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HSP Application note #16

Hansen Solubility Parameter (HSP) and LD50(skin,rabbit)


HSPiP Team Senior Developer, Dr. Hiroshi Yamamoto


This time, I will write about LD50 (but not prediction of LD50).
LD stands for "Lethal Dose". LD50 is the amount of chemicals, given all at once, that causes the death of 50% of a group of test animals.
This test is short-term poisoning potential (acute toxicity) test.


And I found one thing.

Can you imagine which structure is which?

I completely miss understand.

I choose LD50(oral, Rat)<180
The first list is Both toxic for LD50 (oral,Rat) and LD50(skin,rabbit).
These are water soluble compounds.
I've thought hydrophobic materials are toxic.

CAS name LD50Rat



logP logS
75-86-5 acetone cyanohydrin 18.65 15.8 -0.03 2.00
107-19-7 propargyl alcohol 20 16 -0.38 2.00
107-11-9 allylamine 102 35 0.03 2.00
107-18-6 allyl alcohol 64 45 0.17 2.00
107-07-3 2-chloroethanol 71 67 0.03 2.00
1464-53-5 Butadienedioxide 78 89 -0.28 2.00
111-44-4 Di-(2-Chloroethyl) Ether 75 90 1.29 0.24
Average 0.12 1.75


CAS name LD50Rat



logP logS
591-87-7 allyl acetate 130 1021 0.97 0.31
109-75-1 vinylacetonitrile 115 1410 0.40 0.53
13952-84-6 sec-butylamine 152 2500 0.74 1.05
79-22-1 methyl chloroformate 60 7120 0.14 0.97
126-98-7 methacrylonitrile 120 12500 0.68 0.41
Average 0.59 0.65

And in second table, I show the list of very toxic for LD50(oral, Rat) and not so toxic for LD50(Skin Rabbit).
These compounds have intermediate solubility to water.
(There are many compounds between 100<LD50(skin, rabbit)<1000 but hard to understand, so do not show the data.)

With this result, Water soluble materials are go into Sweat pore and go into blood.
So, it is same toxicity with LD50 (Rat) and LD50(skin,rabbit).
And maybe second category materials are very easily dissolve to subcutaneous fat and very hard to release.
It is something like HPLC Solid Phase(Octa decyl silyl) = Fat and moving phase=Blood.
If it come to HPLC, it become much better think with HSP.

Hansen Solubility Parameters (HSP)

Hansen Solubility Parameters(HSP) were developed by Charles M. Hansen as a way of predicting if one material will dissolve in another and form a solution. They are based on the idea that "like dissolves like" where one molecule is defined as being 'like' another if it bonds to itself in a similar way.
Specifically, each molecule is given three Hansen parameters, each generally measured in MPa0.5:
dD:The energy from dispersion bonds between molecules
dP:The energy from dipolar intermolecular force between molecules
dH:The energy from hydrogen bonds between molecules.
These three parameters can be treated as Vector for a point in three dimensions also known as the Hansen space. The nearer two molecules HSP Vector are in this three dimensional space, the more likely they are to dissolve into each other.

What can perhaps be surprising is that one can assign HSP to so many different things. Gases like carbon dioxide, solids like carbon-60, sugar, and biological materials like human skin, depot fat, DNA, and even some proteins all have HSP. The list can be continued with drugs, polymers, plasticizers, and in fact any organic material and even many inorganic materials like salts. The only requirement for an experimental confirmation is that the material must behave differently in a sufficient number of test solvents upon contact.

Pirika JAVA Demo Applet calculate HSP. HSPLight is available here.
Please refer to e-Book of HSPiP if you want know more about HSP.
About the Power Tools that handle HSP more effectively.


If you have Smiles structure and HSPiP software, Y-MB function will calculate HSP immediately.

Smiles(Simplified Molecular Input Line Entry Syntax)

SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph.
"Organic subset" of B, C, N, O, P, S, F, Cl, Br, and I, brackets can be omitted.
Branches are described with parentheses, as in CCC(=O)O for propionic acid
Double and triple bonds are represented by the symbols '=' and '#'
Ring closure labels are used to indicate connectivity between non-adjacent atoms in the SMILES

Pirika JAVA Demo Applet getting Smiles. Draw2Smiles is available here.
Now we have Power Tool "Draw 2 Smiles", GUI HTML5 software on HSPiP ver. 4.


HSPiP(Hansen Solubility Parameters in Practice)






How to purchase HSPiP


Y-MB Properties Estimation

Y-MB break Smiles into correspponding Functional Groups and Estimate various Properties. These estimation schemes are come from Pirika technologies.

Pirika JAVA Demo Applet calculate Properties. PirikaLight is available here.
Now we have Power Tool "Y-Predict", GUI HTML5 software on HSPiP ver. 4.



name dD dP dH Volume
acetone cyanohydrin 16.76 14.99 18.53 87.8
propargyl alcohol 16.13 8.45 20.00 61.8
allylamine 15.18 6.40 9.87 74.5
allyl alcohol 15.57 8.08 17.71 69.2
2-chloroethanol 17.21 11.24 17.49 67.5
Butadienedioxide 17.65 10.22 7.88 80.8
Di-(2-Chloroethyl) Ether 17.18 8.25 4.90 118.3
16.52 9.66 13.77 80.0


name dD dP dH Volume
allyl acetate 15.81 5.05 7.59 108.4
vinylacetonitrile 15.78 11.45 5.59 81.8
sec-butylamine 14.99 4.39 7.18 98.8
methyl chloroformate 16.71 7.47 9.10 76.2
methacrylonitrile 15.74 11.79 5.36 82.3
15.81 8.03 6.96 89.5

I show you calculated HSP values for these compounds.
And I think subcutaneous fat of Rabbit is [15.81, 8.03, 6.96].
(relatively high dP, dH for fat, I think)

Hansen Sphere

To determine if the parameters of two molecules (usually a solvent and a polymer) are within range a value called interaction radius (R0) is given to the substance being dissolved. This value determines the radius of the sphere in Hansen space and its center is the three Hansen parameters.

From version 3.1.X, Double Spheres function is available.

Pirika provide JAVA 3D Demo Applet to browse the Sphere(s).
The HTML5 Sphere Viewer examples are available here.
Now we have Power Tool "Sphere Viewer", GUI HTML5 software on HSPiP ver. 4.

I know molecular volume is also very important. Larger molecule will not permeate skin.
But such molecule is not so toxic for LD50(oral, Rat)

Once we get this value, we can do a lot for Rabbit.
For example, eau de Cologne for Rabbit.
Rabbit (and cat) never take a bath. They dislike water.
That means bad smell. So if you want to design eau de Cologne for Rabbit, if choose fragrance HSP near [15.81, 8.03, 6.96], then that fragrance easily dissolve to subcutaneous fat and last very long.
I searched fragrance FOR RABBIT in our database. 3 compounds are matched.

CAS: 6789-80-6
Zeon make this compound for fragrance.
Odor description: vegetable green.




CAS: 5436-21-5
odor description:ethereal musty nutty alcoholic bitter


CAS: 4440-65-7
Odor description: leafy green stem tomato melon apple

If you want to design some medicine that release drug very slowly FOR RABBIT, it is very good idea to set drug HSP [15.81, 8.03, 6.96] and absorbed via skin.

If you want to design cream for dry skin RABBIT, These structure will work very well I believe.
(Please let me know if you try this)

HSPiP has the function of predict logP and logS.
So, every data is included in HSPiP what you want to do FOR RABBIT that concern about solubility. please try to use HSPiP.

If you want to know how to draw molecules, please refer to Power Tools applications. The full version of this estimation routine is implemented into Y-Predict Powert Tools in HSPiP ver. 4.

You can apply HSP technology to human subcutaneous fat, But unfortunately, I have no data of LD50(skin, human).
But soon FFE project reveal these secret.

In cosmetic area they love to use logP (logKow) instead of HSP.
Please refer to logP article, then you know why we recommend HSP.