4274(82)90072-8. [DOI link]

Study relevance:

Human health
Plant part:

Unspecified (A07XD)
Preparation/Extraction method:

Drying (dehydration) (A07KG)
Type of toxicological test:

short-term toxicity (CHD017TT)
Tested organism:

Rat (as animal) (A0CNV)
Strain of test organism:

Long-Evans (CHD010ST)
Sex:

Male
Route of exposure:

ORAL: FEED (OECD2230PL)
Exposure duration:

21.0
Unit of exposure duration:

Day (G134A)
Number of organisms dosed:

6
Control groups used:

yes, plain diet
Endpoint measured:

Concentration level (CHD013EP)
Concentration unit:

Percent (G138A)
Effect concentration:

30
Critical effect:

HEPATOTOXICITY (TOX02A)
Target tissue:

digestive: Liver (TT023A)
Effect description:

reduced body weight, stimulated activity of aminopyrine N-demethylase
Effect or parameter linked to the endpoint:

body weight (CHD005BE)
Internal remarks:

hepatoxicity, decrease body weight

Genotox #1: Couet, Carole E., Crews, Colin., Hanley, A. Bryan. Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale) . natural toxins, 1996, vol. 4, no. 4, p. 163–167. .

Study category:

Mutagenicity
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 followed
Tested organism:

Other (A07XE)
Exogenous metabolic activation applied:

with
Control groups used:

yes
Endpoint measured:

gene mutation
Is genotoxic:

Positive
Remarks on genotox study:

mutagenic effect on a human change liver cells
Internal remarks:

mutagenic effect on a human cell line
Internal ID:

BCI:BCI199699240405

Genotox #2: Mei, N., Guo, L., Fu, PP., Heflich, RH., Chen, T. Mutagenicity of comfrey (Symphytum Officinale) in rat liver. british journal of cancer, 2005, vol. 92, no. 5, p. 873–875. DOI: 10.1038/sj.bjc.6602420. [DOI link]

Study category:

Mutagenicity
Type of toxicological test:

transgenic BigBlue® rat cell assay for detection of gene mutation in vitro (CHD031TT)
Method type:

in vivo
Guideline used:

No guideline followed
Tested organism:

Rat (as animal) (A0CNV)
Strain of test organism:

Big Blue TM - Rat strain (CHD166ST)
Sex:

Male
Exogenous metabolic activation applied:

not applicable
Route of exposure:

ORAL: FEED (OECD2230PL)
Exposure duration for in vivo:

12.0
Unit of exposure duration:

Week (G205A)
Number of organisms dosed:

6
Control groups used:

yes, concurrent vehicle
Endpoint measured:

gene mutation
Is genotoxic:

Positive
Remarks on genotox study:

Mutant frequencies were statistically significantly greater than in control rats
Internal remarks:

in vivo mutagenicity effect of 2% root in the diet
Internal ID:

WOS:000227827300014

Genotox #3: Mei, Xunbai., Chen, Tao. The mutant frequencies and types of mutations induced by comfrey in the lungs of transgenic big blue rats . journal of food and drug analysis, 2007, vol. 15, no. 4, p. 458–465. .

Study category:

Mutagenicity
Type of toxicological test:

transgenic BigBlue® rat cell assay for detection of gene mutation in vitro (CHD031TT)
Method type:

in vivo
Guideline used:

No guideline followed
Tested organism:

Rat (as animal) (A0CNV)
Strain of test organism:

Big Blue TM - Rat strain (CHD166ST)
Sex:

Male
Exogenous metabolic activation applied:

not applicable
Route of exposure:

ORAL: FEED (OECD2230PL)
Exposure duration for in vivo:

12.0
Unit of exposure duration:

Week (G205A)
Number of organisms dosed:

6
Control groups used:

yes, plain diet
Endpoint measured:

gene mutation
Is genotoxic:

Positive
Remarks on genotox study:

Mutant frequencies in lungs were significantly greater than in control rats
Internal remarks:

positive mutagenicity test in rat lung with 8% root in the diet
Internal ID:

WOS:000252435600015