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Brucine

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First-aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
   3.4 Other characteristics
4. USES/CIRCUMSTANCES OF POISONING
   4.1 Uses
   4.2 High risk circumstance of poisoning
   4.3 Occupationally exposed populations
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Others
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. TOXICOLOGY
   7.1 Mode of Action
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake (ADI) and other guideline levels
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall Interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ears, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. ADDITIONAL INFORMATION
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESSES
    1. NAME
     1.1 Substance
       Brucine
     1.2 Group
       Alkaloid
     1.3 Synonyms
       (-) Brucine
       10.11 - Dimethystrychnine
       2-3-Dimethoxystrychnine
       2.3 - Dimethoxystrychnine-10-one
       Brucin (German)
       Brucina (Italian, Portuguese)
       Brucine Alkaloid
       Dimethoxy Strychnine
       Strychnidin-10-one
     1.4 Identification numbers
       1.4.1 CAS number
             357-57-3
       1.4.2 Other numbers
             CEC: 614-006-00-1
             RTECS:EH 8925000
     1.5 Brand names, Trade names
       (Note: In Portugal there are no rodenticides with brucine)
     1.6 Manufacturers, Importers
       To be done by each centre
       
       (Note: In Portugal there are no pesticides with brucine)
    2. SUMMARY
     2.1 Main risks and target organs
       Brucine is an alkaloid resembling strychnine but it is much 
       less potent than strychnine.  Brucine causes paralysis of the 
       peripheral nerve endings and produces violent convulsions.
       
       Highly toxic by ingestion and inhalation; irritant.
       
       When heated, brucine emits highly toxic fumes of nitrogen 
       oxides.
     2.2 Summary of clinical effects
       Brucine may produce nausea, vomiting restlessness, excitement, 
       twitching and convulsions in large doses.
       
       Contact irritates eyes.
     2.3 Diagnosis
       Brucine can be measured in urine, blood, gastric contents, and 
       vomitus, but concentrations are not relevant for management.
       
       Determine acidosis and serum potassium.
       
       Determine SGOT, LDH and CPK.
     2.4 First-aid measures and management principles
       Management is symptomatic and supportive.
       
       Avoid any secondary sensory input.
       
       Prevent or control convulsions with diazepam, or phenytoin or 
       phenobarbital.
       
       Gastric aspiration and lavage may be indicated when seizures 
       are controlled.
       
       Administer activated charcoal with a cathartic.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Brucine is an alkaloid obtained from strychnos seeds: 
       (Strychnos nux-vomica L. and s. ignatii Berg, Loganiaceae).
       
       S. nux-vomica L. contains approximatly 1.1% brucine 
       
       S. ignatii Berg contains approximately 1 to 1.2% brucine
       
       "Upas tient_" (arrow poison) contains 2.4% of this alkaloid 
       (Kohn-Abrest, 1955).
       
       The bark of S. nux-vomica contains 2.4% brucine (Fabre and 
       Truhaut, 1961).
     3.2 Chemical structure
       Chemical name: 2,3-Dimethoxystrychnidin-10-one
       
       Empirical formula:  C23H26N2O4
       
       Molecular weight: 394.51
       
       (Merck Index, 1989).
       
       Structural formula:
       
       
     3.3 Physical properties
       needles from acetone + water
       
       melting point
       
       anhydrous base 178 C
       hydrated form  105 C (Clark, 1969)
       
       pH (saturated water solution) 9.5
       
       solubility: 1 g dissolves in:
       
                   0.8 ml methanol
                   1.3 ml alcohol
                   5 ml chloroform
                   25 ml ethyl acetate
                   36 ml glycerol
                   about 100 ml benzene
                   187 ml ether
                   1320 ml water
                   750 ml boiling water (Merck Index, 1989).

     3.4 Other characteristics
       Normal state at room temperature: solid monoclinic prisms; 
       forms dihydrate or tetrahydrate (loses water at 100C).
       
       Colour: small white crystals (Clark, 1969).
       
       Odour:  odourless (Derobert, 1954).
       
       Taste: very bitter; bitterness threshold 1:220,000 (Merck 
       Index, 1989).
       
       Products of combustion: when heated emits toxic fumes of 
       nitrogen oxides (Sax, 1984).
    4. USES/CIRCUMSTANCES OF POISONING
     4.1 Uses
       Industry - Brucine and its salts are used as a 
       denaturant in oils and alcohols (Cook & Martin, 1953; 
       Merck Index, 1989), and particularly in cosmetic 
       preparations (Arena, 1986).  Brucine is used in 
       analytical chemistry for separating racemic mixtures 
       (Merck Index, 1989).  It has been patented as additive 
       for lubricants (Merck Index, 1984). Brucine may be a 
       constituent of suntan preparations (Arena, 1986).
       
       Agriculture - Brucine and the other alkaloids obtained 
       from the seeds of Strychnos have been used for 
       destroying birds, rodents, moles and predatory animals 
       (Vallet, 1964).
       
       Medicine - Extracts of nux vomica have been used in some 
       preparations.  Nux vomica (dried ripe seeds of Strychnos 
       nux) contains strychnine and brucine and is used in the 
       preparation of homeopathic medicine.  Ignatia (the 
       extract of S. ignatii) is also used in homeopathic 
       medicine, where it is known as Ignatia amara (Martindale,
       1989).
     4.2 High risk circumstance of poisoning
       Brucine is rarely used and poisoning is uncommon.  The 
       concentration of brucine when used as a denaturant is very 
       low.  Consequently, such preparations do not present any great 
       hazard, unless an unusually large quantity is ingested (Arena, 
       1986).
       
       Ingestion of the whole plant, particularly the seeds of S. nux-
       vomica and S. ignatii can cause poisoning.  These plants 
       contain the alkaloids strychnine and brucine, but lethality of 
       nux vomica is believed to parallel its content of strychnine.
       
       The bark of Strychnos, may be used mistakenly for the bark of 
       Galipea officinalis because of its similar appearance and 
       cause accidental poisoning (Francone, 1963; Fabre & Truhaut, 
       1961).
       
       Brucine when heated emits toxic fumes of nitrogen oxides.

     4.3 Occupationally exposed populations
       Workers who come into contact with the brucine powder in 
       industry.
    5. ROUTES OF ENTRY
     5.1 Oral
       Ingestion of preparations with brucine or plants of species of 
       Strychnos (Loganiaceae).
     5.2 Inhalation
       Inhalation of brucine powder.
       
       Inhalation of fumes of nitrogen oxides resulting from heated 
       brucine.
     5.3 Dermal
       No data available.
     5.4 Eye
       No data available.
     5.5 Parenteral
       No data available.
     5.6 Others
       Unknown.
    6. KINETICS
     6.1 Absorption by route of exposure
       VIDE Strychnine.
     6.2 Distribution by route of exposure
       VIDE Strychnine.
     6.3 Biological half-life by route of exposure
       Unknown.
     6.4 Metabolism
       VIDE Strychnine.
     6.5 Elimination by route of exposure
       VIDE Strychnine.
    7. TOXICOLOGY
     7.1 Mode of Action
       Brucine is a highly toxic alkaloid resembling strychnine, but 
       it is much less potent.It causes paralysis of the peripheral 
       nerve endings and, in large doses, produces neuronal 
       excitability (see Strychnine).
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     The probable fatal dose in adult is estimated at 
                     1 g (Gosselin, 1984).
             7.2.1.2 Children
       7.2.2 Relevant animal data
             oral-rat LD50:        1 mg/kg
             ipr -rat LD50:       91 mg/kg
             ivn -dog LDLo:        8 mg/kg
             oral-rbt LD50:        4 mg/kg
             ivn -rbt LDLo:       30 mg/kg
             ivn -gpg LDLo:      120 mg/kg
             scu -pgn LDLo:       58 mg/kg
             (Sax, 1984)
       7.2.3 Relevant in vitro data
             No data available.

       7.2.4 Workplace standards
             No data available.
       7.2.5 Acceptable daily intake (ADI) and other guideline levels
             Aquatic toxicity rating: TLm 96:10-1 ppm (NIOSH, 1979)
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       No data available.
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       No data available.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
                     Leukocytosis may occur.
             8.3.1.2 Urine
                     Myoglobin should be detected in cases with 
                     rhabdomyolysis.
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
             Arterial pH should be determined.

       8.3.3 Haematological analyses
             Elevation SGOT, LDH and CPK may occur in cases with 
             rhabdomyolysis.
             
             Serum potassium concentrations should be determined.
       8.3.4 Interpretation of biomedical investigations
             No data available.
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Brucine causes nausea, vomiting, restlessness, 
             excitement, twitching, paralysis of the peripheral nerve 
             endings and, in large doses, violent convulsions.
       9.1.2 Inhalation
             The clinical findings are the same as symptoms described 
             after ingestion.
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             No data available.
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       See strychnine.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             See strychnine.
       9.4.2 Respiratory
             See strychnine.
       9.4.3 Neurological
             9.4.3.1 CNS
                     See strychnine.

             9.4.3.2 Peripheral nervous system
                     Brucine may act as a local anesthetic agent and 
                     perhaps as a paralytic substance (Gosselin et 
                     al., 1984).
             9.4.3.3 Autonomic nervous system
                     No data available.
             9.4.3.4 Skeletal and smooth muscle
                     There is no direct effect on skeletal muscle. 
                     Increased muscle tone is due to the central 
                     action of the drug (Goodman et al., 1985).
                     
                     Rhabdomyolysis associated with myoglobinuria may 
                     occur after intense muscular contractions.
       9.4.4 Gastrointestinal
             Nausea and vomiting.
             
             Small quantities of brucine may have an extremely bitter 
             taste in the mouth and cause reflex gastric secretion.
       9.4.5 Hepatic
             No data available.
       9.4.6 Urinary
             9.4.6.1 Renal
                     Rhabdomyolysis and myoglobinuria may produce 
                     renal damage from precipitation of myoglobin in 
                     the renal tubules.
             9.4.6.2 Others
                     No data available.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             No data available.
       9.4.9 Eye, ears, nose, throat: local effects
       9.4.10 Haematological
              No data available.
       9.4.11 Immunological
              No data available.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Seizures and muscular spasms may lead to 
                       lactic acidosis.
              9.4.12.2 Fluid and electrolyte disturbances
                       Hyperkalaemia and dehydration have been 
                       described after repeated convulsions (Gosselin,
                        1984).
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
              No data available.
       9.4.14 Other clinical effects
              No data available.
       9.4.15 Special risks
              No data available.
     9.5 Others
       No data available.
     9.6 Summary

    10. MANAGEMENT
      10.1 General principles
         See strychnine.
      10.2 Relevant laboratory analyses and other investigations
         10.2.1 Sample collection
         10.2.2 Biomedical analysis
         10.2.3 Toxicological analysis
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic treatment
         See strychnine.
      10.4 Decontamination
         See strychnine.
      10.5 Elimination
         See strychnine.
      10.6 Antidote treatment
         10.6.1 Adults
         10.6.2 Children
      10.7 Management discussion
         There are no significant controversies or alternatives for 
         patient management.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         No data available.
      11.2 Internally extracted data on cases
         (Note: we do not know of any case of brucine poisoning).
      11.3 Internal cases
         No data available.
    12. ADDITIONAL INFORMATION
      12.1 Availability of antidotes
         There is no specific antidote.
      12.2 Specific preventive measures
         There is no justification for use of brucine as rodenticide.
         
         Follow carefully the instructions for safe use of the 
         brucine powder and industrial preparations with brucine.
         
         Handle dry powder in a fume hood only (Merck Index, 1989). 
         Wear butyl rubber gloves, full protective clothing, 
         respirator mask and protective shoes (ITI, 1979).
         
         According to Council of Europe and Directive EEC for 
         Dangerous Substances, the packages that contain brucine must 
         have the following phrases relative to the special risks 
         attaching to dangerous substances:
         
         R26 Very toxic by inhalation
         
         R28 Very toxic if swallowed
         
         and the following phrases about safety advice concerning 
         dangerous substances:
         
         S1   Keep locked up
         
         S13  Keep away from food, drink and animal stuffs
         
         S45  In case of accident or if you feel unwell, seek medical 
         advice immediately (show the label where possible).
      12.3 Other
         No data available.
    13. REFERENCES
    Arena JM & Drew RH (1986).  Poisoning, toxicology symptoms, 
    treatments, Springfield, Illinois, USA, CC Thomas, 273, 701 (1128 
    pp).
    
    Clark EGC (1969).  Isolation and identification of drugs, Volume 
    1, London, The Pharmaceutical Press, 225-226 (870 pp).
    
    Cook EF and Martin EW (1953).  Farmacia Practica de Remington, 
    Mexico, Union Tipografica Editorial Hispano Americana, 972 (1786 
    pp) (in Spanish).
    
    Derobert L (1954).  Poisoning and occupational diseases, Paris 
    Editions M_dicales Flammarion, 1239 (1515 pp) (in French).
    
    Fabre R and Truhaut R (1961).  Pr_cis de Toxicologie, Paris, 
    Soci_t_ d'Edition d'enseignement sup_rieur, 469-472 (721 pp) (in 
    French).
    
    Francone MP (1963).  Toxicologia, Buenos Aires, Editorial Medica 
    Panamericana, 243 (336 pp) (in Spanish).
    
    Goodman LS, Gilman AG & Gilman A (1985).  The pharmacological 
    basis of therapeutics, New York, Macmillan Publishing Co. Inc., 
    582.
    
    Gosselin RE, Smith RP & Hodge HC (1984).  Clinical toxicologyof 
    commercial product, Baltimore/London, Williams & Wilkins, 5th ed.,
    II-249, III-375-379.
    
    ITI (1979).  Toxic and hazardous industrial chemicals safety 
    manual, Tokyo, The International Technical Information Institute, 
    81-82 (591 pp).
    
    Kohn-Abrest E (1955).  Pr_cis de Toxicologie.  Paris, G. Doin & 
    Cie., 394-398 (506 pp) (in French).
    
    Martindale (1989).  The extra pharmacopoeia. 29th ed. London, The
    Pharmaceutical Press, 1146 (1896 pp).
    
    Merck Index (1989). Rahway, 11th edition, New Jersey, USA, Merck 
    & Co., Inc., 201.
    
    NIOSH Registry of Toxic Effects of Chemical Substances (1979). 
    Maryland, Tracor Jitco Incorporated, 324 (1598 pp).
    
    NIOSH Registry of Toxic Effects of Chemical Substances (1983-84 
    supplement).  524-525 (2049 pp).
    
    Sax NI (1984).  Dangerous properties of industrial material.  6th 
    ed., New York, van Nostrand Reinhold Company, 542-3 (3124  pp).
    
    Substances chimiques and dang_reuses et propositions concernant 
    leur _tiquettage.  Conseil de l'Europe (1978), 4th ed., 
    Maisonneuve, 894-4 (951 pp).
    
    Vallet G (1964).  Les intoxications en milieu rural.  Institut   
    national de M_dicine agricole, 411-414 (632 pp) (in French).
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), 
    COMPLETE ADDRESSES
    Author:   Arlina Borges
              Centro de Informa_ao Antivenenos
              Instituto Nacional de Emerg_ncia M_dica
              Rua Infante D. Pedro, 8
              1700 LISBON
              Portugal
    
              Tel: 7930503
              Tlx: 13304 SNALP/P
              Fax: 7590141
    
    Date:          April 1990.
    
    Peer Review: Strasbourg, France, April 1990



    See Also:
       Toxicological Abbreviations