Cramer rules

Predicts the toxicological hazard (when administered orally) from the molecular structure.

WWW: http://toxtree.sourceforge.net/cramer.html
Vendor: Ideaconsult Ltd.
Training data: Click to retrieve
Test data: Click to retrieve

References:

  1. Cramer G. M., R. A. Ford, R. L. Hall, Estimation of Toxic Hazard - A Decision Tree Approach, J. Cosmet. Toxicol., Vol.16, pp. 255-276, Pergamon Press, 1978
  2. I.C. Munro, R.A. Ford, E. Kennepohl, and J.G. Sprenger, Correlation of structural class with No-Observed-Effect Levels: A proposal for establishing a threshold of concern, Food Chem. Toxicol. 34 (1996), pp. 829-867.
  3. Patlewicz G, Jeliazkova N, Safford RJ, Worth AP, Aleksiev B. (2008) An evaluation of the implementation of the Cramer classification scheme in the Toxtree software. SAR QSAR Environ Res. ;19(5-6):495-524.

Categories assigned:

Low (Class I)Substances with simple chemical structures and for which efficient modes of metabolism exist,suggesting a low order of oral toxicity.
Intermediate (Class II)Substances which possess structures that are less innocuous than class I substances, but do not contain structural features suggestive of toxicity like those substances in class III.
High (Class III)Substances with chemical structures that permit no strong initial presumption of safety or may even suggest significant toxicity or have reactive functional groups.

Rules:

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 [Open chain] [Heterocyclic] [Aromatic] [Heterocyclic] [Terpene] [Aromatic]

Rule ID

1

Title:

Normal constituent of the body

If YESASSIGN Low (Class I)
If NOGO TO Rule ID 2
ExplanationReturns true if the query is isomorphic to one of the structures loaded from a preconfigured file of a type SDF, SMI, CSV Is the substance a normal constituent of the body, or an optical isomer of such?

This question throws into class I all normal constituents of body tissues and fluids, including normal metabolites. Hormones are excluded, as are, by implication, the metabolites of environmental and food contaminants or those resulting from disease state.

Note the answer of the question relies on an incomplete list of compounds, identified by an expert as a normal body constituents.If you believe a query compound is wrongly identfied as a such, or not recognised, please consult and/or update the list.C:\Users\nina\AppData\Local\Temp\.toxtree.unknown\bodymol.sdf

ExamplesYESNO

Rule ID

2

Title:

Contains functional groups associated with enhanced toxicity

If YESASSIGN High (Class III)
If NOGO TO Rule ID 3
ExplanationDoes the substance contain any of the following functional groups: an aliphatic secondary amine or a salt thereof, cyano, N-nitroso, diazo, triazeno or quaternary nitrogen, except in any of the following forms: >C=N+R2, >C=N+H2 or the hydrochloride or sulphate salt of a primary or tertiary amine?
ExamplesYESNO

Rule ID

3

Title:

Contains elements other than C,H,O,N,divalent S

If YESGO TO Rule ID 4
If NOGO TO Rule ID 5
ExplanationDoes the structure contain elements other than C, H, O, N or divalent S?
ExamplesYESNO

Rule ID

4

Title:

Elements not listed in Q3 occurs only as a Na,K,Ca,Mg,N salt, sulphamate, sulphonate, sulphate, hydrochloride ...

If YESGO TO Rule ID 7
If NOASSIGN High (Class III)
ExplanationDo all elements not listed in Q3 occur only as
  • (a) a Na,K,Ca,Mg or N salt of a carboxylic acid, or
  • (b) a sulphate or hydrochloride of an amine, or
  • (c) a Na,K, or Ca sulphonate, sulphamate or sulphate?
If the answer is yes, treat as free acid, amine, unsulphonated or unsulphated compound, except for the purposes of Q24 and Q33.

This is intended to let through, for further consideration, certain acid,amine, sulphonate and sulphate salts. Sulphamate salts are treated as such because they are not readily hydrolised.

ExamplesYESNO

Rule ID

7

Title:

Heterocyclic

If YESGO TO Rule ID 8
If NOGO TO Rule ID 16
ExplanationIs the substance heterocyclic?Is the substance heterocyclic?
ExamplesYESNO

Rule ID

8

Title:

Lactone or cyclic diester

If YESGO TO Rule ID 9
If NOGO TO Rule ID 10
ExplanationIs it a lactone or cyclic diester?

This question separates the lactones and cyclic diesters from other heterocyclic compounds.

ExamplesYESNO

Rule ID

9

Title:

Lactone, fused to another ring, or 5- or 6-membered a,b-unsaturated lactone?

If YESASSIGN High (Class III)
If NOGO TO Rule ID [Open chain]
ExplanationHas any substructure of the list.Is it a Lactone, fused to another ring, or 5- or 6-membered a,b-unsaturated lactone?

This places certain lactones known or suspected to be of unusual toxicity in class III.

*If it is a lactone, from this point on treat the structure as if it were the hydroxy acid in the form of its more stable tautomer and proceed to Q20 if it is open chain,to 10 if it is heterocyclic and to 23 if it is carboxylic; if it is a cyclic diester treat as the separate components

ExamplesYESNO

Rule ID

[Open chain]

Title:

Open chain

If YESGO TO Rule ID 20
If NOGO TO Rule ID [Heterocyclic]
ExplanationIs the substance open chain?

ExamplesYESNO

Rule ID

20

Title:

Aliphatic with some functional groups (see explanation)

If YESGO TO Rule ID 21
If NOGO TO Rule ID 22
ExplanationIs the structure a linear or simply branched (I) aliphatic (A) compound, containing any one or combination of only the following functional groups (E):
  • (a)four or less, each, of alcohol, aldehyde, carboxylic acid or esters and/or
  • (b)one each of one or more of the following: acetal, either ketone or ketal but not both, mercaptan, sulphide (mono- or poly-), thioester, polyoxyethylene [(-OCH2CH2-)x with x no greather than 4], or primary or tertiary amine
this question should be answered YES if the structure contains one or any possible combination of alcoholic, aldehydic or carboxylic acid or ester groups, provided there are no more than four of any one kind.It should be answered YES if the structure contains in addition to, or instead of, those just listed, any assortment of no more than one each of the following:acetal, either ketone or ketal but not both, mercaptan, mono- or polysulphide, thioester, polyoxyethylene, primary or tertiary amine.

Answer the question NO if the structure contains more than four of any of the first set of groups, more than one of the second set, or any substituent not listed.

ExamplesYESNO

Rule ID

21

Title:

3 or more different functional groups

If YESASSIGN High (Class III)
If NOGO TO Rule ID 18
ExplanationDoes the structure contain >= 3 different types of functional groups (exclude methoxy and consider acids and esters as one functional type)?

Aliphatic (A) compounds containing three or more different functional groups (excluding methoxy) are too complex to permit satisfactory prediction of toxicity. they should go therefore, into class III.however, we do not wish to put into class III polyesters and similar substances, so these and the methoxy compounds get passed along to Q18.

ExamplesYESNO

Rule ID

18

Title:

One of the list (see explanation)

If YESASSIGN Intermediate (Class II)
If NOASSIGN Low (Class I)
ExplanationIs the substance one of the following:
  • (a)a vicinal diketone; or a ketone or ketal of a ketone attached to a terminal vynil group
  • (b)a secondary alcohol or ester of a secondary alcohol attached to a terminal vinyl group
  • (c)allyl alcohol or its acetal, ketal or ester derivative
  • (cellbox)allyl mercaptan, an allyl sulphide, an allyl thioester or allyl amine
  • (e)acrolein, a methacrolein or ther acetals
  • (f)acrylic or methacrylic acid
  • (g)an acetylenic compound
  • (h)an acyclic aliphatic (A) ketone,ketal or ketoalcohol with no other functional groups and with four or more carbons on either side of the keto group
  • (i)a substance in which the functional groups (E) are all sterically hindered (J)
Q18 examines the terpenes and later the open-chain and mononuclear substances by reference) to determine whether they contain certail structural features generally thought to be associated with some enhanced toxicity.
ExamplesYESNO

Rule ID

22

Title:

Common component of food

If YESASSIGN Intermediate (Class II)
If NOGO TO Rule ID 33
ExplanationReturns true if the query is isomorphic to one of the structures loaded from a preconfigured file of a type SDF, SMI, CSV Is the substance a common component of food (C) or stucturally closed related to a common component of food?

(C) Common component of food. In something as diverse , changing and occasionally uncertain as natural occurence, it is only possible to define a guideline, not a firm rule. For a decision tree, the term common component of food denotes a substance that has been reported in the recognised literature as occuring in significant quantity (approximately 50 ppm or more) in at least one major food, or in trace quantities at the ppm level or less in several foods, including minor or less frequently consumed foods. The latter include spices, herbs and ethnic specialities.This definition excludes natural or man made contaminants and hormones.

Note the answer of the question relies on an incomplete list of compounds, identified by an expert as a common component of food.If you believe a query compound is wrongly identfied as a such, or not recognised, please consult and/or update the list.C:\Users\nina\AppData\Local\Temp\.toxtree.unknown\foodmol.sdf

ExamplesYESNO

Rule ID

33

Title:

Has sufficient number of sulphonate or sulphamate groups

If YESASSIGN Low (Class I)
If NOASSIGN High (Class III)
ExplanationDoes the substance bear on every major structural component at least one Na, K or Ca sulphonate or sulphamate for every <=20 carbon atoms,without any free primary amines except those adjacent to the sulphonate or sulphamate.

Na,K,Ca sulphonate and sulphamate salts have a strong tendency to decrease toxicity by promoting solubility and rapid excretion.This is particularly noticeable, for example, with some of the food colourings. It is important that the substance bears sufficient sulphonate groups,including one on each major structural fragments into which the original compound might be metabolized. This question serves to steer sulphonated compoundsexcept those with amines non-adjacent to the sulphonate into a presumptively less toxic classification than the compounds would occupy if unsulphonated.

ExamplesYESNO

Rule ID

[Heterocyclic]

Title:

Heterocyclic

If YESGO TO Rule ID 10
If NOGO TO Rule ID 23
ExplanationIs the substance heterocyclic?
ExamplesYESNO

Rule ID

10

Title:

3-membered heterocycle

If YESASSIGN High (Class III)
If NOGO TO Rule ID 11
ExplanationIs it a 3-membered heterocycle

This places such substances as epoxides and ethylenamine in class III

ExamplesYESNO

Rule ID

11

Title:

Has a heterocyclic ring with complex substituents.

If YESGO TO Rule ID 33
If NOGO TO Rule ID 12
ExplanationDisregarding only the heteroatoms on any one ring, does that heterocyclic ring contain or bear substituents other than simply branched (I) hydrocarbonds (including bridged chains and monocyclic aryl or alkyl structures),alkyl alcohols, aldehydes,acetals,ketones,ketals,acids,esters (including cyclic esters other than lactones),mercaptans, sulphides, methyl ethers, hydroxy or single rings (hetero or aryl) with no substituents other than those just listed?

Questions 11-15 separate out various categories of heteroaromatic substances. Under 11, set aside and do not consider the atom(s), usually O,N and S, making the ring heterocyclic.If there is more than one hetero ring, regard each ring separately, with the remainder of the structure as substituents of that hetero ring.Other than the heterocyclic atoms, does the ring carry anything besides the simple groups listed?

If so, the answer is YES,and the next question 33. If not, then classify further by Q12 et seq. Bridged chain derivatives may be represented by structures like the bicyclic ether 1,4 cineole while monocyclic aryl derivatives may be represented by compounds like benzaldehyde propylene glycol acetal or 3-phenyl-2-furancarboxaldehyde.

ExamplesYESNO

Rule ID

12

Title:

Heteroaromatic

If YESGO TO Rule ID 13
If NOGO TO Rule ID 22
ExplanationReturns true if the query contains substructures specified by SMARTS patterns.This question separates the aromatic heterocyclics for the purpose of considering whether they are polynuclear(Q14) or unsubstituted (Q13).
ExamplesYESNO
Implementation details Name SMARTS
"heteroaromatic" a:[a;!c]:a

Rule ID

13

Title:

Does the ring bear any substituents?

If YESGO TO Rule ID 14
If NOASSIGN High (Class III)
ExplanationDoes the ring bear any substituents?
ExamplesYESNO

Rule ID

14

Title:

More than one aromatic ring

If YESGO TO Rule ID 15
If NOGO TO Rule ID 22
ExplanationDoes the structure contain more than one aromatic (B) ring?
ExamplesYESNO

Rule ID

15

Title:

Readily hydrolised

If YESGO TO Rule ID [Heterocyclic]
If NOGO TO Rule ID 33
ExplanationIs it readily hydrolysed(H) to mononuclear residues?If YES, treat the mononuclear heterocylic residues by Q.22 and any carbocyclic residue by Q16.
ExamplesYESNO

Rule ID

[Heterocyclic]

Title:

Heterocyclic

If YESGO TO Rule ID 22
If NOGO TO Rule ID 16
ExplanationIs the substance heterocyclic?
ExamplesYESNO

Rule ID

16

Title:

Common terpene

If YESASSIGN Low (Class I)
If NOGO TO Rule ID 17
ExplanationIs it a common terpene(D)- hydrocarbon,-alcohol, -aldehyde or -carboxylic acid (not a ketone)?

Q16 and Q17 deal with terpenes. A hydrocarbon terpene that is a common terpeneand has not already been put in class I by Q5, would go into class I by Q16.

ExamplesYESNO

Rule ID

17

Title:

Readily hydrolysed to a common terpene

If YESGO TO Rule ID [Terpene]
If NOGO TO Rule ID 19
ExplanationIs the substance readily hydrolysed (H) to a common terpene (D),-alcohol, -aldehyde or -carboxylic acid?

if the answer is YES, treat the hydrolysed residues separately and proceed to Q.18 for the terpene moiety and to Q19 for any non-terpenoid moiety).

Since there may be substances that are hydrolysed to two or more residues, one of which is terpene, treat the residues separately from Q18 onward to conclusion.

ExamplesYESNO

Rule ID

[Terpene]

Title:

Common terpene

If YESGO TO Rule ID 18
If NOGO TO Rule ID 19
ExplanationIs it a terpene?
ExamplesYESNO

Rule ID

19

Title:

Open chain

If YESGO TO Rule ID 20
If NOGO TO Rule ID 23
ExplanationIs the substance open chain?

Is the substance open chain (G)?

Q19-21 deal with open-chain substances.

ExamplesYESNO

Rule ID

23

Title:

Aromatic

If YESGO TO Rule ID 27
If NOGO TO Rule ID 24
ExplanationReturns true if the query contains substructures specified by SMARTS patterns.Is the substance aromaticIs the substance aromatic

Q 23-26 deal with alicyclic substancesThe implementation follows the Hueckel rule, rather than verifying for the presence of benzene, furan, thiophene, pyridine or pyrrole ring.

ExamplesYESNO
Implementation details Name SMARTS
"aromatic" a~a

Rule ID

27

Title:

Rings with substituents

If YESGO TO Rule ID 28
If NOASSIGN High (Class III)
ExplanationDo(es) the ring(s) have any substituents?

Q27-31 deal with aromatic compounds.

ExamplesYESNO

Rule ID

28

Title:

More than one aromatic ring

If YESGO TO Rule ID 29
If NOGO TO Rule ID 30
ExplanationDoes the structure contain more than one aromatic (B) ring?
ExamplesYESNO

Rule ID

29

Title:

Readily hydrolised

If YESGO TO Rule ID [Aromatic]
If NOGO TO Rule ID 33
ExplanationIs it readily hydrolysed(H) to mononuclear residues?If YES, treat the individual aromatic mononuclear residues by Q.30 and any other residue by Q19.
ExamplesYESNO

Rule ID

[Aromatic]

Title:

Aromatic

If YESGO TO Rule ID 30
If NOGO TO Rule ID 19
ExplanationReturns true if the query contains substructures specified by SMARTS patterns.Is the substance aromatic
ExamplesYESNO
Implementation details Name SMARTS
"aromatic" a~a

Rule ID

30

Title:

Aromatic Ring with complex substituents

If YESGO TO Rule ID 31
If NOGO TO Rule ID [Aromatic]
ExplanationDisregarding ring hydroxy or methoxy does the ring bear substituents other than 1-5-carbon aliphatic (A) groups,either hydrocarbon or containing alcohol, ketone, aldehyde, carboxyl or simple esters that may be hydrolised to ring substituents of <=5 carbons? (If a simple ester that may be hydrolised, treat the aromatic portion by Q.18 and the residue by Q19.

This should be answered NO if the ring bears only aliphatic groups of <=5 carbons, which are either hydrocarbon in nature or contain the groups listed.If the ring bears any other substituents than those listed, the question should be answered YES and proceed to Q31.

ExamplesYESNO

Rule ID

31

Title:

Is the substance an acyclic acetal or ester of substances defined in Q30?

If YESGO TO Rule ID [Aromatic]
If NOGO TO Rule ID 32
ExplanationIs the substance an acyclic acetal, -ketal or -ester of any of the above substances (see Q30)?(If YES, assume hydrolysis and treat the non-aromatic residues by Q19 and the aromatic residue by Q18.)

This question is simply designed to see whether the substance would fit within the definition of Q30 if it were not an acetal, a ketal or an ester.In other words, would the substance carry only the groups listed in Q30.

ExamplesYESNO

Rule ID

[Aromatic]

Title:

Aromatic

If YESGO TO Rule ID 18
If NOGO TO Rule ID 19
ExplanationReturns true if the query contains substructures specified by SMARTS patterns.Is the substance aromatic
ExamplesYESNO
Implementation details Name SMARTS
"aromatic" a~a

Rule ID

32

Title:

Contains only the functional groups listed in Q30 or Q31 and those listed below.

If YESASSIGN Intermediate (Class II)
If NOGO TO Rule ID 22
ExplanationDoes the substance contain only the functional groups (E) listed in Q30, or their derivatives listed in Q31, but with any or all of the following:
  • (a)a single fused non-aromatic carbocyclic ring
  • (b)aliphatic (A) substituent chains longer than 5 carbon atoms, or
  • (c)a polyoxyethylene [(-OCH2CH2-)x, with x <= 4] chain either on the aromatic ring or on an aliphatic side chain?

Part (a) is intended to allow simple derivatives of tetralin into class II while putting polyciclic compounds such as steroids ultimately into class III except those that may be normal food components.

Part (b) allows compounds with permitted functional groups but longer side chains into class II instead of sending them eventually into class III.

Part (c) puts short-chain polyoxyethylene derivatives of aryl compounds into class II rather than class III.

ExamplesYESNO

Rule ID

24

Title:

Monocarbocyclic with simple substituents

If YESGO TO Rule ID 18
If NOGO TO Rule ID 25
ExplanationIs the substance monocarbocyclic (excluding cyclopropane or cyclobutane and their derivatives) with ring or aliphatic (A) side chains,unsubstituted or containing only alcohol, aldehyde, side-chain ketone, acid, ester, or Na, K or Ca sulphonate or sulphamate, or acyclic acetal or ketal?/
ExamplesYESNO

Rule ID

25

Title:

Cyclopropane, etc. (see explanation)

If YESASSIGN Intermediate (Class II)
If NOGO TO Rule ID 26
ExplanationIs the substance
  • (a)a cyclopropane or cyclobutane with only the substituents mentioned in Q24 or
  • (b)a mono- or bicyclic sulphide or mercaptan?
ExamplesYESNO

Rule ID

26

Title:

Monocycloalkanone or a bicyclocompound

If YESASSIGN Intermediate (Class II)
If NOGO TO Rule ID 22
ExplanationDoes the structure contain no functional groups other than those listed in Q24 and is either a monocycloalkanone or a bicyclic compound with or without a ring ketone?
ExamplesYESNO

Rule ID

5

Title:

Simply branched aliphatic hydrocarbon or a common carbohydrate

If YESASSIGN Low (Class I)
If NOGO TO Rule ID 6
ExplanationIs it a simply branched (I)acyclic aliphatic (A) hydrocarbon or a common carbohydrate?

This drops out the generally inocuous hydrocarbons and carbohydrates.

ExamplesYESNO

Rule ID

6

Title:

Benzene derivative with certain substituents

If YESASSIGN High (Class III)
If NOGO TO Rule ID 7
ExplanationIs the substance a benzene derivative bearing substituents consisting only of
  • (a)hydrocarbon chains or 1'hydroxy or hydroxy ester-substituted hydrocarbon chains and
  • (b)one or more alkoxy groups, one of which must be para to the hydrocarbon chain in (a)?
this places in class III safrole, myristicin and related substances.
ExamplesYESNO