Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns

Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns

Accepted Manuscript Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns Loubna Kharchoufa, Ilyass Alami Merroun...

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Accepted Manuscript Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns Loubna Kharchoufa, Ilyass Alami Merrouni, Amal Yamani, Mostafa Elachouri PII:

S0041-0101(18)30375-1

DOI:

10.1016/j.toxicon.2018.09.003

Reference:

TOXCON 5980

To appear in:

Toxicon

Received Date: 2 March 2018 Revised Date:

13 September 2018

Accepted Date: 15 September 2018

Please cite this article as: Kharchoufa, L., Merrouni, I.A., Yamani, A., Elachouri, M., Profile on medicinal plants used by the people of North Eastern Morocco: Toxicity concerns, Toxicon (2018), doi: https:// doi.org/10.1016/j.toxicon.2018.09.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Profile on Medicinal Plants Used by the People of North Eastern Morocco: Toxicity Concerns

Loubna Kharchoufa, Ilyass Alami Merrouni, Amal Yamani, Mostafa Elachouri *, 1(PhD)

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Laboratoire de Physiologie, Génétique et Ethnopharmacologie URAC-40, Département de Biologie, Faculté des Sciences, Université Mohammed Premier, Oujda-Maroc. [email protected]

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[email protected]

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[email protected]

[email protected] / [email protected]

*Correspondence to: Pr Elachouri Mostafa, Laboratoire de Physiologie, Génétique et Ethnopharmacologie, Département de Biologie, Faculté des Sciences, Université Mohamed Premier, Oujda – Maroc. Tel: +21265218052

Award CV Raman International Fellowship for African Research 2010

Abstract

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In the North Eastern region of Morocco, many people are interested in medicinal plants and

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their uses. However, the rationale for the utilization of medicinal plants has remained largely underestimated with little or no scientific data on plant safety. In this paper we attempt to

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describe and establish a detailed list of current knowledge in relation to the toxicity of these plants and to evaluate the scientific data concerning the harmful effects of the selected natural products.Our approach consists of collecting published data from literature in specialized journals, books and website related to the toxic plants.This research revealed that 89 plant species, retrieved from 287 plants used as medicine in the North-Eastern region of Morocco, are considered toxic or present some kind of toxicity. Our data determines 55 compounds isolated from the plants which are dominated by five groups of toxic compounds: alkaloids

ACCEPTED MANUSCRIPT followed by glucosides, terpenoids, protides and phenolics. The present work discusses toxicity- related issues arising from the use of medicinal plants by local people. We conclude that the database considered in this study could serve as an important source of information on the toxicity of medicinal plants used by this society.

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Key words: Medicinal Plants, North Eastern region, Morocco, Toxic plants, Alkaloids Abbreviations

AT, acut toxicity; ATR, atractyloside; C, cultivated; CA, cutaneous application; CATR,

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carboxyatractyloside; CBCH, cannabichromene; CBD, cannabidiol; CBN, cannabinol; CT, chronic toxicity; EFT, Embryo- and feto-toxicity; FM, female mice; I, imported; IC,

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intracerebrale; IP, intraperitoneal; IV, intravenous; M, mousse, MM, male mice; MR, male rat; O, oral; PBMC, peripheral blood mononuclear cell; R, rat; RLM, rat liver mitochondria; RT, reproductive toxicity; S, spontaneous; SADT, Sub acute dermal toxicity; SA, subacute; SCT, subchronic toxicity; SBC, subcutaneous; Subgr, Subgroup; THC, tetrahydrocannabinol;

1. Introduction

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VKORC1,vitamin K epoxide reductase complex subunit 1.

Since ancient times, plants were widely used in many indigenous medicine systems for

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therapeutic treatment of diseases.Currently, this botanical medicine is increasingly becoming popular throughout the world, especially in developing countries, where medicinal plants are

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available and inexpensive.In addition, the users believe that medicinal plants have less side effects than synthetic drugs. However, the general perception that herbal drug is very safe and devoid of adverse effects is not only untrue, but also misleading. In fact, many studies show that medicinal plants are able to produce a wide range of undesirable and adverse reactions such as carcinogenicity, teratogenicity, life-threatening conditions and even death (Kristanc and Kreft, 2016; Okem, 2014). According to the annual report of American Association of Poison Control Centers (Mowry et al., 2014), herbs are the cause of 3 to 5 % of all poisoning

ACCEPTED MANUSCRIPT in United State of America. In South Africa, poisoning plants represent 12% of medicinal plants used by the population (Joubert and Mathibe, 1988).This type of poisoning is critical in Moroccan society, where plant-based traditional medicines are part of the social culture. In reality, previous reports issuing from the Moroccan Poison Center “MPC”, indicate that

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medicinal herbs were responsible for about 3-5% of toxicity, with a lethality rate of 7%(CAPM - Centre Anti-Poison du Maroc, 2010). Statistical data on people of developing countries suggests an underestimation of that report because the harmful effects of plants is

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not adequately diagnosed and the information is not accurately reported by the patients (Peacok et al., 2009). Moreover, many cases of poisoning from the use of medicinal plants are

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unreported due to the fact that victims may die before reaching the hospital. In addition, people are generally reluctant to admit using traditional medicine because of the cultural secrecy surrounding their uses (Steenkamp et al., 1999). Therefore it is evident that the use of plants as medicine represents a real potential danger that threatens public health specifically in

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developing countries like Morocco where the medicinal plants sector is not structured, standardized, regulated or recognized by the national health system (Elachouri, 2018, 2009).Additionally, the rationale for the utilization of medicinal plants in Morocco has rested

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largely on underestimations with little or no scientific data on plant safety.The Moroccan scientific community often overlooks the importance of plant toxicity research and assesment.

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We point out that traditional medicine in Morocco remains completely anarchic and disorganized, leading to inadequate management of knowledge reagarding the safety of these products. Particularly, in the North-Eastern region of Morocco, there is a large deficiency in the knowledge about medicinal plants and their potential toxicities. That is why it is important to have an awareness regarding studies on toxicity of plants used as medicine by the people in this region. For that reason, we undertook this work, focusing our attention on the assessment of knowledge regarding the toxicity and adverse effects of these phytotherapeutic products

ACCEPTED MANUSCRIPT used for medication by the local people. Since the population in this region is heavily dependent on traditional herbal medicines for their primary health care, it is imperative to be aware about the harmful of herbs.Until now, there was no global standard documentation highlighting the toxic potentialities of medicinal plants used by the people in this area. Hence,

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it has become pertinent to study the toxicological profile of commonly used medicinal plants and to provide a database on toxicity of these plants. The efficacy and toxicity of phytogenetic ressources employed in folk medicine by indigenous people need to be scientifically

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evaluated. In this paper, we attempt to review and document the current data related to the

chemical constituents. 2. Material and Methods 2.1 Study area

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toxicological potencies of medicinal plants used as medicine by this society as well as their

The study area is situated in the North-Eastern part of the Morocco, along 200 kilometers of

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coastline.The region is limited in the North by the Mediterranean Sea, in the East by the Moroccan-Algerian frontier, in the West by the regions of Taza-AlHoceima and the South by Highland and desert of Figuig.

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This part of the country is one of the twelveregions of the Kingdom of Morocco, including 7 provinces (districts). It covers an area of 90,127 km², more than tenth of the total area of

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Morocco. According to the 2014 census, the population reached 2,314,346 inhabitants. The language spoken, in the North eastern part of Morocco, is distributed as following:“Moroccan dialect” used primarily in speech (86,2%)and the Amazigh Rif dialect “Tarifit”(38,4%) (RGPH, 2014).The climate is temperate in the north, becaming arid and Saharan in the south. Owing to this geographic variation, the region is endowded by rich biodiversity including a large diversity in the ecosystems and flora and especially medicinal plants.

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2.2 Background Review of the Literature

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Fig 1: Geographical location of the study area

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Based on a study conducted previously by our team in North-Eastern Morocco in which we regrouped 287 plant species used as medicine by local people, we performed a bibliographic research aiming to select the toxic plants by using engines such as: PubMed, Scopus, Google Scholar, ScienceDirect and Free Full PDF. In this research, we take note of papers published in English and French, from PhD thesises, books, articles and relevant reviews. Our

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evaluation extended to 2017.The references in each article were used as sources for further searches. The data listed from this investigation were confronted with specialized literature

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regarding the toxicity of plants and possible drug interactions.The following keyword combinations were used: scientific names of medicinal plants, toxicity and ethnobotany.

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2.3 Systematization of plant names In order to check the state of plants compiled from literature research and to update the name of plant species, in accordance with International Plant Names Index and “Angiosperm Phylogeny Group III” 2009 (APG III), we used the following databases:“African Plant Database 2016”(https://www.ville-ge.ch/musinfo/bd/cjb/africa/recherche.php) and “The plant list 2009”(http://www.theplantlist.org). Only the names of plants accepted by one of these databases were retained to be listed in this paper. 3. Results and discussion

ACCEPTED MANUSCRIPT 3.1 General data Based on the methodology applied in this work, we found 89 valid plant species that were potentially toxic or present some kind of toxicity. Focusing our attention only on the toxicity of plants, we undertook a bibliographic research using articles and repository of books. This

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literature survey utilized a total of 274 downloaded articles and five books covering all aspects of toxicity (Charnot, 1945; Bruneton, 1996; Bellakhdar, 1997; Hammiche et al., 2013; Kuete, 2014).The results were then cross-referenced to generate a total number of 232

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references cited in this review.

With this assessment, the most common toxic plants and the main data related to these plant

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species have been regrouped in two tables:Table 1 regrouping 36 plant species, which have been only cited as toxics and Table 2 including 27 plant species, whose toxicities have been tested and 26 plant species whose causative toxin compounds have been identified. 3.1.1

Floristic diversity

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Our results delineate that the 89 poisonous species listed in this paperwere mainly distributed into 45 families and 81 genera. The family Apiaceae has the highest number of plants diversity (8 genera and 8 species), followed by Fabaceae (7 genera and 8 species), Asteraceae

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(5 genera and 7 species), Brassicaceae (5genera and 6 species), Lamiaceae and Solanaceae (4 genera and 5 species), Euphorbiaceae (4 genera and 4 species), Amaranthaceae (3 genera and

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3 species). Otherwise Cucurbitaceae, Fagaceae, Papaveraceae, Ranunculaceae, Rutaceae and Thymelaeaceae families possess 2 species for each one and 32 families are represented by only 1 genera and 1 species each (Fig 2). Most parts of these species were growing spontaneously in the region of study, representing 70%, followed by cultivated species with 27% and 3% imported from other countries.

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Fig 2: Family and genera spectrum of toxic plant species 3.1.2.Target of toxicity

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Toxicity is defined as “the potential of substances (extract of plants or toxin compounds) to exert a harmful effect on humans or animals. These effects can be harmful to the cell, organ or the whole body. The potential harm related to herbal medicine could be attributed to inherent

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(intrinsic) toxic effects of herbs, or extrinsic effects, by contamination, adulteration, plant misidentification, or interactions with other herbal products or pharmaceutical drugs (Drew

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and Myers, 1997). All information on toxicity of the plants selected in this paper are attributed to inherent (intrinsic) toxic effects. Our results indicate that multiple organs or cells damaged have been observed after the use of these poisonous natural products. The toxicity of these herbs can affect the entire spectrum of organ systems: such as digestive, liver, skin, renal, nervous, respiratory and cardiovascular system. Also, we found that some plants have a large spectrum of toxicity, affecting more than one organ system. In order to categorize the toxic plants in relationship with the target systems affected, we adopt a classification depending on their major effects of toxicity, into broad disease

ACCEPTED MANUSCRIPT categories.The symptoms due to the toxic effects of plants used are dominated by the following areas: the gastro-intestine (Diarrhea, vomiting, nausea, etc.), the brain (depression, anorexia, convulsions, paralysis, dizziness, shivers, coma, etc.), the kidney (necrosis , acute renal failure , urination, etc.) and the liver (liver dysfunction and cell destruction, necrosis,

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lobar hepatitis, etc.) (Fig3). The most dominant toxic plant species affect the gastrointestinal system with 38 species, followed by 37 plant species causing neurotoxic effects, 23 species affecting renal system, 19 plants affecting liver and the remaining species affect various

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systems, organs and cells. These harmful effects are arranged from minor symptoms such as mild headache and abdominal discomfort to much more serious outcomes that can cause

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major organ damage and even death as indicated in Tables 1 and 2.

We observed and noted that the gastrointestinal system remained the most vulnerable to toxic effects. This observation is explained bythe fact that the digestive system is the most common target for herbal toxicity and the first system to be exposed to the toxins of poisonous plants.

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In addition, this system is the principal route of administration of the extracts. In practice, the frequency of oral administration of the plant extracts are quite elevated (65 %).These findings are in accordance with the results found by Gilbert (Gilbert, 2012). Ranking second is the

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nervous system, a vital organ system which is highly perfused by blood. The third system most effected by herbal toxicity is the kidney and is considered to be the principal route of

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degradation and excretion for many chemical compounds both in the active and/or inactive forms. In fourth position is the liver, which is expected to be the principal site of degradation of chemical substances..

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Figure 3: Different ailments caused by toxic plants 3.2 Medicinal plants only cited as toxic

In table (1), we show global information about medicinal plants cited as toxic without any

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investigation of their toxicology including the basic details such as the family names, accepted botanical names, plant species, vernacular names, parts used, the ethnomedicinal

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uses of these plants, symptoms of toxicity and references.

ACCEPTED MANUSCRIPT According to the information in Table 1, we found these plants have various therapeutic effects. For example Haloxylon scoparium Pomel, Launaea arborescens (Batt.) Murb., Euphorbia resinifera O. Berg, Myrtus communis L. and Thymelaea hirsuta (L.) Endl., are used to treat diabetes; Vicia ervilia (L.) Willd, Quercus suber L., Linum usitatissimum L. and

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Myrtus communis L. are used for digestive treatment and Brassica napus L., Vicia faba L., Rosmarinus officinalis L. and Linum usitatissimum L. are used for respiratory treatments. These plants have also adverse effects targeting some organs systems such as the following:

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neural disorders (headaches, shivers, paleness, dilated pupils, hyper salivation, depressivness, dizziness, convulsions), gastro-intestinal disorders (stomachache, constipation, nausea,

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vomiting, anorexia), acute nephritis, pulmonary edema, accelerated breathing, cerebral hemorrhage, spasmodic paraplegias and respiratory paralysis.

Because scientific evidence is lacking, these plants need to be assessed for their respective

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toxicology.

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Table 1 Selected plants cited as toxic, with common name, traditional uses, part used, physical signs of toxicity and references.

‫السلك‬ ‫بطراف‬ ‫بربى‬ ‫الرمت‬ ‫اساي‬

Apiaceae Deverra scoparia Coss. & Durieu Subgr X/S

‫تعاطشت‬ ‫لغزاح‬

Part used

Physical signs of toxicity

Diabetes, slimming

Seeds

Stomach troubles (leaves and tuber)

Cutaneous neoplasms, scorpions and snake bite, dermatisis, diabetes, stomachache, gastroenteritis, food poisoning, colds, rhumatism, scabies, wound healing, indigestion, disinfection and cleaning, inhibits superinfection

Aerial parts Leaves Stem Roots Seed

Headache

Aerial part

Serious ophthalmia

Leaves Fruit

Vomiting, diarrhoea

Neural disorders, leg tremors,major weakness

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Amaranthaceae Beta Vulgaris L. Subgr X/C Haloxylon scoparium Pomel (Hammada scoparia (Pomel)Iljin) Subgr X/S

Traditional uses

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Common name

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Family plant / Botanical name

Boils, skin abscesses, used in the treatment of sores and wound, fatigue, rheumatism.

‫الشيح‬ ‫إزري‬

Digestive system, diabetes, anthelmintic, dermocosmotology, poison antidote, gastrointestinal antiseptic. Diuretic, hypoglycemiant, stomachic, liver disorders, diabetes.

Leaves Aerial parts Flowers Seeds Roots

Dizziness, convulsions

‫الشيبة‬

Problems of hearing and the ear, problems of the sphere buccodentaire, diabetes, vaginal antiseptic, auditory, stomach pains

Leaves Aerial part

Convulsions, the construction of jaws, foaming at the mouth

Artemisia arborescens (Vaill.) L. Subgr X /S

‫الشيبة‬

Anthelmintic, diuretic, aperitive, colds, vertigo

Leaves Aerial part

Convulsions, the construction of jaws and the appearance of foam with lips

Launaea arborescens (Batt.) Murb.

‫لبينةمو‬

Diabetes, fever, hypertension

Whole plant Latex

Gastro-intestinal disorders due to the inflammation of the mucous

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‫تسكرة‬

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Echinops spinosissimus Turra (Echinops spinosus L.) Subgr X/S Artemisia absinthium L. Subgr X/S

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‫لواية‬

Araliaceae Hedera helix L. Subgr X/S Asteraceae Artemisia herba-alba Asso Subgr X/S

Neurovegetative disorders, exciting and convulsive effects

References (Al-qura, 2005) (Hafian et al., 2014) (Alami et al., 2015) (Bellakhdar, 1997) (Abouri et al., 2012) (Rhaffari and Zaid, 2002)

(Charnot, 1945) (Rhaffari and Zaid, 2002)

(Charnot, 1945) (Boukhira et al., 2013) (Rhafouri et al., 2015) (Bellakhdar, 1997) (Fakchich and Elachouri, 2014) (Bellakhdar et al., 1991) (Bellakhdar et al., 1991) (Alami et al., 2015) (Charnot, 1945) (Garnier et al., 1961) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014) (Ouhaddou et al., 2014) (Ziyyat et al., 1997) (Garnier et al., 1961) (Bellakhdar, 1997) (Merzouki et al., 2000) (Eddouks et al., 2002) (Bellakhdar, 1997)

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Euphorbiaceae Euphorbia resinifera O. Berg Subgr X/S Mercurialis annua L. Subgr X/S

Rhizome Leaves Roots Seeds

Warming and vermifug

Leaves Seeds

‫لفجل‬

Diabetes, intestinal disorders

Rhizome Seeds

‫تيكي‬

Cutaneous affections, skin

The inflammation of stomach and intestinal mucous membranes, the gastroenteritis, the convulsion.

The animals present a great abasement constantly groan, refuse all food. The rumination is stopped, the animal no longer digests what it has swallowed. Epigastric pain

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‫جرجير‬ ‫كلكاز لبيض‬

membranes Tympany, colics, bloody diarrhea, hematuria, abortion

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‫الحرة الفاللية‬

Stimulant, digestive, bronchitis, constipation, bladder diseases, rheumatic pains

Fruit Oil

Abortion and sterility

Skin diseases, purgative and diuretic

Roots Berries

Irritation of the mouth and the pharynx

‫أزرام‬ ‫زازا‬

Diabetes, hair care

Leafy stem Arial part

Psychotic disorders

‫زكوم‬ ‫تكاوت‬

antidote, head problems, abortive, drastic, magic, skin infections and carache, diabetes.

Cortex Resin Whole plant

Serious inflammation of the mucous membranes of the digestive tract with gastroenteritis

‫حريكة الملسة‬

Infection of the respiratory system, genitourinary, metabolic, dermatological, digestive tract, skin care, rheumatology.

Aerial part Whole plant

Diarrheas, vomitings and hematuria, urinary cylinder, erythema

‫ماموﻧبن‬ ‫آلكرمة السودة‬ ‫بوكودز‬

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Raphanus raphanistrum subsp. s ativus (L.) Domin (Raphanus sativus L.) Subgr X/C Cupressaceae Juniperus oxycedrus L. Subgr X/S Dioscoreacea Dioscorea communis (L.) Caddick & Wilkin (Tamus communis L.) Subgr X/S Ephedraceae Ephedra fragilis Desf. Subgr X/S

‫الخردل‬

Microbial infection, respiratory, fever

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Eruca vesicaria (L.) Cav Subgr X/S

‫اللفت‬

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Subgr X/S Brassicaceae Brassica napus L. Subgr X/C Brassica nigra (L.) K.Koch Subgr X/C

(Fakchich and Elachouri, 2014) (Charnot, 1945) (Fakchich and Elachouri, 2014) (Slimani et al., 2016) (Charnot, 1945) (Bellakhdar, 1997) (Merzouki et al., 2000) (Abouri et al., 2012) (Bellakhdar, 1997) (Charnot, 1945)

(Charnot, 1945) (Jouad et al., 2001) (El-hilaly et al., 2003) (Benkhnigue et al., 2014) (Al-qura, 2005) (Rhafouri et al., 2015) (Ouhaddou et al., 2014) (Charnot, 1945) (Ouarghidi et al., 2013)

(Charnot, 1945) (Bruneton, 1996) (Rhaffari and Zaid, 2002) (Katiri et al., 2017) (Bellakhdar, 1997; Bellakhdar et al., 1991) (Abouri et al., 2012) (Fakchich and Elachouri, 2014) (Bellakhdar, 1997) (Doukkali et al., 2015) (Slimani et al., 2016) (Hilah et al., 2016)

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‫عرق السوس‬

Allergy, renal disease, carminative, ulcers, constipation, stomatitis, pathologies of the respiratory system, diabetes.

Stem Seeds Roots

Medicago sativa L. Subgr X/C

‫الفصة‬

Diabetes, scurvey, reconstruction, asthenia, menopause, anemia, arthritis and osteoarthritis, loss of appetite, lactation.

Retama monosperma (L.) Boiss Subgr X/S

‫الرطم‬

Gum aliments, skin, skeleton

Seeds Aerial part Leaves Fruits Stem Stem Leaves Fruits

Vicia ervilia (L.) Willd. Subgr X/C Vicia faba L. Subgr X/C

‫كرساﻧة‬

Digestive system, allergy, power problems

Seeds

Spasmodic paraplegias

‫إباون‬

Respiratory system, allergy, diabetes, cardio stimulant, anti-inflammatory, renal lithiasis, pulmonary tuberculosis, cold

Seeds Leaves Fruits

Headache, nausea, vomiting, fever, anemia.

Fagaceae Quercus faginea Lam. Subgr X/S

‫لعصفة‬ ‫طاست‬

Problems of the sphere buccodentaire, dermocosmotology,vaginal antiseptic, haircare, antidiarrheal, astringent, mouth hygiene, cold, astringent, antibacterial, haemostatic,ophthalmia, hypoglycaemic,

Leaves Gall Fruits

Anorexia, depression, a stomachic lifelessness, digestive disorders, constipation, an elevation of the blood urea and the creatinine

Quercus suber L. Subgr X/S

‫بلوط‬ ‫الدبغ‬

Hair-care, column infections, pathologies of the digestive system, problems of the sphere buccodentaire, dermocosmotology.

Cortex Bark Leaves

Anorexia, depression, a stomachic lifelessness, digestive disorders, constipation, an elevation of the blood urea and the creatinine

‫ازير‬ ‫يزير‬

kidney stones, diabetes, pathologies of the digestive system, allergy, pathologies of the respiratory system, dermocosmotology

Roots Leaves Whole plant

Respiratory paralysis (rabbit).

‫زريعة الكتان‬

Diabetes, hypertension, cardiac diseases, digestive system, respiratory system, allergy,

Seeds

Mydriasis, colics, numbness, acute nephritis, pulmonary

‫فرﻧان‬ ‫دالم‬ Lamiaceae Rosmarinus officinalis L. Subgr X/S Linaceae Linum usitatissimum L.

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Severe hypokalemia with arterial hypertension, ventricular fibrillation

Fall of glandular fertility, hyperplasia of the uterus and cervix

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Fabaceae Glycyrrhiza glabra L. Subgr X/I

Urinary retention (camel)

(Bruneton, 1996) (Ziyyat et al., 1997) (Jouad et al., 2001) (Abouri et al., 2012) (Fakchich and Elachouri, 2014) (Bellakhdar, 1997) (El-hilaly et al., 2003) (Bousta et al., 2014)

(Bellakhdar, 1978) (Ouhaddou et al., 2014) (Bouayyadi et al., 2015) (Bellakhdar, 1997) (Charnot, 1945) (Fakchich and Elachouri, 2014) (Bruneton, 1996) (Bellakhdar, 1997) (Fakchich and Elachouri, 2014) (Hachi et al., 2015) (Bouayyadi et al., 2015) (Bellakhdar, 1997; Bellakhdar et al., 1991) (Merzouki et al., 2000) (Fakchich and Elachouri, 2014) (Bousta et al., 2014) (Keeler and Balls, 1978) (Mouhajir et al., 2001) (Bellakhdar, 1997; Bellakhdar et al., 1991) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014) (Keeler and Balls, 1978) (Ouhaddou et al., 2014) (Ghourri et al., 2013) (Charnot, 1945) (Fakchich and Elachouri, 2014) (Garnier et al., 1961) (Charnot, 1945)

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kidney diseases

‫ﺧرﺧاﺷة‬

Poaceae Cynodon dactylon (L.) Pers. Subgr X/S Ranunculaceae Clematis flammula L. Subgr X/S Rhamnaceae Rhamnus alaternus L. Subgr X/S Scrophulariaceae Verbascum sinuatum L. Subgr X/S

‫النجم‬

‫النار الباردة‬ ‫امليلس‬ ‫صالح لنضر‬

Leaves Flowers Seeds

Soothing of nervous system, analgesic, somniferous, anxiety.

Fruit

Pathologies of the circulatory system, diseases of the urinary system, cardiovascular diseases, rheumatism, uterus disease, dysmenorrhea, kidney pains, stomachic, arthritis Diaphorétic, diuretic purgative and venereal, used against scabies and cancer

Rhizome Roots Leaves Whole plant Whole plant

Anemia, digestive, metabolic

Roots Leaves

Buzzing of ears, urinary retention, breathing disorder, vomiting, constipation

Antihemorrhoidal, toothache, psoriasis, ulcers, ocular infections, rhumatismes.

Flowers Leaves whole plant Seeds

‫لبتينة‬ ‫سكران‬ ‫بولرجف‬

Sedative, dental analgesic, antihemorrhoidal

Thymelaeaceae Thymelaea hirsuta (L.) Endl. Subgr X/S

‫المتنان‬

Diabetes, laxative, pathologies of the respiratory system, problems of the sphere buccodentaire.

Stem Leaves Seeds

Xanthorrhoeaceae

‫الصبار‬

Dermocosmotology, cancer, diabetes,

Leaves

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Solanaceae Hyoscyamus albus L. Subgr X/S

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Headache, depressivness

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Papaveraceae Papaver somniferum L. Subgr X/S

Allergy, diabetes, hair care, cardiac diseases, pathologies of the digestive system, hypertension

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‫الريحان‬

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Myrtaceae Myrtus communis L. Subgr X/S

edema,accelerated breathing, cerebral hemorrhage

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Subgr X/C

Cyanogenic activity

Edema of the mouth, abdominal pains, lesions of the gastrointestinal mucosa Renal failure and rhabdomyolysis, which is possibly associated with a chronic consumption Irritation of the throat and the digestive tract

Dryness of the mouth and throat with burning sensation, mydriasis, drunkenness and vertigo, excitement and then a heaviness of the head, lassitude, deep sleep, hallucinations and erotic visions Headaches, shivers, paleness, dilated pupils, hyper salivation, a swelling of the mouth and the lips, difficulties with swallowing, nausea Intense congestion of the organs, an

(Jouad et al., 2001) (Eddouks et al., 2002) (Fakchich and Elachouri, 2014) (Charnot, 1945) (Merzouki et al., 2000) (Tahraoui et al., 2007) (Fakchich and Elachouri, 2014) (Charnot, 1945) (Doukkali et al., 2015) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Hafian et al., 2014) (Le Floch , 1983) (Delaveau, 1974) (Fakchich and Elachouri, 2014) (Abouri et al., 2012) (Bellakhdar, 1997)

(Ghezala et al., 2015) (Zerkani et al., 2015) (Slimani et al., 2016) (Benkhnigue et al., 2011) (Merzouki et al., 2000) (El-hilaly et al., 2003) (Boukhira et al., 2013) (Charnot, 1945) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Khabbach et al., 2011)

(Charnot, 1945) (Bruneton, 1993) (Bellakhdar et al., 1991) (Fakchich and Elachouri, 2014) (Alami et al., 2015) (Bruneton, 1996)

ACCEPTED MANUSCRIPT

oxytocic action, eczematous dermatitis or erythema

TE D

M AN U

SC

RI PT

pathologies of the urinary system

EP

‫الصبرة‬

AC C

Aloe succotrinaLam. Subgr X/I

(Paris and Moyse, 1976-1981) (Eddouks et al., 2002) (Fakchich and Elachouri, 2014)

ACCEPTED MANUSCRIPT 3.3 Medicinal plants tested as toxics A large number of experiments have been carried out concerning the toxicity of several plant extracts. All the results are assembled in table 2, with their scientific names, toxic parts used, route of administration, dosage, duration of assessments, model used in experiments,

related works.

RI PT

symptoms and adverse effects observed, LD50 values, toxic compounds and references of In these groups of plants, various advanced analytical techniques and

biological experimental models, related to toxicological studies, have been implemented.

SC

The duration of the assessment is represented by acute, subacute, subchronics and chronics experiments. Furthermore, we enumerate variable routes of administration of plants extracts.

M AN U

The most commonly used modes of administration for animals are via oral route (65%),

AC C

EP

TE D

followed by the parenteral injection “Intrapeitoneal (25%) and Intravenous (10 %) ”.

ACCEPTED MANUSCRIPT

Table 2

Common name

Traditional uses

Apiaceae Foeniculum vulgare Mill. Subgr Y/S

‫البسباس‬ ‫النافع‬

Diabates, cough, tonic cardiovascular diseases, abdominal colics, anti-spasmodic, bladder ailment, flatulence, lactation, renal pain, stomachic, liver complaint

Fruits Oil

‫مخينزة‬ ‫تويجاﻧت‬

Diabetes, colds, asthma, cardiac disease,hypertension,he adache, carminative and febrifuge, intestinal, oral affection

Essential oil Leaves

Toxic compound Not yet identified

Route, duration, model for experimentation, toxic dose and LD50 LD50= 1326 mg/kg (AT/R/O) 3 g/kg (AT/M/O) 100, 200, 400, 600, 800, 1000, 2000, mg/kg (AT/M/O) 0.93mg/ml (Limb bud mesenchymal cells/R) 21 g (oil) lethal for rabbit for 36 h

M AN U

1 and 3 g/kg (AT/R/O) 0.3 or 1 g/kg (SCT/R/O) 12.31g/kg to 31.89 g /kg (CT/R/O) 50, 500 mg/kg (SCT/M/O) 1, 10, 100, 1000 mg/ml (human lymphocyte cell cultures) Caryophyllene oxide (RLM) IC50 = 123 ± 11 µM) Carvacrol (RLM) IC50 =265±9.9 µM) Ascaridole (RLM) IC50 = 613 µM Essential oil IC50=60.6±2.7 LD50=3034 mg/kg (AT/Rabbit/SBC) LD50 =5000 mg/kg (AT/R/O)

TE D

Carvacrol Ascaridole Caryophyllene oxide

AC C

EP

Amaranthaceae Dysphania ambrosio ides (L.) Mosyakin & Clemants (Chenopodium ambr osioides L.) Subgr Y/S

Toxic part

SC

Family name / Botanical name

RI PT

Recapitulative table of plants and their toxicity

Amarillydaceae Allium sativum L. Subgr Y/C

‫الثوم‬

Diabetes, cough, skin, hypertension, antifungal,resperatory problems, skeleton, circulatory.

Bulbs

Not yet identified

Anacardiaceae Pistacia lentiscus L.

‫الضرو‬

Diabetes, cardiovascular

Vegetable oil

Not yet identified

1ml/kg (SADT/Rabbits/AC) 1and 2 ml/kg(SCT/Rabbits/O)

Advers effect

References

Hyperactivity, grooming, convulsions, and hypothermia, reduced locomotor activity and piloerection, prostration, sedation, respiratory distress, movement disorder, hind limb weakness, tremor and fasciculation in dorsal muscles during, teratogenicity. Hepatotoxic lesions in rats, inhibition of the respiratory chain, inhibited the mitochondrial electron transport chain, abcess in peritoneal cavity, metaplastic changes in the mucosal surface of the stomach, and necrosis of the kidney tubules were noticed, alterations in the kidney and liver, genotoxic effects.

(Lewin, 1903) (Tanira et al., 1996) (Kishore et al., 2012) (Ostad et al., 2004, 2001) (Bellakhdar et al., 1991) (EL Abbouyi et al., 2014) (Fakchich and Elachouri, 2014)

Depression, loss of appetite, partial paralysis, intense erythema tachycardia and disorientation.

Decrease in blood glucose Irritating eyes, irritant contact

(Silva et al., 2014) (Gille et al., 2010) (Monzote et al., 2009, 2007) (Degenhardt et al., 2016) (Amole and Izegbu, 2005) (Pereira et al., 2010) (Gadanoa et al., 2002) (Ziyyat et al., 1997) (Eddouks et al., 2002) (Rhafouri et al., 2015) (Abouri et al., 2012)

(Mikail, 2010) (Lawal et al., 2016) (EL Abbouyi et al., 2014) (Abouri et al., 2012) (Ouhaddou et al., 2014) (Pereira et al., 2010) (Maameri et al., 2016) (Djerrou et al., 2013)

ACCEPTED MANUSCRIPT

‫زياتة‬ ‫سكران‬ ‫كجكجة‬

Apiaceae Ferula communis L. Subgr Z/S

‫الكلخة‬ ‫لكلخ‬ ‫فاصوغ‬ ‫اﻧسالل‬

Apiaceae Thapsia garganica L. Subgr Z/S

‫الدرياس‬

Imperatorin

Seed Fruit Roots A.parts Leaves

Coniine Conyrine Conhydrine N-methylconiine Gammaconiceine

Rheumatism, aphrodisiac, as spasmolytic, sterility, gain weight

Whole plant Roots Latex

Ferprenin Ferulenol

Respiratory diseases , genito-urinary disorders,osteoarticular affection

Roots

Imperatorin (3.10-4 M) 50, 100 g /day (Birds /O)

Coniceine (AT/M) LD50 = 12 mg/kg (O), 2.6 mg/kg (IV), and 12 mg/kg (subcut) Coniine (AT/M) LD50 = 100 mg/kg (O), 19 mg/kg (IV), 80 mg/kg (SBC). N-methylconiine (AT/M) LD50 = 204.5 mg/kg (O), 27.5 mg/kg (IV), 105.5 mg/kg (SBC). 1.5 to 3.0 gm/day (Coniine/cows) 1 et 8 g/kg (Gilts) 25, 50, and 100 mg/kg (chickens, quails, turkeys /O) Ferulenol 1, 10, 100 µM (liver mitochondria rat) Ferprenin 10, 25, 50 µM (livers from lamb, cow, horse, goat, pig and calf)

EP

TE D

Whole plant

RI PT

Apiaceae Conium maculatum L. Subgr Z/S

dermatitis, reversible skin thickening

SC

‫اتريالل‬ ‫تريالل‬ ‫باللة‬

Fruit (fatty oil)

M AN U

Apiaceae Ammi majus L. Subgr Z/S

diseases, cardiac stimulant and to menstruation, gastrointestinal disorders, hair-care, diuretic, astringent Vitiligo, infection of respetory system, cardiovascular, dermatological disorders Typhoid fever, as abortifacient, sterility, facilitates childbirth.

AC C

Subgr Y/S

Thapsigargin Thapsigargicin

Thapsigargin 0.1 -100 nmol (R/IC)

(Bellakhdar et al., 1991) (Fakchich and Elachouri, 2014)

Inhibits respiration and phosphorylation in the presence of succinate by 33 and 50 percent, liver lesion

(Kramar and Kaiser, 1968) (Egyed et al., 1974) (Bellakhdar et al., 1991) (Daoudi et al., 2015)

Neuromuscular block, teratogenic effects, blockaging of the spinal reflexes through the action on the medulla, hyperthermia, tachycardia, polypnea with dyspnea.

(Hammiche et al., 2013) (Keeler and Balls, 1978) (Panter et al., 1983) (Radulovic et al., 2012) (Bowman and Sanghvi, 1962) (Franka and Reed, 1990) (Binev et al., 2007) (Benkhnigue et al., 2011) (Merzouki et al., 2000) (EL Abbouyi et al., 2014)

Inhibition of oxidative phoshorylation. Ferulenol specifically inhibits succinate ubiquinone reductase at the level of the ubiquinone cycle. Inhibitory effect of prenylated coumarins of Ferula communis on mammal liver microsomal VKORC1 activity Inhibitor of the microsomal Ca2+-ATPase, neurotoxic in vivo in perinatal rodent brain. Vomitings and violent diarrheas, inflammation of the

(Appendino et al., 1988) (Alzweiri et al., 2015) (Lahouel et al., 2007) (Louvet et al., 2015) (Valle et al., 1987) (Merzouki et al., 2000) (Ouarghidi et al., 2013) (Rhafouri et al., 2015)

(Hammiche et al., 2013) (Silverstein and Nelson, 1992) (Bellakhdar, 1997) (Charnot, 1945)

ACCEPTED MANUSCRIPT

Apiaceae Coriandrum sativum L. Subgr Y/C

‫القصبر‬ ‫القزبر‬

Apiaceae Petroselinum crispu m (Mill.) Fuss (Petroselinum sativu m Hoffm) Subgr Y/C Apocynaceae Nerium oleander L. Subgr Z/S

‫معدﻧوس‬

‫الدفلة‬ ‫أليلي‬ ‫اريلي‬

Araceae Arisarum vulgare O.

LD50 = 5000 mg/kg (AT/M/O) 2000 and 3000 mg/kg (SCT/M/O)

Leaves

Not yet identified

1000 mg/kg (8 weeks/R/O)

Problems of the sphere buccodentaire, skeleton–muscular system problems, diabetes.

Leaves

Neritaloside Neridiginoside Odoroside H Oleandrin Nerizoside

‫تبكوكة‬ ‫أيرﻧة‬ ‫إرﻧي‬

Skin cancer, sores or wounds, catharic purgative

Tubers

Irniine Bgugaine

‫برزطم‬

Digestive disorders, cancer, diabetes, aorta palpitation, metabolic, rheumatism, magic, pacifying children.

Roots Rhizome

(Patel et al., 2012)

(Awe and Banjoko, 2013) (Jouad et al., 2001) (Eddouks et al., 2002) (EL Abbouyi et al., 2014) (Rhafouri et al., 2015)

LD50= 150 mg/kg (M/IP) Lethal dose = 110 mg/kg (AT/ Goats/O) Lethal dose =110 mg/kg (Sheep and rat/O) 25, 50 mg/kg (M/IP/ Nerizoside, Neritaloside, Odoroside H) 50, 110, 330 mg/kg (AT/Goats/O) 3 g (Dog/O) Irniine : 40 and 50 µM (Hepatocytes /R) Bgugaine: 30, 40 and 50 µM (Cell line HepG2).

Cardiac problems. Gastrointestinal diseases Central nervous system depressant activity, extensive tubular necrosis in kidneys, acute renal failure, liver dysfunction and cell destruction,

(Faliu, 1991) (Barbosa et al., 2008) (Akhtar et al., 2014) (Aslani et al., 2007) (Siddiqui et al., 1997) (Ozmaie et al., 2013) (Zia et al., 1995) (Boswell et al., 2013) (Fakchich and Elachouri, 2014) (Rakba et al., 2000, 1999) (Bammi and Douira, 2002)

1.25, 2.5 g/kg (SCT/M/O) 2.5 g/kg (AT/M/O) IC50 = 50 mg/ml (HK-2 cells) Aristolochic acid LD50 = 203.4 mg/kg (AT/R/O) LD50= 82.5 mg/kg (AT/R/IV) LD50 = 55.9 mg/kg (AT/M/O) LD50 = 8.4 mg/kg (AT/M/IV) 2.5 mg/kg (Aristolochic acid /M/IP)

Renal toxic effects, necrosis affecting the renal tubules, atrophy of the lymphatic organs and large areas of superficial ulceration in the forestomach, carcinogenic action.

M AN U

SC

Hepatotoxic and nephrotoxic

TE D

EP Aristolochic acid I Aristolochic acid II

digestive mucous membranes Convulsion, salivation, diarrhea, lethargy

RI PT

Not yet identified

AC C

Targ.Tozz. Subgr Z/S Aristolochiaceae Aristolochia fontanesii Boiss. & Reut Subgr Z/S

Seeds

Diabete, abdominal colics, aphrodisiac, bladder ailment, flatulence, rheumatism, sedative, sleep disorder, cardiac disease, hypertension, stomachic High blood pressure , cardiac disease, renal disease, diuretic, tonic, emmenagog, insect bite, stomachache, facilitate rules.

Hepatotoxicity, hepatocyte DNA damage

(Charnot ,1945) (Benzakour et al., 2012) (Teresa et al., 1983) (Mengs, 1987; Mengs et al., 1982) (Sato et al., 2004) (Yamani et al., 2015) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014)

ACCEPTED MANUSCRIPT

Asteracea Warionia saharae Benth. & Coss. Subgr Y/S

‫افساس‬

Brassicaceae Anastatica Hierochuntica L. Subgr Y/S

‫لكميشة‬ ‫كف مريم‬ ‫تمكلت‬

Brassicaceae Lepidium sativum L. Subgr Y/C

‫حب رﺷاد‬

‫افزداز‬

Seed Roots Rhizomes

Carboxyatractylo -side Atractyloside

Rheumatism pains, jaundice, epileptic seizures, intestinal diseases, cervical diseases Labour pains, menstrual pains, epilepsy, constipation, sterility, colds, rheumatoid arthritis,ophtalmia, Gastro intestinal disorders, diabetes cardiovascular

Aerial parts

Not yet identified

Digestive disorders: nausea, vomiting. Neurosensory disorders: obnubilation and drowsiness, headache, myalgia and asthenia, Eye disorders: blurred vision, dyschromatopsia. Cardiac events; bradycardia, arrhythmias ventricular. Impairment of renal function.

RI PT

Skin care, abortifacient, pathologies of the digestive system, allergy

SC

Scillaren A Scillirosid Proscillaridin A

M AN U

Bulbs

TE D

‫اداد‬ ‫داد‬

Degestive tract, rheumatism pains

Animal: an inhibitor of the adenine-nucleotide translocation, nephrotoxic effect, hepatorenel toxicity Human: digestive disorders, neurologic disorder.

5g/kg (SAT/R/O)

Nephrotoxicity, liver damage.

EP

Asteracea Carlina gummifera (L.) Less. (Atractylis gummifer a Salzm. ex L.) Subgr Z/S

‫بصل الذيب‬ ‫بصيلة‬

AC C

Asparagaceae Drimia maritima (L. ) Stearn (Urginea maritima ( L.) Baker) Subgr Z/S

0.1, 1 or 10 mg/kg (Aristolochic acid /3-16 months/R/O) LD50 = 490 mg/kg (R/per os) LD50= 145 mg/kg (Dog/per os) LD50= 100-500 mg/kg (cattle/per os) LD50 =250-500 mg/kg (sheep/per os) Proscillaridin LD50 = 0.73 mg/kg (R/Per os) Scillirosid LD50 = 0.5 - 0.7 mg/kg (R/Per os) LD50 < 20 mg/kg (Dog/Per os) LD50= 143 mg/kg (ATR /R/IP) LD50 = 2.9 mg/kg (CATR /R/IP) LD50= 1000 mg/kg (ATR/R/O) LD50 = 350 mg/kg (CATR/R/O) LD50= 49 -101.5 mg/kg (M/IP) LD50 = 250 mg/kg (R) 3.75ml/kg (R)

(Ouarghidi et al., 2013) (Slimani et al., 2016) (Hammiche et al., 2013) (Bruneton, 1996) (Fitzpatrick, 1952) (Windholz, 1983) (EMEA-The European Agency for the Evaluation of Medicinal Products, 1999) (Salhi et al., 2010) (Slimani et al., 2016)

(Kephalas et al., 1999) (Calmes et al., 1994) (Vignais et al., 1971) (Carpenedo et al., 1974) (Haouzi et al., 2002) (Hedili et al., 1989) (Zaim, 2009) (Abtroun, 1986) (Balansard G, 1994) (Fakchich and Elachouri, 2014) (Abouri et al., 2012) (Hammiche et al., 2013) (Amezouar et al., 2012) (Fakchich and Elachouri, 2014) (Bellakhdar, 1997)

Powdered plant

Not yet identified

3g/kg (AT/M/O)

Decreased locomotor activity.

(Shah et al., 2014) (Abouri et al., 2012)

Seeds

Not yet identified

2, 4,8g/100/ml (6 weeks/R/O)

Histological changes in rat liver, effect on liver fonction.

(Baffel and Ali, 2009) (Merzouki et al., 2000) (Tahraoui et al., 2007)

ACCEPTED MANUSCRIPT

Cannabinol Cannabidiol ∆9'tetrahydrocannab inol

LD50 = 212 mg/kg (CBD/A/ Rhesus Monkeys/ IV) LD50= 270 mg/kg (CBCH/AT/ Rhesus Monkeys/ IV) LD50= 326-435 mg/kg (AT/oil/ Rhesus Monkeys/ IV) 0. l - 10 µM (Strongylocentrotus purpuratus/ CBD, THC, CBN) 120mg/kg bw (CBD /M/IP) 10 and 100ng/ml(CBD/ Human PBMC) 10 mg/kg (CBD/R/IP) 1ml /kg (SCT/R/O)

‫عنب الذيب‬ ‫لواية‬

Whole plant

Urinary canals, rheumatism

Fruits Roots

TE D

‫ﺷيطة‬

Kidney, pancreas ailments, colds, urinary pain, skin face care.

Not yet identified

4g/kg (AT/R/O)

EP

‫ھراس الحجر‬ ‫ﺧريشة‬

AC C

Caryophyllaceae Herniaria hirsuta su bsp. cinerea (DC.) Cout. (Herniaria cinerea DC) Subgr Y/S Cucurbitaceae Bryonia cretica subs p. dioica (Jacq.) Tutin (Bryonia dioicaJacq.) Subgr Z/S

Cucurbitacin E Cucurbitacin I Brydiofin Bryodin

Cannabinoids directly affect the process of fertilization in sea urchins by reducing the fertilizing capacity of sperm. Inhibition of hepatic microsomal cytochrome p450. Hepatorenal lesions, the changes in the organ section were characterized by pale kidney, Increased mitogen-induced indoleamine 2, 3-dioxygenase and IFN-γ activity. ∆9'-tetrahydrocannabinol caused muscle spasms, salivation, dyspnea, arrhythmia, and hypothermia. The larger doses of CBD elicited tremors, convulsions, hypopnea, bradycardia, and cardiac failure. Anorexia and bloody diarrhea, respiratory dysfunction (nasal hemorrhage with polypnea).

(Mechoulam and Gaoni, 1965) (Jenny et al., 2009) (Musa et al., 2012) (Narimatsu et al., 1990) (Rosenkrantz et al., 1981) (Schuel et al., 1987) (Merzouki et al., 2000) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014)

Apoptosis in BL41 cells, nephrotoxicity, necrosis in the liver, in the red pulp of the spleen and in the proximal tubules of the kidneys, inactivating ribosomes, increase in heart rhythm, respiratory

(Munoz et al., 1992) (Benarba et al., 2012) (Yamani et al., 2015) (Stirpe et al., 1986) (El-hilaly et al., 2003) (Charnot, 1945)

RI PT

Seed (Oil)

SC

‫الحشيش‬ ‫لكيف‬

(Fakchich and Elachouri, 2014)

M AN U

Cannabaceae Cannabis sativa L. Subgr Z/C

diseases, bronchopulmonary infections, migraine Dermocosmotology, problems of the nervous system, skin diseases, hair strengthening, narcotic, sedative, antiemetic, stomachic, antipedileculous and cholagogue.

LD50= 8.85 mg/kg (Brydiofin 4 week /M/IP) LD50=14.5 mg/kg (IP/M/Bryodin) IC50= 15.63 µg/ml (BL41 cells) IC50= 2 µg/ml (HK-2 cells)

(Sokar et al., 2003) (Abouri et al., 2012) (Ouhaddou et al., 2014)

ACCEPTED MANUSCRIPT

Cucurbitaceae Citrullus colocynthis (L.) Schrad. Subgr X /S

‫حنطل‬ ‫لحدج‬ ‫حندل‬

Diabetes, hypertension, cardiac diseases, circulatory system, cholesterol, respiratory, digestive, skeleton

Euphorbiaceae Croton tiglium L. Subgr Z /I

‫ملكحبة‬

Purgative energetic, diabetes, diarrhoea, drastic.

Seeds

Crotin I Crotin II

Alterations of behaviour, neurological symptoms, autonomic symptoms and alterations of the liver,

(Stirpe et al., 1976) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Merzouki et al., 2003)

Dermocosmotology , skeleton–muscular system problems, cow jaundice, cold, fever

Seeds

Ricine

Crude crotin (AT/M/IP) : LD50= 3.37 (mg/mouse) Crotin I (AT/M/IP) : LD50= 1.33 (mg/mouse) Crotin II (AT/M/IP): LD50= 4.3(mg/mouse) LD50= 20-30 mg/kg (Per os/R) LD50= 30 mg/kg (Per os/M) LD50 (M) : inhalation: 3-5 µg /kg; IP: 22 µg /kg; IV: 5µg /kg; SBC: 24 µg/kg ; 20 mg/kg by intragastric administration

Gastro-enterite severe avec nausees, coliques violentes, diarrhee.

Anagyrine : IC50 = 18.0±1.3µM (HL-60) IC50 = 3.3±0.3 µM ( LoVo) Petroleum ether extract IC50= 5.13±0.73 µg/ml (HL-60) IC50= 16.1±0.3 µg/ml ( LoVo) 100, 200 and 300 mg/kg (R/65 days)

Cytotoxicity

(Audi et al., 2005) (Hammiche et al., 2013) (Franz and Jaax, 1997) (Cook et al., 2006) (Kumar et al., 2007) (Merzouki et al., 2000) (Mouhajir et al., 2001) (Fakchich and Elachouri, 2014) (Merzouki et al., 2000) (Daoudi et al., 2015) (Nassiri et al., 2016)

‫اوفني‬ ‫ري‬U ‫حبة‬ ‫ﺧروب‬ ‫الخنزير‬

Ringworm, kidney stones, neurological affection, microbial affection, typhoïde.

Leaves

Glycine max (L.) Merr. Subgr Y/C Trigonella foenumgraecum L. Subgr Z/C

‫صوجا‬

Diabetes, digestive system, allergy, dermocosmotology Gastric - intestinal ailments, pathologies of the respiratory system , diabetes,

Seeds

AC C

‫الحلبة‬

Anagyrine

EP

Fabaceae Anagyris Foetida L. Subgr Z/S

SC

RI PT

100 or 200 mg/kg/day (rabbits/1 month) 100, 200, 400 g/kg (R/IP/2 week) LD50 of saponin = 200mg/kg (AT/O/mouce)

M AN U

‫الخروع‬ ‫ارويورة‬ ‫كرﻧك‬

Not yet identified

TE D

Ricinus communis L. Subgr Z/S

Pulb Seed Fruit

activity and small convulsion. Gastro –enteritis, vomiting, colics, diarrhoea. Sever lesions in the small intestine, kidny and liver. Haemorrhage and erosion of the mucosa, necrosis of liver cells and renal tubules

Not yet identified

Leaves

Trigonelline

LD50= 4.1 g/kg (FR/IP) LD50= 3.5 g/kg (MR/IP) 3.2 g/kg (R/IP/20 days) 0.5, 1, 3 g/kg (AT/M/O)

DNA fragmentation, DNA diffusion, oxidative stress.

Reduce spermatogenic activities and sperm quality, reproductive dysfunctions and infertility Alterations in rat fetus. Fore-limb inflammation and alopecia, spermatotoxic effects. Fenugreek in teratogenic

(Diwan et al., 2000) (Dehghani and Panjehshahin, 2006) (Shafaei et al., 2012) (Eddouks et al., 2002) (Fakchich and Elachouri, 2014) (Ouhaddou et al., 2014)

(Ekaluo et al., 2013) (Merzouki et al., 2000) (Fakchich and Elachouri, 2014) (Mozaffari et al., 2010) (Araee et al., 2009) (Mishkinsky et al., 1974) (Ziyyat et al., 1997)

ACCEPTED MANUSCRIPT

RI PT

(Merzouki et al., 2000) (Fakchich and Elachouri, 2014) (EL Abbouyi et al., 2014)

Whole plant

Not yet identified

LD50 =12.13 g/kg (AT/M/O) 600, 1200 mg/kg (SCT/RO/)

Syncope, piloerection, asthenia, diarrhoea, convulsions

(Tahraoui et al., 2010) (Merzouki et al., 2000) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014)

100, 1000 g/kg (21 days/R/O)

Renal and hepatic damage

(Gregoretti et al., 2004) (Bammi and Douira, 2002) (Doukkali et al., 2015)

1, 2.5, 5 g/kg (EFT/R/O/21days) 2 and 4 g/kg (AT/M/O)

Reproductive performance of female rats and induces fetotoxicity

LD50 = 13 606 mg/kg (AT/M/O) 1000 and 1500 mg/kg (SAT/R/O)

Hyperurination, abdominal muscle twitches and convulsions. Cellular infiltration and tissue degeneration (lung). Hepatotoxicity, tonic-clonic seizures.

(Gerenutti et al., 2014) (Bellakhdar et al., 1991) (Eddouks et al., 2002) (Tahraoui et al., 2007) (Fakchich and Elachouri, 2014) (Mugisha et al., 2014) (Bellakhdar et al., 1991) (Ouhaddou et al., 2014) (Tahraoui et al., 2007)

‫حمرة‬

Digestive system, reproductive system, cold problems

Whole plant

Not yet identified

‫فليو‬

Diabetes, hypertension, cardiac, bronchopulmonary infections, digestive system, cold problems. Hypertension, skin, respiratory system

Whole aerial flowering parts of the plant Leaves

Not yet identified

Diabetes, gastricintestinal ailments, respiratory, circulatory,cold, hypertension.

A.parts (oil)

Not yet identified

SC

‫مرارة الحنش‬ ‫كوزة الحية‬

dosages can decrease the severity of bone marrow cell proliferation and increase fetal mortality rate.

100 mg/kg (CT/M/O) Trigonelline LD50 = 5 g/kg (R/O)

M AN U

Gentianaceae Centaurium erythrae a Rafn Subgr Y/S Hypericaceae Hypericum perforatum L. Subgr Y/S Lamiaceae Mentha pulegium L. Subgr Y/S

uterine pains, hypertension, laxative, anaemia, appetite stimulant, cough, fever, promote lactation, tonic Diabetes, power problemes, kidney diseases, helmintiasis, digestive system

Lamiaceae Mentha spicata L. Subgr Y/C

‫النعناع‬ ‫لقامة‬

Lamiaceae Salvia officinalis L. Subgr Y/C

‫السالمية‬

Lamiaceae Teucrium poliumL. Subgr Y/S

‫الجعدة‬

Chill, liver pain, vasopressor, digestive system.

A.parts

Not yet identified

LD50=3.15 g/kg (AT/M/O) LD50= 8 g/kg (AT /R/O) LD50=262 mg/kg (CT/R/IP) 300, 600 mg/kg (SCT/R/O) 0.1 and 0.2 g/kg (CT/M/O)

Histopathological effects on the liver and kidney, lobar hepatitis, infiltration of lymphocytes, coagulation necrosis.

Molluginaceae Corrigiola litoralis s

‫سرغينة‬ ‫تسرغينت‬

Lung disorders, hair care, rheumatic pains,

Roots

Not yet identified

LD50>14000mg/kg (AT/M/O) 5, 70 and 2000 mg/kg (SCT/R/O)

Abdominal contractions, inactivity, prostration, intense

TE D

Not yet identified

AC C

EP

2000 nl/ml (Rat hepatocytes)

(Lima et al., 2003) (Halicioglu et al., 2011) (Tahraoui et al., 2007) (Ouhaddou et al., 2014) (Mouhajir et al., 2001)

(Sitta, 2009) (Rasekh et al., 2005) (Khleifat et al., 2002) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Fakchich and Elachouri, 2014) (Lakmichi et al., 2011) (Merzouki et al., 2000)

ACCEPTED MANUSCRIPT

RI PT

‫التوت لبيض‬

diarrhea, and anorexia, respiratory complication.

Leaves

Not yet identified

300, 2000 mg/kg (AT/M/IP)

1, 2, 3% mg/ kg (AT/R/SBC) 5-100 mg/kg (AT/M/IV) Harmine IC50= 2.43-18.39 µg/ml (Med-mek carcinoma ; UCP-med carcinoma ; UCP-med sarcoma) IC50=20-120 µg/ml (UCP-Med and Med-mek carcinoma, and UCP-Med Ž. sarcoma) IC50 =0.011–0.021 µmol/ml in HepG2 cells LD50 =5000 mg/kg (AT/R/O)

‫الحرمل‬

Diabetes, nervous hypertension,respirator y, dermocosmotology, digestive system, skeleton–muscular system problems, genital.

Seeds

Harmol Harmalol Harmine Harmaline

Palmaceae Phoenix dactylifera L. Subgr Y/C

‫النخلة‬

Fruit

Not yet identified

Papaveraceae Papaver rhoeas L. Subgr X/S

‫بنلعمان‬ ‫بودي‬ ‫كبابوش‬

Plantaginaceae Globularia alypum L. Subgr Y/S

‫عين لرﻧب‬

Diabetes, hypertension, digestive system, respiratory system, cardiovascular diseases. Stomachique, allergy, pathologies of the urinary system, diabetes, sedative, sterility, cough, pulmonary diseases , analgesic, spasmolitic, dermocosmotology Stomachic, purgative, carminative, antirheum, anxiolytic, antidiabetic, menstrualpain analgesic,

EP

Not yet identified

AC C

Seeds

TE D

Nitrariaceae Peganum harmala L. Subgr Z/S

Leave

SC

Moraceae Morus alba L. Subgr Y/C

diuretic, stomachic, allergy, skeleton– muscular system problems, pathologies of the reproductive system As tonic, reconstituting and good for the blood

M AN U

ubsp. telephiifolia (P ourr.) Briq. (Corrigiola telephiif olia Pourr.) Subgr Y/S

Not yet identified

LD50 = 2.4x10-2 mg/ml (Brine shrimp eggs/ dichloromethane extracts) LD50 = 4000 mg/kg (AT/M/O)

800 mg/kg in (30 days/R/O)

Increase in ALT, AST and alkaline phosphatase, reduction in the hematocrit, hemoglobin, lymphocytes and monocytes. Hemorrhage in interstitial connective tissue and blood vessels of the white and red bulbe of spleen, degeneration and necrosis in the epithelial lining of spleen, acute neurotoxicities, namely visual and auditory, hallucinations, locomotor ataxia, nausea, vomiting, confusion and agitation, cytotoxicity. Pathological changes in the liver tissue sections.

CNS depression, and epileptic seizures. Cytotoxicity. Tears, salivation, stomach hypertrophy, presence of a yellowish liquid in the internal intestinal liquid. Pancreatic haemorrhages. Fetotoxic potentials.

(El-hilaly et al., 2003) (Fakchich and Elachouri, 2014) (Hafian et al., 2014) (Rhafouri et al., 2015)

(Oliveira et al., 2016, 2015) (Bellakhdar, 1997)

(Kartal et al., 2003) (Frison et al., 2008) (Rasekh et al., 2005) (Adeeb, 2015) (Chen et al., 2005) (Lamchouri et al., 2013, 2000) (Jouad et al., 2001) (Fakchich and Elachouri, 2014) (Ouhaddou et al., 2014)

(Agbon et al., 2014) (Ziyyat et al., 1997) (Tahraoui et al., 2007) (Fakchich and Elachouri, 2014) (Middleton et al., 2005) (GünaydJn et al., 2015) (Benlamdini et al., 2014) (Merzouki et al., 2000) (Fakchich and Elachouri, 2014) (Ouhaddou et al., 2014) (Katiri et al., 2017) (Soulimani et al., 2001) (Khabbach et al., 2012) (Fakchich and Elachouri, 2014) (Elbetieha et al., 2000)

ACCEPTED MANUSCRIPT

Rosaceae Prunus dulcis (Mill.) D.A.Webb (Prunus amygdalus Batsch) Subgr Z/C Rubiaceae Rubia tinctorum L. Subgr Z/S

‫اللوز المر‬

‫الفوة‬

Rutaceae Citrus aurantium L.

‫طرﻧج‬ ‫رﻧج‬

Stigmas

Diabetes, hypoglycemic, tonic, head problems, dermocosmotology

Seeds

Diabetes, cardiac disease, hypertension,renal diseases, stomachique

Roots

Head problems, diabetes, allergy, and

Fruits Leaves

Not yet identified

LD50 = 28.8 ml/kg (AT/M/O) LD50= 2.06 ml/kg (AT/M/IP) 15 and 25ml/kg (SCT/R and M/O) 21 g/kg (AT/M/O) 2 ml /kg (CT/R/O)

Not yet identified

3 g/kg (AT/M/O and IP) 180 mg/kg (SAT/R/IP) LD50=3.5 g /kg (SAT/R/IP) LD50 (AT/IP) = 1.48 ml/kg (MM), 1.88 mL/kg (FM), 1.50 mL/kg (MR). LD50(AT/O) = 21.42 ml/kg (MM), 11.42 ml/kg (FM), and 5.53 ml/kg (MR). Amygdaline LD50=880 mg/kg (R/Per os) LD50= 0.1 mmole (M/IP)

Amygdalin

Alizarin Rubiadin

p-synephrine

Sedation, respiratory arrest, convulsions.

RI PT

500, 1000, 1500 and 2000 mg/kg (AT/M/O)

SC

‫الزعفران‬ ‫الحر‬

Seeds (oil)

Not yet identified

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Iridaceae Crocus Sativus L. Subgr Y/C

Diabetes, hypertention, allergy, carminative, menstrual pains, antiasthmatic, pathologies of the digestive system, pathologies of the respiratory system Tonic, laxative, labour pains, aphrodisiac, menstrual pains, sterility.

Whole plant

TE D

‫الساﻧوج‬

diabetes, allergy Diabetes

EP

‫الرجلة‬

AC C

Portulagaceae Portulaca oleracea L. Subgr Y/S Ranunculaceae Nigella sativa L. Subgr Y/C

0.6, 1.2, 2.5 or 5.0% (SCT/R/O) 0.2%, 1.0% or 5.0% (CT/R) 0.06%, 0.3% and 1.5% (Rubiadin/R/one week) 0.008 % or 0.04% (Alizarin /R/one week) 0.04% (Alizarin and Rubiadin /R/26 week) P-synephrine : 300, 450, 600, 800, 1000 or 2000

Toxic effects on the histological structure of the kidney, hepatic toxicity, changes in hemoglobin metabolism and the fall in leukocyte and platelet.

Pathological changes were seen in the kidney and lung, increased platelet count, ataxia, lethargy, hypothermia.

(Shafi and Tabassum, 2013) (Katiri et al., 2017)

(Zaghlol et al., 2012) (Vahdati-Mashhadian et al., 2005) (Zaoui et al., 2002) (Merzouki et al., 2000) (Tahraoui et al., 2007) (Fakchich and Elachouri, 2014) (Hachi et al., 2015) (Mohajeri et al., 2007) (Hosseinzadeh et al., 2013, 2010) (Abouri et al., 2012)

Metabolic, respiratory, acidosis, coma, death.

(Adewusi and OKE, 1985) (Hammiche et al., 2013) (Solomonson, 1981) (Bellakhdar et al., 1991) (Jouad et al., 2001) (Fakchich and Elachouri, 2014)

Carcinogenicity in the kidney and liver, microvesicular vacuolar, degeneration in the cortex and karyomegaly in the outer medulla, hepatotoxicity.

(Inoue et al., 2009, 2008) (Alami et al., 2015) (Jouad et al., 2001) (Eddouks et al., 2002) (Benlamdini et al., 2014)

Reduction in locomotor activity, piloerection gasping, salivation

(Arbo et al., 2009, 2008) (Eddouks et al., 2002)

ACCEPTED MANUSCRIPT

Solanaceae Atropa Belladonna L. Subgr Z/S

‫زبيب ليدور‬

Solanaceae Datura stramonium L. Subgr Z/S

‫ﺷدك الجمل‬

Solanaceae Solanum nigrum L. (Solanum americanu m Mill)

‫عنب الذيب‬ ‫بوكنينة‬

Aphrodisiac, memory stimulant

Respiratory infection, narcotic, hallucinant, sedative, emetic, asthma, cough, tremor in the elderly, frigidity, jaundice, hypertension. Eczema, burns, wound healing, edema pregnancy, emetic

Not yet identified

The green parts

Viscumin

Fruits Berries

Atropine

SC

‫لنجبر‬

A.parts

Seeds

Aerial plant

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Santalaceae Viscum album L. Subgr Z/S

Diabetes, renal disease, respiratory, skin, skeleton, circulatory, auditory abscesses treatment, against evil spirits, emetic in pediatric Diabetes, pathologies of the digestive system, power problems

Crude extract LD50=235 µg/kg (M/IV) ID50= 53 ng/kg (mouse 3T3 cells or mouse 501.1 cells) 3 or 4 berries would have caused mydriasis and tachycardia in children aged 10-12 years -0.2 mg / kg (atropine) could lead to death. -4 to 10 mg of total alkaloids would present a letal risk for the child 5.2 mg/kg of atropine / 2.6 mg/kg of scopolamine (SAT /R/IP) 4.2 mg/kg of atropine / 1.6 mg/kg of scopolamine (CT /R/IP) 100 mg/kg (AT/R/IP) 0.5, 1.58 and 5.0% (SCT/R)

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‫اورمي‬ ‫فيجل‬

EP

Rutaceae Ruta montana (L.) L. Subgr Y/C

mg/kg (AT/M/O) 30 and 300 mg/kg (SCT/M/O) C. aurantium containing 2.5% psynephrine 1000, 2500, 3500 or 5000 mg/ kg (AT /M/O) 400, 2000 and 4000 mg/kg (SCT/M/O) 12 g/kg (AT/M/O) 100, 300, 600 mg/kg (CT/R/O)

Atropine Scopolamine

α-Solanine Solanidine

and exophthalmia, decrease in hematocrit, decrease in total proteins.

RI PT

hypertension, cardiac, cosmetic.

AC C

Subgr Z/C

300, 2000 ,5000 mg/kg (AT/M/O) α-Solanine LD50= 590 mg/kg (R/O) LD50= 67-75 mg/kg (R/IP) LD50= 30-42 mg/kg (M/IP)

(El-hilaly et al., 2003) (Tahraoui et al., 2007) (Fakchich and Elachouri, 2014)

Diarrhea and vomiting, vascular congestion and lesions of interstitial nephrite

(Merghem et al., 2013) (Jouad et al., 2001) (Ouhaddou et al., 2014) (Khabbach et al., 2012)

Inactivation of 60 S Ribosomal Subunits, endocytosis is involved in the entry of viscumin. Hepatits. Persistent and strong mydriasis, intense thirst and burning sensation in the throat and mouth, drunkenness, hallucinations, redness of the face and cyanosis, deep sleep, anticholinergic toxic syndrome Manifold centrolobular necrotic areas, and blood congestion and dilated central veins. A mydriase, hallucinations and a state of agitation.

(Olsnes et al., 1982) (Stirpes et al., 1982) (Fakchich and Elachouri, 2014) (Harvey and Colin-Jones, 1981)

Behaviour, movements, reactivity to various stimuli, bradypnoea, dyspnoea, palpation of cardiac region, feces consistency, events, acute

(Schneider et al., 1996) (Boustie et al., 2002) (Hammiche et al., 2013) (Demirhan et al., 2013) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Dugan et al., 1989) (Bouzidi et al., 2011) (Roblot et al., 1995) (Bellakhdar et al., 1991) (Merzouki et al., 2000) (Tahraoui et al., 2007) (Abouri et al., 2012) (Oh et al., 2016) (Rumiyati et al., 2015) (Lewin, 1903) (Balazs, 1970) (Charnot, 1945)

ACCEPTED MANUSCRIPT

Subgr Z/S

interstitial nephritis. Vomiting, diarrheoa.

‫الزاز‬

Fever, diabetes, head problems, abortive dermocosmotology, hair loss- prevention

The stem bark

Urticaceae Urtica dioica L. Subgr Y/S

‫حريكة‬

Pathologies of the urinary system, allergy, diabetes, renal weakness, digestive system

Leaves

Daphnetoxin Mezerein

Not yet identified

Extract plant LD50 =130 ± 30 mg/kg (AT/M/IP) Solasodine LD50= 1200 mg/kg (Hamter/O) LD50=4978 mg/kg (R/O) LD50= 103 mg/kg (Hamter/IP) LD50= 396 mg/kg (R/IP) 100 µM (Daphnetoxin /RLM) LD50 = Or unknown 0.25mg/kg

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Thymelaeaceae Daphne gnidium L. Subgr Z/S

Solasodine

SC

Berries

M AN U

Rheumatism, the fruit is used in laundry against ringworm.

2000 mg/kg (AT/R/O) LC50> 1000 µg/mL A. salina

AC C

EP

TE D

‫تفاح الغول‬ ‫مطيشة‬ ‫الحمير‬

Solanaceae Solanum sodomaeum L. Subgr Z/S

Gastrointestinal, neurological, anticholinergic effects.

Digestive diseases, respiratory diseases, mitochondrial permeability transition, inhibition of ATP synthase and inhibition of the mitochondrial respiratory chain.

Convulsion, ataxia, diarrhea or increased dieresis.

(IPCS, 1997) (Merzouki et al., 2000) (Abouri et al., 2012) (Boukhira et al., 2013) (Paris and Moyse, 1976-198) (Boukef and Marzouk, 1982) (Benkhnigue et al., 2011)

(Peixoto et al., 2004) (Paris & Moyse, 1976-198) (Duke, 1992) (Diogo et al., 2009) (Ziyyat et al., 1997) (Boukhira et al., 2013) (Fakchich and Elachouri, 2014) (Rhafouri et al., 2015) (Dar et al., 2012) (El-hilaly et al., 2003) (Fakchich and Elachouri, 2014)

ACCEPTED MANUSCRIPT 3.3.1

Toxicity assessments of plant extracts

3.3.1.1 In vivo assessments According to the results presented in Table 3, we can note that the value of LD50 is influenced by the nature of the plant extracts and the animal model involved in the experiment and the

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route of exposure of the extract (intravenous, oral, subcutaneous). Inter-studies comparison of these parameters show wide variations of LD50 values. For example: the value of LD50 corresponding to a given plant species Teucrium polium L. is 3.15 g/kg of body weight of

SC

mouse, when the extract was administred orally. Conversely, in the same experimental conditions, the value of LD50 is 8 g/kg, when the animal model is a rat.

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The route of administration of extract affects the values of LD50; for instance, the values of LD50, corresponding to the species Ricinus communis L., when the administration of the extract is intravenous, the value average 2-10 mg/kg, however by intraperitonial injection, the value of LD50 equal to 22 mg/kg, and for oral administration the LD50 is elevated (30 mg/kg).

TE D

For the species Conium maculatumL., the values of LD50 are around 19 mg/kg, in intravenous administration, 80 mg/kg in intraperitoneal, and 100 mg/kg when the extract is administred orally.

EP

These observations are explained by the fact that the LD50 is lower when the compounds is introduced intravenously, because the compounds quickly reach the target, without any

AC C

transformation or degradation. However when the route of administration is oral, the substances were transformed or partially altered before reaching the target cells. Other paremeters could influence the value of LD50, such as how the compounds were absorbed, transported, chemically altered, excreted, and bound to specific molecules within the body. Finally, we must know that the severity of toxic effect of plants consumed depends on the route of administration, growth stage or part of the plant, the amount consumed and the

ACCEPTED MANUSCRIPT vulnerability of the victim (Botha and Penrith, 2008). Other factors that may influence the severity of toxins include the solubility of the toxin in body fluids, frequency of intoxication as well as the age of the consumer. Table 3

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Toxic medicinal plants with their LD50, animal models and the route of administration of the extract.

Ricinus communis L.

Mouse Rat Mouse Rat Mouse Mouse Mouse Rat Mouse Rat

Teucrium polium L. Bryonia dioica Jacq. Solanum sodomaeum L. Carlina gummifera (L.)

Foeniculum vulgare Mill. Phoenix dactylifera L. Allium sativum L. Nigella sativa L. Crocus Sativus L.

Rat Rat Rat Mouse Mouse Rat Mouse Mouse Mouse Mouse Mouse

20-30 mg/kg (IP)

3150 mg/kg 8000 mg/kg

8.85 mg/kg(IP) 130 ± 30 mg/kg (IP) 49 -101.5 mg/kg (IP)

250 mg/kg

150 mg/kg (IP)

490 mg/kg

1326 mg/kg 5000 mg/kg 5000 mg/kg 28.8 ml/kg 21.42 ml/kg 5.53 ml/kg 5000 mg/kg 13606 mg/kg 14000 mg/kg 8500 + 420 mg/kg 12130 mg/kg

TE D

Nerium oleander L. Drimia maritima (L.)Stearn

Route of administration Oral Parenteral 30 mg/kg 22 mg/kg (IP) ; 2-10 mg/kg(IV)

AC C

EP

Coriandrum sativum L. Mentha spicata L. Corrigiola telephiifolia Pourr Herniaria cinerea DC Centaurium erythraea Rafn.

SC

Species

M AN U

Plant extract

2.06 ml/ kg (IP) 1.48 ml/kg(IP) 50 ml/kg (IP) ; 3500 mg/kg (IP)

3.3.1.2 Invitro assessments

The experiments related to in vitro toxicity assessment are limited; in fact, only 8 plant extracts have been devoted to the this type of toxicity test. As indicated in Table 4, variable types of cells have been used such as Mouse 3T3 cells for Viscum album L., HK-2 cells and BL41 cells for Bryonia dioica Jacq and HK-2 cells for Aristolochia fontanesii Boiss. & Reut. The values of IC50, regrouped in Table 4, are very indicative for the toxicity test of plant

ACCEPTED MANUSCRIPT extracts. As matter of fact, for Bryonia dioica Jacq, only 2 µg/ml of extract is enough to cause 50% of cell inhibition, contrariwise to Aristolochia fontanesii Boiss. & Reut, the IC50 reached the value 50 µg/ml.

IC50 of plants extracts tested on cells

Aristolochia fontanesii Boiss. & Reut Bryonia dioica Jacq.

3.3.2

Cells HL-60 LoVo HK-2 cells HK-2 cells BL41 cells Mouse 3T3 cells

M AN U

Viscum album L.

Extract plant IC50= 5.13±0.73 µg/ml IC50= 16.1±0.3 µg/ml IC50= 50 µg/ml IC50= 2 µg/ml IC 50= 15.63 µg/ml ID50= 53 ng/kg

SC

Botanical name Anagyris Foetida L.

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Table 4

Diversity of toxic compounds extract from plants

Vascular plants produce a plethora of secondary metabolites that are subdivided by chemists into several classes based on their molecular structure. Among secondary metabolites are

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alkaloids, terpenoids, glycosides, cyanogenic, saponins, tannins, toxic amino acids (Dai and Mumper, 2010). Some herbs contain powerful toxic compounds; if introduced into the body of an animal, these compounds will have a deleterious effect on different systems of the

EP

organism (Kuete, 2014). These harmful effects may be immediate or accumulated (Apollo et al., 2006). In this part of the text, we have enriched the data collection of 26 toxic plants

AC C

which have been investigated phytochemically. Table 2 resums the main results of the information related to the plants phytochemically studied. These plant species are investigated in terms of chemical composition, with respect to various plant families. In figure 4, we relate the ratio of toxic compounds of the plant species to the families. The pie chart (Fig 4.a) shows that Apiaceae family contains the most part of toxic compounds with 18%, followed by Apocynaceae and Solanaceae with 9% for each, Nitrariaceae and Cucurbitaceae with 7%, Amaranthaceae, Asparagaceae, Euphorbiaceae and Cannabaceae with 5%, for each one, Asteraceae, Araceae, Thymelaeaceae, Aristolochiaceae,

ACCEPTED MANUSCRIPT Rubiaceae and Fabaceae with 4%, while in families Rosaceae, Rutaceae and Santalaceae with only 2 % for each familly. A total of 55 distinct compounds had been identified and tested on different biological models. Based on their structural and chemical properties, we classified these toxic

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compounds into five classes as follows: the alkaloids were the most abundant, constituting 44% followed by glucosides with 20%, terpenoids with 16%, toxin proteins with 11%

M AN U

SC

andphenolic compounds with 9% (Fig 4. b).

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Fig 4: Distribution of toxic compounds by plant family (a) and by compound types classes 3.4 Specificity of toxic compounds extracted from plants 3.4.1

Cardiovascular system

EP



Targeted sytems :

Cardiac glycosides are specific types of toxic compounds that affect the cardiac muscle,

AC C

sometimes they cause fatal toxicosis. Cardiac glycosides increase contraction force of the heart by inhibiting the myocardial Na-K/ATP-ase, which can lead to cardiac arrest (Poindexter et al., 2007). Two types of cardiac glycosides are recognized depending on their chemical characteristics, namely, cardenolide and bufadienolide glycosides. For example the species Nerium oleander L. contains a mixture of very toxic cardiac glycosides, the cardenolides (Langford and Boor, 1996). Cardenolides inhibit cellular membrane Na+/K+/ATPase, resulting in electrolytic disturbance that affects the electrical conductivity of

ACCEPTED MANUSCRIPT heart (Aslani et al., 2004; Joubert, 1989). The whole plant species Drimia maritima (L.), contains several related steroidal cardioactive glucosides including scillaren A, scillaridin A, glucoscillaren A, and scilliroside that exert digitalis- like toxicity (Yesim Tuncok et al.,



Liver and Hepatic system

RI PT

1995).

The liver is often the first major metabolizing organ that ingested toxicant encounters, in which there is very high metabolic activities (Kuete, 2014). As indicated in table 2, some plants

such

as

Arisarum

vulgare

Targ.Tozz,

SC

medicinal

Chenopodium ambrosioides L.,Cannabis sativa L., Rubia tinctorum L, Citrullus colocynthis

M AN U

(L.) Schrad, used in traditional medicine, have lately been reported to produce hepatic lesions. Pyrrolizidine alkaloids (PAs) are a large group of hepatotoxins, characterized by the presence of a pyrrolizidine nucleus in their structure and are capable of causing hepatocellular necrosis. Plants compounds, known by their hepatotoxicity and hepatocyte DNA damage, are the

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Irniine, bgugaine and pyrrolidine alkaloid extracted from a tubers of Arisarum vulgareTarg.Tozz(Rakba et al., 2000, 1999). •

Nervous system

EP

Plant poisonings affect the nervous system in various ways, which include stimulation, depression, tremors, convulsions, paresis, paralysis, and abnormal behavior (Botha and

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Penrith, 2008). A large number of plant species have been associated with the development of nervous signs. Six of the most important plant poisonings result in severe nervous damage as seen with Solanum nigrum L., Solanum sodomaeum L., Peganum harmala L., Conium maculatum L., Atropa belladonna L. and Datura stramonium L. (Table 2). The family Solanaceae is well known byits parasympatholytic tropane alkaloids, such as hyoscyamine. Classic examples are Atropa beladdonaL., Datura stramonium L. and Hyoscyamus niger L.(Wiart, 2006).

ACCEPTED MANUSCRIPT •

Kidneys and Urinary tract

The kidneys and bladder are the main route of elimination of hydrophilic toxicant metabolites; therefore the urinary system is vulnerable to the toxicity.Impaired kidney function and bladder cancer are major adverse effects (Manahan, 2003). Aristolochia species are nowadays

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acknowledged as poisonous herbs. Aristolochic Acids (AA), commonly present in Aristolochia (Heinrich et al, 2009), are responsible for the toxic activity of this species. AA mainly target renal proximal tubular epithelial cells (RPTECs). Regular intakes of AA-

SC

containing herbs are associated with the progression of renal interstitial fibrosis, ultimately

2015). 3.5 Comparative remarks 3.5.1

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leading to end-stage kidney disease, named “Aristolochic acid nephropathy (Yamani et al.,

Severity of toxic effects related to plant extract

In general, from one plant to another, a dose that can cause damage varies according to both

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the chemical compounds present in the plant and their quantity. It has been shown that the toxicity of a given plant depends on various parameters, including thequantity consumed, the strength of secondary metabolites, the time of exposure, the different parts of the plant (root,

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oil, leaves, stem bark and seeds), the individual human’s body chemistry, the climate and soil, and the genetic differences within the species, as well as the nature of the solvant used for

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extraction (Tülay, 2012).

The level of toxicity of particular plant species is achieved through the determination of its Lethal Dose fifty (LD50). This indicator of the lethality (ability to kill 50% of the animals) for a given substance (Fulder, 1988).The results presented in this paper indicate that the severity of the plants tested, on different animal models, are arranged, in their respective administration route with decreasing order: Bryonia dioica Jacq. (8.85 mg/kg /IP/mice), Ricinus communis L. 2 mg /kg/IP/mice and 30 mg/kg/O/rats), Solanum sodomaeum L. (130 ±

ACCEPTED MANUSCRIPT 30 mg/kg /IP/mice), Carlina gummifera (L.) (49 -101.5 mg/kg/IP in mice and 250 mg/kg in rats), Nerium oleander L., (150 mg/kg/IP/mice). For Hodge and Sterner (Hodge and Sterner, 2005), with the help of LD50 determination in rats (single PO administration), six classes of toxicity are possibles:“Class 1 = extreme toxicity,

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LD50 < 1 mg/kg; Class 2 = high toxicity, LD50 at 1–50 mg/kg; Class 3 = moderate toxicity, LD50at 50–500mg/kg; Class 4 = low or slight toxicity, LD50 at 500–5000mg/kg; Class 5 = practically non toxic, LD50 at 5000-15,000 mg/kg and Class 6 = relatively harmless with

SC

LD50>15,000mg/kg” (Berezovskaya, 2003).According to this classification and taking account of the LD50 (by oral administration in rat), we can note that Foeniculum vulgare Mill.,

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Phoenix dactylifera L., Allium sativumL., with values of LD50 respectively 1326, 5000, 5000, could be graded in the slight toxic category, while Teucrium polium L., with LD50 value : 8000 mg/kg is considered as practically non-toxic. Concerning the toxicity assessment on the mice, the oral LD50 of the five plants Corrigiola telephiifolia Pourr., Mentha spicata L.,

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Centaurium erythraea Rafn, Herniaria cinerea DCand Coriandrum sativumL. are: 14000, 13000, 12130, 8500,5000 mg/kg respectively. According to this classification, Coriandrum sativumL.can be slightly toxic while Corrigiola telephiifolia Pourr., Mentha spicata L.,

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Centaurium erythraea Rafn and Herniaria cinerea DC can be classed practically non toxic. However the criteria developed by Bensoussan et al., 2002consisted of only three levels of

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toxicity grading, where ‘‘Severe’’ herbs indicating death occurrence, ‘‘Moderate’’ herbs reported life-threatening human adverse drug reactions (ADRs), and ‘‘Mild’’herbs reported non-life- threatening human. Referring to the latest classification, as indicated in table 5, we ranked some plants according to their degree of toxicity in three subgroups: Severe toxicity, Moderate toxicity and Mild toxicity.

ACCEPTED MANUSCRIPT Table 5 Classification of some plants according to their degree of toxicity, referring to the classification of Bensoussan et al, 2002 Moderate toxicity

Mild toxicity

Conium maculatumL. Viscum album L. Carlina gummifera (L.) Nerium oleander L. Prunus dulcis (Mill.) D.A.Webb Ricinus communis L. Arisarum vulgare Targ.Tozz, Aristolochia fontanesii Boiss. & Reut, Drimia maritima (L.)

Citrullus colocynthis (L.) Schrad. Trigonella foenum-graecum L. Rubia tinctorum L. Citrus aurantium L.

Crocus Sativus L. Hedera helix L. Croton tiglium L. Vicia faba L. Glycine max (L.) Mentha pulegium L. Morus alba L.

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Severity of toxic effects related to compounds extracted from plants

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3.5.2

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Severe toxicity

The toxic compounds found in all parts of the plant species, Datura stramoniumL., especially in the seeds, are tropane alkaloids which possess strong anticholinergic properties (Binev et al., 2006; Şanlıdağ et al., 2014). The majority of these alkaloids are hyoscyamine (generally

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the most abundant) and scopolamine, while atropine may be formed from hyoscyamine by racemization during the extractive procedure.

The alkaloids of Atropa belladonna L., atropine and scopolamine are known to be antagonist

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for muscarinic receptors (Rajput, 2013).They block the muscarinic receptor acetylcholine, which plays an important role in the functioning of the brain for learning, memory and

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orientation. In the event of the muscarinic blockade, the absence of acetylcholine causes dysfunctional memory, disorientation and hallucination (Joshi et al., 2003). Conium maculatum was one of the most poisonous plants, due to the presence of piperidine alkaloids in all parts of the plant, including the leaves, flowers, fruits, seeds, and roots (Alsnafi, 2016). This plant contains at least five main piperidine alkaloids, of which the most important are coniine and γ-coniceine. The other three alkaloids are N-methylconiine, conhydrine, and pseudoconhydrine. In literature, the toxicosis has been reported in horses, pigs, sheep, and cattle (Walelign and Mekuriaw, 2016). The clinical signs of Conium

ACCEPTED MANUSCRIPT maculatum poisoning include an initial stimulation of motor nerve endings and central nervous system, followed by paralysis and depression, respectively, problems in movement, slow and weak, then later, rapid pulse, hyperventilation, urination, and finally coma and death (Vetter, 2004).

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The actions of these three alkaloids (coniine, Nmethylconiine and α-coniceine) have been examined on isolated tissues; the most pronounced action of the alkaloids was the blocking of spinal reflexes by an action exerted in the spinal cord. Their peripheral actions on

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autonomically innervated structures were mainly a consequence of an initial stimulant and a secondary depressant action on autonomic ganglia. Large doses of the alkaloids stimulated

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skeletal muscle and subsequently caused neuromuscular block. This blocking action differ in many respects from that produced by decamethonium or tubocurarine (Bowman and Sanghvi, 1962).

As indicated in table 6, the severity of compound toxicity depends on the route of

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administration of the toxic compounds.Among some examples, illustrate this observation: for the Coniceine the values of LD50 are 2.6 mg/kg/mouce/IP and 12 mg/kg/mouce/O, the same remark for Carboxyatractyloside, (a rat as animal used in experiment), the values of LD50 are

Table 6

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respectively 350 mg/kg, with oral administration and2.9 mg/kg, by intraperitoneal perfusion.

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Toxic compounds as identified by their LD50 Toxic Compound

Species

Coniceine Coniine N-methylconiine Viscumin Amygdaline

Mice Mice Mice Mice Mice Rat Mice Mice Rat Rat

Brydiofin α-Solanine Carboxyatractyloside

Oral 12 mg/kg 100 mg/kg 204.5 mg/kg 0.235 mg/kg 45.7 mg/kg 880 mg/kg

590 mg/kg 350 mg/kg

Route of administration Parenteral 2.6 mg/kg (IV) ; 12 mg/kg (SC) 19 mg/kg (IV) ;80 mg/kg (SC) 27.5 mg/kg (IV) ;105.5mg/kg (SC)

14.5 mg/kg (IP) 30 à 42 mg/kg (IP) 67 à 75 mg/kg (IP) 2.9 mg/kg (IP)

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Rat Rat Rat Rat

1000 mg/kg 4978 mg/kg 0.5 à 0.7 mg/kg 0.73g/kg

143 mg/kg(IP) 396 mg/kg (IP)

4. Concluding remarks

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The traditional medicine involving medicinal plants is still taking a very important position in the life of many people in North Eastern region of Morocco. The problem of efficacy and safety, of plants used as medicine, continues to remain a major issue of concern. There is

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insufficient pragmatic information regarding the pharmacology and toxicology of plants commonly used traditionnally.Our results show that onlya relatively small number of plant

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species have been scientifically investigated in toxicological aspects, representing 31% of the total species recorded.

With some weakness of findings related to the toxicity assessments of some plant species, listed in the current work, variability in results may be attributed to differences in the

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approaches implemented by some workers. As matter of fact, we found that accuracy in taxonomical identity of the plant, proper identification and authentication of species tested as well as the exactness in appellation of the test durations are not respected. The divergences in

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the approaches and methodologies implemented by researchers for calculation of LD50 and

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IC50 could affect the quality of the toxicological assessments of plants and make the results difficult to compare. This is why it is recommended to harmonize the methodology usedfor the calculation of these parameters by using some method such as: Graphic method, described by Randhawa (Randhawa, 2009), and/or Dragstedt method, described by El Allaoui (El Allaoui et al., 2011), are considered the suitable methods for search evaluation. It is important to homogenize and standardize the methodologies adopted in toxicological assessments, as claimed by UNESCO, in the report of the Alma–Ata declaration, which reaffirmed the need to regard the traditional medical practices as something that “should be respected, preserved,

ACCEPTED MANUSCRIPT promoted, and communicated widely and appropriately based on the circumstances in each country”. Furthermore, the responsibility of the authorities must ensure safe and effective use of medicinal plants, through suitable policies, regulations, and standards (UNESCO, 2013). In this respect, some countries have already implemented regulatory, in the aim to harmonize the

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sector of phytomedicine, for example in Europe, USA and China (EPCD- The European Parliament and of the Council, 2004; Ekor, 2014; Fan et al., 2012; Street et al., 2008).Unfortunately, in Morocco, the lack of controlled and standardized the toxicity

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assessment of medicinal plants and the absence of the regulation of the traditional medical practices could have some effectson insurance and security of health public. All these

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parameters regrouped, disabled the development of medicinal plant sector as well as the insurance of sustainable use of these herbs.

5. General conclusion and recommendation

This study shows that several plants used for medicinal purposes by people in the North

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Eastern region of Morocco could cause damage and harm to their users. The present paper gives an overview on the chemical diversity of toxic bioactive compounds extracted fom plants listed. Medicinal plants should be used with caution. Further toxicological studies must

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be conducted on plants, especially in species that have never been toxicologically assessed

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(e.g plants listed in Table 1). It is imperative to validate these herbs with respect to using toxicological assessments. Furthermore, we recommend that, in Moroccan society, where the sector of medicinal plants is not regulated, efforts must be made to gather input from all stakeholders, including health authorities, traditional healers, scientists and policy makers, to establish affordable procedures to make safer the use of medicinal plants. Finally, it is worth noting that any plants ommitted in this paper does not mean that they are non toxic. Acknowledgements

ACCEPTED MANUSCRIPT Thanks to Asma Syed (Emory University School of Medicine of Atlanta - USA) for in

improving

the

quality

of

written

English

in

the

manuscript.

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assistance

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Ethical statement We are committed to declare that our seeking review is in accordance with the policy of our institution. In this work, ethical conduct has been respected for compliance with

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applicable laws and University policies and directives.