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. 2020 Oct 12;9(10):1345. doi: 10.3390/plants9101345

Table 3.

Existing studies that screened toxicity of medicinal plants using the zebrafish model.

Plant/Family Common Name Extraction/Part of Plant Concentrations Range (µg/mL) LC50 (µg/mL) Characteristics of Effect Reference
Acorus calamus/Acoraceae Sweet flag Ethanol/rhizome n.a. n.a. Fish treated with this extract returned to normal condition and revealed a decrease level in superoxide dismutase and decreased mitochondrial volume and cell viability. [74]
Achyranthes aspera/Amaranthaceae Chaff-flower, prickly chaff flower, devil’s horsewhip, burweed Ethanol/leaf n.a. n.a. Fish treated with this extract returned to normal condition and revealed decrease in superoxide dismutase level and decreased mitochondrial and cell viability. [74]
Achyranthes bidentate/Amaranthaceae Ox knee, niu xi (Chinese) Aqueous/root 0–30.01 µg/mL No mortality observed The extract did not exhibit noticeable lethal or severe side effects on zebrafish larvae/embryos. [75]
Allium carinatum/Amaryllidaceae Keeled garlic, witch’s garlic 70% aqueous methanol/whole plant 1–60 µg/mL 55.8 µg/mL The extract reduced developmental toxicity and neutropenia. No teratogenic effects were seen. [76]
Allium flavum/Amaryllidaceae The small yellow onion, yellow-flowered garlic 70% aqueous methanol/whole plant 1–60 µg/mL 50.3 µg/mL The extract reduced developmental toxicity and neutropenia. No teratogenic effects were seen. [76]
Andrographis paniculata/Acanthaceae Green chiretta, creat Aqueous/leaf 0–10,000 µg/mL 525.5 µg/mL (48 hpf)
525.6 µg/mL (96 hpf)
Morphological defects were observed at 96 hpf after exposure to teratogen concentration. [2]
Annona squamosa/Annonaceae Sugar apple, sweetsop Ethanol/young leaf 100–1000 µg/mL n.a. Late hatching process and morphological deformations occurred at higher concentrations up to 800 µg. [77]
Avicennia marina/Acanthaceae Grey mangrove or white mangrove Methanol/bark, leaf, stem, flower and fruit 50–100 µg/mL n.a. n.a. [78]
Azadirachta indica/Meliaceae Neem Ethanol (cold)/fruit 1000–5000 µg/mL n.a. Not toxic to adult zebrafish and did not alter the locomotor system. [79]
Bougainvillea galbra/Nyctaginaceae The lesser bougainvillea, paperflower Aqueous/bracts 1–300 µg/mL 85.51 µg/mL Yolk sac edema was observed at different concentrations. Hypopigmentation in the embryo was caused by the purple bract extract at 30 µg/mL. Overall, this extract generally showed moderate embryo toxicity. [80]
Bixa Orellana/Bixaceae Achiote Hot water/leaf 50–10,000 µg/mL n.a. Plant extract affected the hatchability of embryos and was linked to delayed development. Also, a coagulated embryo, and tail malformation were observed as teratogenic effects. [81]
Capsicum chinense/Solanaceae Habanero type pepper Ethanol/fruit 0.39–100 µg/mL 39.7 ± 2.1 µg/mL The embryo demonstrated late development represented by an absence of pigmentation of the tail, and irregular formation of the somites demonstrated the noticeable tail curve with a wide end. [82]
Carthamus tinctorius/Asteraceae Safflower (English), Kashefeh (Persian) Aqueous/flower 40–1000 µg/mL 345,600 µg/L Hatching inhibition, depressed heart rate, abnormal spontaneous movement, pericardial edema, yolk sac edema, unusual head-trunk tilt, suppression of melanin release, enlarged yolk, and short body length were identified. [83]
Clinacanthus nutans/Acanthaceae Sabah snake grass Hexane/leaf 15.63–500 µg/mL 75.49 µg/mL Morphological disorders (less pigmentation, tail bending, edema, abnormal yolk sac). [84]
Cinnamon zeylanicum/Lauraceae True cinnamon tree, Ceylon cinnamon Aqueous/bark 0–10,000 µg/mL 985.8 µg/mL (48 hpf)
50.58 µg/mL (96 hpf)
This plant showed minimum embryotoxicity on zebrafish. In 72 hpf embryos, higher concentration of extract provoked yolk sac and pericardial edema. [2]
Croton tiglium/Euphorbiaceae Purging croton, Jamaal gota (Hindi) Aqueous/seed 4000–24,000 µg/mL 11,880 µg/mL (24 h)
8160 µg/mL (48 h)
Signs of stress, enhanced respiratory rate, jerky movements, loss of equilibrium, circular swimming before losing balance. [10]
Curcuma longa/Zingiberaceae Turmeric Methanol/rhizome 7.8–125 µg/mL 92.42 µg/mL (24 hpf)
79.20 µg/mL (48 hpf)
68.32 µg/mL (72 hpf)
56.68 µg/mL (96 hpf)
55.90 µg/mL (120 hpf)
Physical anatomy deformities as teratogenic effects; tail bending, yolk sac edema extension, and a curved trunk were observed at high concentration among hatched embryos. [1]
Curcuma longa/Zingiberaceae Turmeric Methanol/rhizome No concentration ranges were mentioned (10 µg/mL used) n.a. No visible symptoms of toxicity were observed: no change in heart rate, body impairment, absence or delay in reaction to tactile stimuli, or mortality. [85]
Curcuma xanthorrhiza/Zingiberaceae Javanese ginger, Temulawak Ethanol/rhizome 100–500 µg/mL 180.52 µg/mL at 48 h
79.55 µg/mL at 96 h
Major malformations of the pericardial edema of embryos at a concentration of 100 µg/mL, yolk sac edema and tail malformation also were observed. [43]
Javanese ginger, Temulawak Aqueous/rhizome 0–10,000 µg/mL 748.6 µg/mL (48 hpf)
703.7 µg/mL (96 hpf)
Decreased survival rate, organ deformity, unusual heartbeat, and delayed hatching rates. [2]
Cynodon dactylon/Poaceae Scutch grass Hexane, chloroform, acetone, methanol/n.a. 10–100 µg/mL 32.6 µg/mL The period of systole and diastole was decreased by the methanol extract. [86]
Derris elliptica/Fabaceae Tuba root (Indonesia), opay (Philippines) Aqueous/leaf 50 (0.05%), 500 (0.5%) µL/mL n.a. The concentration of 0.5% led to the early death of embryos: unformed head, unformed tail, coagulation, and death. A delay in growth and restricted movement compared to the control group were present at 0.05%. [53]
Dieffenbachia amoena/Araceae Spotted dumbcane Aqueous/leaf 0–10,000 µg/mL 1190 µg/mL Growth retardation, no heartbeat was noticed at 500 µg/mL and higher concentrations (cardiotoxicity). [87]
Diospyros discolor/Ebanaceae Velvet persimmon, velvet apple, mabolo tree Aqueous/leaf 0.05–10% 1% Tail malformation, delayed growth, head abnormality, yolk malformations, and abdominal swelling were observed. [88]
Eclipta prostrata/Asteraceae False daisy, yerba de tago, Karisalankanni and bhringraj Aqueous/leaf 0.01–40% 1% At the concentration of 0.01% v/v and 1% v/v, did not observe any mortality and abnormality [89]
Enydra fluctuans/Asteraceae Marsh herb, water cress Ethanol/leaf 12,500–400,000 µg/mL 24 h: 204,132 µg/L
48 h: 170,513 µg/L
72 h: 139,478 µg/L
96 h: 92,956 µg/L
The death rate was found as the exposure period was extended from 24 to 96 h, the median lethal concentration decreased. A negative relationship between exposure time and LC50 was found. [90]
Eugenia polyantha/Myrthaceae Bay leaf Aqueous/leaf 0–10,000 µg/mL 921.2 µg/mL (48 hpf)
60.39 µg/mL (96 hpf)
Decreased survival rate, organ deformity, unusual heartbeat, and delayed hatching rates. [2]
Euphorbia pekinensis Rupr/Euphorbiaceae The Peking spurge, daji (Chinese) Aqueous/commercial raw herb 100–250 µg/mL 250–300 µg/mL (previous study) n.a. [91]
Euodia rutaecarpa (Tetradium ruticarpum)/Rutaceae Goshuyu (Japanese), Bee tree Evodiamine (Commercial product) 0.05–1.6 µg/mL 0.354 µg/mL (LC10) Evodiamine (bioactive compound) had a 10% lethality at 354 ng/mL and caused heart defect, changes in heartbeat and blood flow, and pericardial malformation. Also, it could cause cardiovascular side effects involving oxidative stress. [92]
Excoecaria agallocha/Euphorbiaceae Back mangrove Methanol/bark, leaf and stem 50–100 µg/mL n.a. Higher concentrations induced intense impacts on embryo melanogenesis. Those concentrations also reduced the eye melanin material of the embryo. [78]
Ficus glomerate/Moraceae Cluster fig tree, Indian fig tree, goolar fig Hot aqueous/leaf 125–2000 µg/mL 239.88 µg/mL Lower hatchability, body size, heartbeat rate, and morphological growth defects of the embryo were exhibited. [73]
Garcinia hanburyi/Clusiaceae Siam gamboge, Hanbury’s Garcinia Commercial product/dried yellow resin 0.5–1.0 µM 1.76 µM Gambogic acid triggered a lack of fin developmental in the zebrafish embryo. [93]
Garcinia mangostana (Xanthone crude extract)/Clusiaceae Mangosteen Mixture of acetone and water (80:20) 7.81–250 µg/mL 15.63 µg/mL Among surviving zebrafish, no deformities were found. [28]
Geissospermum reticulatum/Apocynaceae Challua caspi (Kichwa language) Ethanol/bark 0.1 µg/mL n.a. This plant was nontoxic and caused no deformations to zebrafish, even at high concentrations. [94]
Himatanthus drasticus/Apocynaceae Janaguba milk (latex) Commercial product 500–1500 µg/mL 1188.54 µg/mL This plant can be considered to have low toxicity. No teratogenic effect was observed. [95]
Hylocereus polyrhizus/Cactaceae Pitaya Ethanol; water solution (70:30, v/v)/peel & pulp 100–1000 µg/mL and 20 µL) >1000 µg/mL (96 h) The results indicated the pulp and peel of this plant were non-toxic. [96]
Leonurus japonicus/Lamiaceae Oriental/Chinese motherwort Essential oil/the aerial parts 6.25–100 µg/mL 1.67 ± 0.23 µg/mL Motherwort essential oil was toxic to embryos. Morphological abnormalities: partial or complete absence of eye development, yolk sac oedema, curved spine, tail deformities, scattered haemorrhages in the oedematous yolk sac, incomplete heart development, and pericardial oedema. [97]
Ligusticum chuanxiong/Apiaceae Szechuan lovage A protein-containing polysaccharide/rhizome 0–800,000 µg/L 965 µg/mL No significant morphological anomalies were found. [98]
Maerua subcordata (Gilg) DeWolf/Capparaceae Methanol/fruit, leaf, root tuber, and seed 150,000–1,500,000 µg/L 209,000 µg/L ≤5% sub-lethal abnormalities (signs of malformation of the heart). [4]
Marsdenia tenacissima (Xiaoaiping extract)/Asclepiadaceae Murva (Hindi), Tong-Guan-Teng (Chinese) Commercial product 0–3200 µg/mL 2660 µg/mL (24 hpf)
2310 µg/mL (48 hpf)
1920 µg/mL (72 hpf)
1910 µg/mL (96 hpf)
1790 µg/mL (120 hpf)
Severe malformation such as impairment of the swim bladder, retaining the yolk, pericardial oedema, and tail curvature. Histopathological study: Xiaoaiping induced lesion of the liver, muscle, and heart. [99]
Millettia pachycarpa/Fabaceae Bokol-bih, Holsoi, Bokoa-bih (Assamese or Hindi) Aqueous/root 1–7.5 µg/mL 4.276 µg/mL There were a few developmental anomalies, such as yolk sac oedema, curvature of the spinal cord, pericardial oedema, swim bladder swelling, reduced heart rate, and late hatching. This plant extract is also linked to reactive oxygen species and apoptosis, which induced embryonic mortality and toxicity (identified in trunk, brain, and tail). [6]
Momordica charantia/Cucurbitaceae Bitter melon, bitter gourd, bitter apple Methanol/fruit, seed 1–400 µg/mL 50 µg/mL (only seed extract) Although it affected the heartbeat, the fruit extract is considered to be harmless and no mortality was observed. The seed extract demonstrated a slight level of developmental failure and had significant cardiac toxicity. [100]
Hot and cold aqueous/leaf 15.625–1000 µg/mL 144.54 µg/mL: Hot aqueous Chinese extract
199.53 µg/mL: Hot aqueous Indian extract
251.19 µg/mL: Cold aqueous Chinese extract
For all samples the heart beat differed at higher concentrations. Also, mild toxicity was observed, although consumption of this plant is assumed to be safe. [12]
Aqueous/leaf 0.05–3% 3.0% at 24 h Teratogenic effects such as bent back, tip of tail bent, oedema in the yolk sac, and scoliosis. Delayed development and morphological deformities of the embryo were observed. [101]
Moringa oleifera/Moringaceae Drumstick tree, Moringa Hot water/leaf and bark 0.3–6 µg/mL 1.5 µg/mL at 36 h (leaves);
3 µg/mL at 36 h (bark)
Even low concentration was embryo-toxic and had teratogenic impacts on the developing embryos. [102]
Essential oil/seed 0.1–1000 µg/mL 21.24 ± 0.44 µg/mL High concentrations (≥ 50 µg/mL) caused 100% mortality of embryos. The process of angiogenic blood vessel formation in zebrafish embryos was substantially disturbed by the seed oil. [103]
Aqueous/seed 12.5–200 µg/mL 190 µg/mL (48 h)
133 µg/mL (72 h)
49 µg/mL (96 h)
No toxic endpoint was seen after 24 h, hatching was prolonged, and the larval period at 96 h compared with the control was decreased. [104]
Moringa peregrina/Moringaceae Miracle tree Essential oil/seed 0.1–1000 µg/mL 25.11 ± 0.547 µg/mL High concentrations (≥ 50 µg/mL) caused 100% mortality of embryos. The process of angiogenic blood vessel formation in zebrafish embryos was substantially disturbed by the seed oil. [103]
Olea europaea/Oleaceae Olive Raw and polar fraction (raw oil: commercial)/fruit 1–100% Raw oil: 11.98% (EC50)
Polar fraction: 61.87 (EC50)
Abnormalities observed included non-hatching, pericardial oedema, and blood accumulation, and more were expressed at a concentration of 11.98%. Raw oil induced 50% of developmental abnormalities compared with the polar fraction. After 96 h, strong developmental retardations such as developmental delay and absence/prolongation of pigmentation formation were observed. [105]
Onosma dichroantha/Boraginaceae n.a. Cyclohexane, ethyl acetate, methanol/root 0.02–50 µg/mL n.a. n.a. [106]
Orthosiphon stamineus/Lamiaceae Java tea Aqueous/whole plant 0–10,000 µg/mL 1685 µg/mL (48 hpf)
1685 µg/mL (96 hpf)
n.a. [2]
Palicourea deflexa/Rubiaceae n.a. Methanol (fraction)/leaf 1–100 µg/mL 72.18 µg/mL At high concentration (100 µg/mL), some possible anomalies, such as no development of somites, decreased pigmentation, and formation of oedema were observed. Lethality only appeared after 96 h. [52]
Palmaria palmata/Archaeplastida Dulse, dillisk (dilsk), red dulse, sea lettuce flakes (creathnach) Crude protein (hydrolysate)/leaf 1–10,000 µg/mL n.a. At high concentration (10 mg/mL), larvae started developing spinal curvature and a deformed yolk sac. At 5 mg/mL, larvae appeared to have a swollen yolk sac and developed a curved spine. [51]
Passiflora caerulea/Passifloraceae Bluecrown Passionflower Aqueous/leaf 40–120 µg/mL 80 µg/mL (40–120 µg/mL) Mortality increased based on concentration and delay in hatching. No apparent signs of abnormal growth or morphology were detected in embryos at 96 hpf. [107]
Peucedanum alsaticum/Apiaceae n.a. n-heptane, ethyl acetate, methanol, water/fruit 50–400 µg/mL n.a. n.a. [33]
Phyllanthus niruri/Phyllanthaceae Gale of the wind, stonebreaker Aqueous/leaf 0.05–10% Tail malformation and coagulation were detected as the most remarkable toxic effect from the extract; dose-dependent impacts on the heartbeat and hatchability of the embryo also were detected. [108]
Piper betle/Piperaceae Betel, Ikmo, Daun sirih (Malay), Paan (Hindi) Hot water/leaf 50–10,000 µg/mL The plant extract affected the hatchability of embryos and was linked to delayed development. Also, a coagulated embryo and tail malformation were observed as a teratogenic effect. [81]
Polygonum multiflorum/Polygonaceae Tuber fleeceflower n-hexane, ethyl acetate, water/root 0–175,000 µg/L TIs: 1430 (ethyl acetate), 630 µg/L 40 and 105 mg/L concentrations (all extracts) induced yolk sac oedema (heart oedema), hemovascular defects, abnormal trunk, and necrosis. The water extract induced synthesis of melanin in zebrafish through stimulation of tyrosinase. [109]
Water, ethanol, methanol, acetone/dried roots 0–10,000 µg/mL 129.4 ± 2.7 µg/mL (water)
58.2 ± 1.9 µg/mL (30% ethanol)
39.8 ± 0.8 µg/mL (50% ethanol)
27.9 ± 2.3 µg/mL (70% ethanol)
25.5 ± 2.0 µg/mL (95% ethanol)
48.8 ± 2.8 µg/mL (methanol)
23.6 ± 2.2 µg/mL (acetone)
Teratogenic effects included coagulated embryos, lack of development of the somite, absence of tail detachment and heartbeat, and malformation of the notochord [110]
Psoralea corylifolia/Fabaceae Babchi Commercial product (Psoralen) 0–6.70 µg/mL 3.40 µg/mL (LC50)
2.52 µg/mL (LC10)
1.98 µg/mL (LC1)
Psoralen therapy caused hatching rate and body size to decrease and the abnormality rate of zebrafish to increase significantly. Yolk retention, pericardial oedema, swim-bladder malformation, and curved body form were observed. [111]
Punica granatum/Lythraceae pomegranate Ethanol/peel 100–250 µg/mL 196,037 ± 9.2 µg/mL No issues with the reproductive organs, heart, and androgen hormones were detected. [112]
Rhizosphora apiculata/Rhizosphoraceae Mangrove Methanol/bark, leaf, stem and root 50–100 µg/mL n.a. Higher concentrations of the extract from bark, leaf, and stem did not cause mortality. [78]
Salvia miltiorrhiza/Lamiaceae Red sage Commercial product/Tanshinone IIA (diterpene quinone)/root 0.44–7.06 µg/mL 5.44 µg/mL (72 hpf)
3.77 µg/mL (96 hpf)
Tan-IIA showed potential cardiotoxicity and growth inhibition in zebrafish embryos. Scoliosis, tail deformity, and pericardium oedema were the primary signs of teratogenicity. [45]
Sida acuta/Malvaceae Wireweed Hexane, chloroform, acetone, methanol/n.a. 10–100 µg/mL 20.9 µg/mL The methanolic extract led to heartbeat rate reductions (more significant than nebivolol as a positive control). This study reported no teratogenic effects. [86]
Solidago canadensis/Asteraceae Canada goldenrod, Canadian goldenrod Ethanol/leaf 0–500µg/mL 0.42 ± 0.03 µg/mL (24 h)
0.33 ± 0.04 µg/mL (48 h)
0.32 ± 0.03 µg/mL (72 h)
This paper only mentioned that low toxicity on zebrafish was observed. [113]
Sonneratia alba/Lythraceae Mangrove tree Methanol/bark and leaf 50–100 µg/mL [78]
Spilanthes acmella/Asteraceae Paracress, toothache plant, Sichuan buttons, buzz buttons, tingflowers, electric daisy Kradhuawean (Thai) Aqueous/leaf 0.01–20% n.a. No mortality was observed in the highest concentration test. [89]
Spondias mombin/Anacardiaceae Yellow mombin, hog plum Hydroethanolic/leaf 1–9 g/kg (LD50);
25,000–75,000 µg/L (LC50)
4.515 g/kg (LD50: 48 h: immersion)
49.86 µg/mL (LC50: 48 h: oral)
There were no recorded teratogenic effects. [114]
Streblus asper/Moraceae Siamese rough bush, khoi, serut, thoothbrush tree Methanol/bark 50–100 µg/mL 2,000,000 µg/mL Slight oedema of heart muscles at 100 µg/mL. No other severe malformations were observed. [115]
Sutherlandia frutescens/Fabaceae Cancer bush, balloon pea, sutherlandia Aqueous and 80% ethanol 5–50 µg/mL 30.00 µg/mL Both extracts showed bleeding and pericardial cyst development at high concentration, but the aqueous extract was less toxic to larvae. [8]
Aqueous, ethanol/aerial part 5–300 µg/mL 297.57 µg/mL (aqueous)
40.54 µg/mL (ethanol)
The high concentration of both extracts inhibited hatching rate and mortality. [116]
Terminalia chebula/Combretaceae Myrobalan Ethanol/fruit, leaf, root n.a. n.a. At 50 µg/L, fish treated with this extract came back to normal condition and showed a related decrease in superoxide dismutase and decreased mitochondria and cell viability. [74]
Tetrapterys (Melanolepis) multiglandulosa/Malpighiaceae Pakalkal (Tagalog) Dichloromethane, hexane, ethyl acetate, methanol and water/leaf n.a. 200 µg/mL (methanol extract) A significant ecdysteroid was the most toxic in the zebrafish. [117]
Tinospora cordifolia/Menispermaceae Heart-leaved moonseed, gaduchi, guduchi, giloy, Makabuhay (Filipino) Aqueous/leaf and bark 0.01–10% 1% (leaves),
10% (barks)
Abnormalities of head and tail, delayed development, reduced mobility, stunted tail, and scoliosis/flexure were observed. [118]
Thuja orientalis/Cupressacae Oriental Arbor-vitae Ethanol/leaf 150–2400 µg/mL 702.9 µg/mL At 2.4 mg/mL embryos were coagulated; at 1.2 mg/mL they did not hatch and oedema was observed; 0.6 mg/mL resulted in skeletal deformities; at 0.3 mg/mL slight oedema was observed; at 0.15 mg/mL normal growth was observed. [50]
Trapa natans/Lythraceae Water chestnut, water caltrop Acetone, methanol and ethyl acetate/leaf 100,000–1,000,000 µg/mL 50 µg/mL (methanol)
40 µg/mL (acetone)
30 µg/mL (ethyl acetate)
Methanol and acetone extracts did not show toxicity to zebrafish. [119]
Tripterygium wilfordii/Celasteraceae Thunder god vine, léi gōng téng (Mandarin) Purchased commercially each compound 1/10, 1/5, 1/2 LC50 Taxol: 0.10, 0.21, 0.53 µg/mL;
Gambogic acid 0.03, 0.05, 0.13 µg/mL;
Triptolide: 0.04, 0.07, 0.18; Auranofin: 0.84, 1.68, 4.21 µg/mL;
Mycophenolic acid: 0.44, 0.95, 2.22;
Curcumin: 0.43, 0.87, 2.17 µg/mL; Thalidomide: 0.71, 1.43, 3.56 µg/mL
From those 7 compounds, gambogic acid followed by taxol showed high anticancer activity [120]
Zanthoxylum sp./Rutaceae n.a. Commercial product; zanthoxylum 0–1000 µg/mL 81.18 µg/mL No teratogenic effects were reported. [121]

Days post-fertilization: dpf; Hours post-fertilization: hpf; n.a.: not applicable.