Designing a safer chemical

Let’s get right into the meat of this topic. Here are some strategies for safer chemical design:

1. Reduce absorption
2. Use of toxicity generating mechanism
3. Use of structure activity (toxicity) relationships
4. Use of isosteric replacements
5. Use of retrometabolic (‘soft’ chemical) design
6. Identification of equally efficacious less toxic chemical substitutes of another class
7. Elimination for the need for associated toxic substances

While considering these aspects, it is best to divide them into two categories, namely external considerations and internal considerations.

External considerations

Reduction of exposure or accessibility:

Properties related to environmental distribution/dispersion:

• Volatility, density, melting point. For example, Carbon disulphide is stored in pool of water because it is denser than water. Also, petrol/diesel are stored underground to keep the temperature low.
• Water solubility.
• Persistence/Biodegradation: Oxisdation, hydrolysis, photolysis, microbial degradation. These are all related to structural stability.
• Conversion to biologically active substances.
• Conversion to biologically inactive substances.

Properties related to uptake by organisms:

• Volatility
• Lipophilicity
• Molecular size
• Degradation: Hydrolysis, effect of pH, susceptibility to digestive enzymes.

Consideration of routes of absorption by mass, animals or aquatic life:

• Skin/eyes
• Lungs
• GI tract
• Gills or other species-specific routes

Reduction/elimination of impurities:

• Generation of impurities of different classes
• Presence of toxic homologues
• Presence of toxic, geometric, conformational or stereoisomers.

Internal considerations

Facilitation of detoxication:

• Facilitation of excretion: Selection of hydrophilic compounds, facilitation of conjugation/acetylation
• Facilitation of biodegradation: Oxidation, reduction, hydrolysis.

Avoidance of Direct Toxication:

• Selection of chemical class or parent compound
• Selection of functional groups: Avoidance of toxic groups, planned biochemical elimination of toxic structure.
• Structural blocking of toxic grouos
• Alternative molecular sites for toxic groups

Avoidance of Indirect Biotoxication (Bioactivation):

• Addressing Bioactivation: Avoiding chemicals with known activation routes – (1) highly electrophilic or nucleophilic groups (2) unsaturated bonds (3) other structural features
• Structural blocking of bioactivation

You must already be familiar with isosteres by now. Here are some other ways to deal with toxic substances.

Use of Retrometabolic (Soft Chemical) Design

A ‘soft’ chemical can be defined like soft drugs. A substance deliberatly designed such that it contains the structural features necessary to fulfill its commercial purpose but if absorbed into exposed individuals, it will break down quickly and non-oxidatively to non-toxic readily excretable substances. For example, safer alkylating agents and safer analog of DDT.

Equally efficacious, less toxic substitutes of another class

Focus on commercial application and depends on the successful identification of a less toxic substance of a different chemical class.

Examples:

1. Acetoacetate as substitutes for isocyanates in sealants and adhesives
2. Isothiazoles as substitutes for organotin anti-foulants
3. Sulfonated diaminobenzanilides for benzalidines in dyes

Elimination of associated toxic substances

The subtance per se is not toxic but its storage, transportation or use may require an associated substance which is toxic. For example, solvent replacement.

Examples:

1. Water based paints instead of oil based paints
2. Supercritical CO2 for organic solvents
3. Dibasic esters (e.g. methyl esters of adipic, succinic acid and glutaric acids) to replace glycol ethers, cyclohexanone, isophorone, cresylic acid, methylene chloride and others)

Cetylpyridinium chloride and its soft analog:

Cetylpyridinium chloride (CPC) is a cationic quaternary ammonium compound in some types of mouthwashes, toothpastes, lozenges, throat sprays, breath sprays, and nasal sprays. Cetylpyridinium chloride is present in commercial products listed in this Wikipedia article.

Acetoacetate based sealants and adhesives:

Carcinogenicity of Aromatic Amines:

Simplest of these systems is Aniline. The unattached bonds on these ring systems indicate the positions where attachment of amines or amine generating group(s) gives rise to carcinogenic compounds.

Have a look at the molecular design of aromatic amine dyes with lower carcinogenic potential. Find it here: OncoLogic™ – The Cancer Expert System – An Overview