A.
Goossens and L. Geusens
Depending
on the type of product and exposition, several occupation-induced dermatoses
may occur among workers in the pharmaceutical industry. They include irritation, contact allergy,
photo-sensitivity, urticaria, acne venenata, and, less frequently, fixed drug
eruption and steroid rosacea (H. Degreef, personal communication), and even
toxic epidermal necrolysis (as was the case with the transcutaneous absorption
of an intermediary product in the synthesis of tetramisole, an anthelminthic
drug. The dermatoses can be located at
the site of contact, which is generally the hand in an occupational
context. Airborne reactions on exposed
and non-exposed areas (e.g. by particles trapped under clothing) are not
uncommon, and generalized reactions may occur due to inhalation or
transcutaneous absorption. Workers in
the pharmaceutical industry are considered to be particularly at risk for
irritation and allergic contact dermatitis.
Irritant reactions are frequent but are rarely reported in the
literature: occasionally, "epidemics" of such reactions have been
described, as was the case in Israel, where pharmaceutical industry workers
suffered from burning, erythematous, and vesicular lesions shortly after
putting on sterile working clothes.
This was caused by a high residual content (500 ppm!) of ethylene oxide,
the recommended safety level being 200 ppm.
An example of occupation-induced non-immunological contact urticaria
reactions due to sodium benzoate, notwithstanding the use of protective
clothing, gloves, and mask, has been reported.
With regard to contact allergenicity, many substances used in the
pharmaceutical industry are very reactive chemically so they are liable to
induce not only irritation but also contact sensitization. The allergenic potential as well as the
concentration of the contacted substances are, of course, very important
contributing factors. With a highly
allergenic compound, one accidental exposure may cause a chemical burn, primary
sensitization, and allergic contact dermatitis. An example from the pharmaceutical industry was reported: a
chemical student working with the synthesis of procaine, accidentally spilled
some droplets of p-nitrobenzoyl chloride, a chemical intermediate onto her
forearm. After rinsing with water, an
erythematous lesion developed (first-degree burn) that faded the next day. Two weeks later, however, she presented a
non-vesicular erythematous and edematous dermatitis on the same forearm and
also the hand. Patch testing revealed
contact allergy to this substance. In
the pharmaceutical industry, people come in contact with both chemical
intermediates and finished products.
The risk of developing contact allergy is greatest for chemists and
laboratory technicians who are involved in research for new compounds and for
cleaning personnel and technicians in general, who are often less well
protected than are the workers in production units. Pharmacists are also exposed to medications when preparing
compounded formulations, and the conditions they work in are similar to those
of medical personnel. Here, we will
concentrate on the pharmaceutical components responsible for occupation-related
contact allergic reactions. Because
little attention has been given in the literature to cosmetic ingredients, we
will mention them briefly first. The
test concentrations and vehicles for the allergenic substances and chemical
intermediates (listed alphabetically along with their CAS numbers, whenever
possible) as reported in the literature are given in Table 1. The pharmaceutical products described are
classified as is in Martindale (1993).
Allergens in
the cosmetic industry
Methyl heptine carbonate (MHC) and methyl octine carbonate (MOC)
2-bromonitropropanediol
Ylang-ylang oil
Allergens in
the pharmaceutical industry
1. Analgesic and
anti-inflammatory agents: Pyrazinobutazone
2. Anthelmintics: Albendazole
Morantel
Piperazine
3. Anti-arrhythmic agents: Quinidine sulfate
2,6-dichloropyrimidine
4. Anti-bacterial agents:
Penicillin G or benzylpenicillin
Penicillin V or phenoxymethylpenicillin
Semi-synthetic penicillins: Pivampicillin
Pivmecillinam
Ampicillin
Carbenicillin
Cloxacillin
Mecillinam
Cefamandole
Cefazolin
Cephradine
Methacycline
Oxytetracycline
Tetracycline
Paromomycin
Streptomycin
2-aminothiazole
Sulfathiazole
Chloramphenicol and its chemical synthesis intermediates: p-nitrobromacetophenone, p-nitroaminoacetophenone, p-nitroacetamidoacetophenone and p-nitroacetamido-hydroxy propiophenone.
Virginiamycin
Hydrazine
5. Anti-gout agents: Ethyl ethoxymethylene cyanoacetate
6. Anti-malarials: Chloroquine
4,7-dichloroquinoline
7. Anti-muscarinic agents: Biperiden
8.
Anti-neoplastic agents and immunosuppressants:
4-nitrophenyl-N-(2-chloroethyl)-N-nitrosocarbamate
Both of these substances are intermediates in the synthesis of
tauromustine.
Cytarabine intermediate
4-amino-5-nitro-6-chloropyrimidine, intermediary product in the
synthesis of mercapto-purine.
9. Anti-thyroid agents: Carbimazole
10.
Anti-viral agents:
3,4,6- trichloropyridazine
Ethyl-5-acetoxy-6-bromo-2-(bromomethyl)-1-methyl indole-3-carboxylate
(SI-4),
an intermediary product in the synthesis of Arbidol, an antiviral
medication
11. Anxiolytic sedatives, hypnotics, and neuroleptics:
12. Beta-adrenoceptor blocking agents:
13. Cough suppressants: Oxolamine
14. Dermatological agents: Diphencyprone (DPCP)
Squaric acic dibutyl-ester (DBSA)
Coal tar
15. Diuretics: Bumetanide pro-drugs: Cl-5-Cl-sulfonyl
benzoic acid
4-Cl-5-CL-sulfonyl-3-nitrobenzoic acid
4-Cl-3-nitro-5-sulfonyl benzoic acid
16. Gastro-intestinal agents:
Chloromethyl heterocyclic intermediates of a histamine antagonist.
4-chloromethyl-2-guanidinothiazole-nitrochloride (FIP)
2-diamino-ethylene-aminothiazolyl-methylenethiourea-dichloride
(uranium),
two intermediates from the synthesis of famotidine, an H2-antagonist
Omeprazole
17. Local anaesthetics: p-nitrobenzoyl chloride
Procaine
18. Opoid analgesics: Morphine
Codeine
Thebaine
19. Vasodilators: Nitroglycerin
Trans-methyl-3-(4-methoxyphenyl)glycidate
Methyl 2,3-epoxy-3-(4-methoxyphenyl)propionate chemical intermediates in the synthesis of diltiazem.
Chromonar (or carbocromen)
20.
Vitamins: Retinyl (vitamin A) acetate
Thiamine (vitamin B1)
2-methyl-3-nitro-4-methoxymethyl-5-cyano-6-chloropyridine in the synthesis of vitamin.
Pyritinol
Cyanocobalamin (vitamin B12)
Vitamin K3 (sodium bisulfite)
Vitamin K4
21. Supplementary drugs and other substances:
Nicergoline
10-alpha-methoxy-dihydrolysergo
1-N-methyl-10-alpha-methoxy-dihydrolysergol
Lysergol
Vincamine tartrate
22. Chemical intermediates of various drugs
Halogenated molecules:
Chloromethyl imidazoline: an
intermediary compound from the synthesis of drugs such as phentolamine (an
antihypertensive agent), naphazoline (a sympathomimetic), and antazoline (a
histamine-H1-receptor antagonist).
Tosyl chloride (p-toluenesulfonyl chloride): an intermediate in the
synthesis of pharmaceutical, plastic, and chemical products. Its hydrolysis into p-toluene sulfonic acid
makes it an irritant.
4-bromomethyl-6,8-dimethyl-2(1H)-quinolone
4-bromoacetoacet-2,4-dimethylanilide intermediary chemicals in the
synthesis of halogenated quinolones and quinolines.
2,6-dichloropurine standard intermediary product, widely used in
pharmaceutical and other industries.
4-chloro-7-nitrobenzofurazan (NBD-CL). This is a reagent used in
analytical chemistry.
Diethyl-beta-chloroethylamine (DBCEA).
The two cases of allergic contact dermatitis to this substance described
were due to inadequate protective measures and thus accidental contact with
these highly irritant and sensitizing pharmaceutical intermediates (Deschamps et
al. 1988).
Ethyl-2-bromo-p-methoxyfenyl acetate.
This is a derivative of ethyl-p-methoxyfenyl acetate, a frequently used
chemical intermediate.
Non-halogenated molecules:
Ethylenediamine
2,2 dimethyl-1,3-propane diamine
Intermediary substance C
Butyl acetate
2-aminothiophenol
3,4-dicarboxy hexane-2,5-dione intermediate from the synthesis of a
contrast medium used in X-rays produced.
N-hydroxyphtalimide (N-HPI)
Dicyclohexyl carbodiimide (DCC)
Diisopropyl carbodiimide (DIC)
Coupling reagents in the pharmaceutical industry, mainly in peptide
chemistry, and DCC is also an intermediate in the synthesis of angiotensine.
Occupation-related
allergic contact dermatitis is not infrequently observed in the pharmaceutical
industry. If several cases occur in the
same company, then the working conditions must be changed to prevent their
recurrence. Measures to be taken
include dust control and the installation of closed filter equipment and
keeping the workers informed about the potential cutaneous and other risks
associated with the manipulation of the chemicals they are likely to come in
contact with. Moreover, individual
protective measurements - adequate protecting gloves, clothing, mask, and, if
necessary boots - followed by close monitoring of their effectiveness, are also
necessary.
Appendix:
Summary Table
Allergen patch test concentration vehicle
Albendazole
(54965-21-8) 3.8 % and 1.9 %; 1 % Suspension Petrolatum
10-alfa-methoxy-dihydrolysergol
7 % Ethanol
Alprenolol
(13655-52-2) 1 %; 0.5 %; 0.25 % and 0.125 % Water
4-amino-alfa-bromo-3,5-dichloroacetophenone
1 % and 0.5 % Petrolatum
5[(2-aminoethyl)thiomethyl]-N,N-dimethyl-2-furanmethanamine
1 % Water
4-amino-5-nitro-6-chloropyrimidine
??
2-aminothiazole
(96-50-4) ??
2-aminothiophenol
(137-07-5) 0.1 %; 0.01 % and 0.001 % Petrolatum
Ampicillin
(69-53-4) 20 %; 5 %; 1 % and 0.1 % Petrolatum
Azathioprine
(446-86-6) 1 % and 0.1 % Petrolatum
Biperiden
(514-65-8) 1 % Petrolatum
4-bromoacetoacet-2,4-dimethylanilide
1 % and 0.1 % Petrolatum
4-bromomethyl-6,8-dimethyl-2(1H)-quinolone
1 % and 0.1 % Petrolatum
2-bromo-2-nitro-1,3-propanediol
(52-51-7) 0.5 % Petrolatum
Butyl
acetate (123-86-4) 5 % Olive oil
Carbenicillin
(4800-94-6) 20 % Petrolatum
Carbimazole
(22232-54-8) 50 %; 25 % and 10 % Pet. + UVA
Cephalotin
(58-71-9) 5 % and 1 % Water
Allergen
patch test concentration vehicle
Cefamandole
(30034-03-8) 5 % Water
Cefazolin
(27164-46-1) 5 % and 1 % Water
Cephradine
(38821-53-3) 20 % Petrolatum
Chloramphenicol
(56-75-7) 5 % and 1 % Petrolatum
p-chlorbenzene
sulfonyl glycolic acid nitrile ??
Chloromethyl
imidazoline 0.001 % and 0.0001 % Water
Chlorpromazine
(50-53-3) 1 %; 0.001 % Pet. + UVA
4-chloro-5-chloro-sulfonyl
benzoic acid 1 % Petrolatum
4-chloro-5-chloro-sulfonyl-3-nitrobenzoic
acid 1 % Petrolatum
4-chloromethyl-2-guanidothiazole-nitrochloride1 %
Water
Chloromethyl
heterocyclic intermediates 1 % and 0.1 % Petrolatum
5-chloro-1-methyl-4-nitroimidazole
10 %; 1 %; 0.1 % and 0.01 % Petrolatum
4-chloro-7-nitro-benzofurazan
0.1 %; 0.05 % and 0.01 % Petrolatum
4-chloro-3-nitro-5-sulfonyl
benzoic acid 1 % Petrolatum
Chloroquine
(54-05-7) 1 % Petrolatum
Chromonar
(804-10-4) 1 % Water
Cloxacillin
(7081-44-9) 20 % and 1 % Petrolatum
Codeinephosphate
hydrochloride (76-57-3) 1 %; 1 % Water Petrolatum
Colistin
(1066-17-7) 1.000.000 U/g
Cyanocobolamin
(68-19-9) 10 % Petrolatum
Cytarabine
intermediate 1 %; 0.5 % and 0.1 % Water
2,4-diamino-6-chloromethylpteridine
HCL 1 %; 0.1 % and 0.01 % Petrolatum
2-diamino-ethylene-aminothiazolyl-methylene-nitrourea-dichloride
1 % Water
3,4-dicarboxyhexane-2,5-dione
1 %; 0.1 %, 0.032 %; 0.01 % and 0.0032 % Acetone
2,6-dichloropurine
(5451-40-1) 1 % Petrolatum
2,6-dichloropyrimidine
(3934-20-1) ??
4,7-dichloroquinoline
(86-98-6) 5 % Petrolatum
Dicyclohexyl
carbodiimide (538-75-0) 0.1 % Acetone or Petrolatum
Diethyl-beta-chloroethylamine
as is
Diisopropyl
carbodiimide (693-13-0) 0.2 % Acetone
2,2-dimethyl-1,3-propane
diamine 2 % Petrolatum
Diphencyprone
(886-38-4) 0.01 % Acetone
Doxycycline
(10592-13-9) 10 % Petrolatum
Epichlorohydrin
(106-89-8) 0.001 % Water
Ethyl-5-acetoxy-6-bromo-2-(bromomethyl)-1-methyl indole-3-carboxylaat 0.1 % Petrolatum
Ethyl-2-bromo-p-methoxyphenyl
acetate 10 %; 1 %; 0.1 % and 0.01 % Ethanol
Ethylenediamine
(107-15-3) 1 % Petrolatum
Ethylethoxymethylene
cyanoacetate 0.01 % Petrolatum
Hydrazine
(302-01-2) 1 % Petrolatum
N-hydroxyphtalimide
(524-38-9) 0.001 % Ethanol
Kitasamycin
Kitasamycintartrate as is 4 % Water
Coal
tar 5 % Petrolatum
Lysergol
7 % Ethanol
Mecillinam
10 % and 1 % Petrolatum
Menadiol
(481-85-6) 0.1 % Olive oil
Menadione
(58-27-5)
Menadione
sodium bisulfite (57414-02-5) 0.1 % 0.1 % Olive oil Petrolatum
Methacycline
(3963-95-9) 10 % Petrolatum
1N-methyl-10-alfa-methoxy
dihydrolysergol 7 % Ethanol
1-methylamine-1-methylthio-2-nitroethylene
1 % and 0.5 % Petrolatum
Methyl
2,3-epoxy-3-(4-methoxyphenyl)propionate 1 % Ethanol
Methyl
heptinecarbonate 1 % MEK
2[4(5)methyl-5(4)-imidazolyl-methyl-thio]-C
131 % and 0.1 % Water or Ethanol
Allergen patch test concentration vehicle
2-methyl-3-nitro-4-methoxymethyl-5-cyano-6-chloro-pyridine
??
Methyl
octinecarbonate1 % MEK
Midecamycin
(35457-80-8) as such
Morantel
(20574-50-9) 5 % and 1 % Petrolatum
Morphine
(57-27-2) 1 % 10 % and 5 % Ethanol Water
Neomycin
sulfate (1404-04-2) 20 % Petrolatum
Nicergoline
(27848-84-6) 7 % Ethanol
p-nitroacetamidoacetophenone
1 % Ethanol
p-nitroacetamido-hydroxypropiophenone
0.5 % Ethanol
p-nitroamino-acetophenone
1 % Methylalcohol
p-nitrobenzoyl
chloride (122-04-3) 3 % and 1 % Petrolatum
p-nitrobromacetophenone
0.1 % Ethanol
Nitroglycerin
(55-63-0) 0.02 % 2 % Water Petrolatum
4-nitrophenyl-N-(2-chloroethyl)carbamate
0.01 %; 0.001 % and 0.0001 % Water
4-nitrophenyl-N-(2-chloroethyl)-N-nitrosocarbamate
0.01 % and 0.001 % Water
Omeprazole
(73590-58-6) 1 %; 0.5 % and 0.25 % 1 %; 0.5 % and
0.1 % Petrolatum Ethanol
Oxolamine
(959-14-8) 0.5 % and 0.1 % Water (+ Ethanol)
Oxprenolol
(6452-71-7) 1 % Petrolatum
Oxytetracycline
(6153-64-6) 10 % Petrolatum
Paromomycin
(1263-89-4) 20 % Petrolatum
Penicillin
G (1538-09-6) 3.000.000 U/g 10 % and 1 % Petrolatum
Penicillin
V (87-08-1) 10 % and 1 % Petrolatum
Perphenazine
(58-39-9) 0.01 % Pet. + UVA
Piperazine
(110-85-0) 1 %; 0.5 % and 0.1 % Petrolatum
Pivampicillin
base (33817-20-8) 5 % Petrolatum
Pivmecillinam
10 % Petrolatum
Procaine
(59-46-1) 2 % Water
Promethazine
(58-33-3) 1 % Petrolatum
Propranolol
(525-66-6) 1 % Petrolatum
Pyrazinobutazone
5 % and 1 % Petrolatum
Pyritinol
(1098-97-1) 2 % Water
Quinazoline
oxide (253-82-7) 1 % Petrolatum
Quinidine
sulfate (50-54-4) 0.5 % Water
Allergen patch test concentration vehicle
Ranitidine
(66357-35-5) 10 %; 5 %; 2 %; 1 % and 0.1 % Petrolatum
Retinyl
acetate (127-47-9) 0.5 % and 0.1 % Petrolatum
Squaric
acid dibutyl-ester 0.02 % Petrolatum
Streptomycin
(57-92-1) 10 % and 1 % Water
Sulfanilamide
(63-74-1) 5 % Petrolatum
Tetracycline
(60-54-8) 10 % Petrolatum
Thebaine
(115-37-7) 5 % Ethanol
Thiamine
(59-43-8) 10 % and 5 % Water
Thiothiamine
5 % and 1 % Water
Tosyl-chloride
(98-59-9) 1 % Ethanol
Trans-methyl-3-(4-methoxyphenyl)glycidate
10 %; 1 % and 0.5 % Petrolatum
3,4,6-trichloropyridazine
1 % Petrolatum
Vincamine
tartrate (1617-90-9) 1 % Water
Virginiamycin
(M1: 21411-53-0) (S1: 23152-29-6) 5 % Petrolatum
Ylang-ylang
oil 2 % Petrolatum
Goossens
A, Geusens L. The Pharmaceutical and
Cosmetic Industries. Chapter 163. In: Handbook of Occupational
Dermatology. Kanerva L, Elsner P,
Wahlberg JE, Maibach HI (eds.), Springer-Verlag, Berlin, Heidelberg 2000, pp
1041-1052.
Key words: cosmetic - occupational - pharmaceutical