114 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Erdman patented paraphenylenediamine and the allied compounds in 1883 for dyeing hair and feathers. It was considered a great advance when it was first introduced in the dyeing of furs and human hair. In a short while nine times as many cases of dermatitis were being reported as caused by this hair dye as against any other single cosmetic. The rising tide of reports of toxicity, especially the proved cases of dermatitis, asthma, and even systemic poisoning, resulted in the prohibition of the use of para containing dyes in Germany. Soon after they were introduced in Germany the para dyes became widely used in other countries. Especially in England there was a sudden marked increase in fur dye dermatitis among the dyers and wearers of paraphen- ylenediamine dyed furs. It became such a public health problem that a special commission was appointed by the Government to investigate the irritant properties of these dyes. Its use as a hair dye has now been forbidden in several European countries. A Federal law in the United States forbids the use of para and other organic dyes on eyelashes and eye- brows because of several cases of injury, including blindness and ulcera- tive keratitis, attributed to their use. A provision of the Federal Food, Drug and Cosmetic Act, Sec. 601-A, provides as follows: A cosmetic is deemed to be adulterated if it bears or contains any poisonous or deleterious substance which may render it injurious to the user under the conditions of use prescribed in the labeling thereof, provided that this provision shall not apply to coal tar hair dye, the label of which bears the following legend conspicuously dis- played thereon: "Caution. This product contains ingredients which may cause skin irritation on certain individuals and a preliminary test according to the accompanying directions should first be made. This product must not be used for dyeing the eyelashes or eyebrows. To do so may cause blindness." According to Sollman (1) the systemic poisoning which may be observed after applications of para-containing dyes comprises vertigo, gastritis, asthenia, diplopia, lachrymation, chemosis, exophthalmus, asthma, and exfoliative dermatitis. The effects agree in principle with those of histamine that is, stimu- lation of smooth muscle, regardless of its innervation. This includes bronchial constriction which is partly responsible for the asthma and in- creased permeability of the capillaries, resulting in the inflammatory and edematous phenomena. The oral or subcutaneous administration of paraphenylenediamine (0.2 gm. per kg.) to rabbits is followed in about one and one-half hours by an intense watery edema of the entire head. This increases until the next day, and gradually disappears by the sixth day if the animal survives. Not all rabbits develop the edema. It occurs generally in cats and dogs,

TOXIC AND ALLERGIC COMPLICATIONS OF HAIR DYES 115 but not in rats. It is due to increased permeability of the vessels, and may be prevented by diminishing the local blood supply. The reason for this restriction of the edema to the head is not known. It is not strictly spe- cific for the edema involves any other part of the body if it is rubbed with turpentine. The meta-isomer does not produce head edema, but instead causes hydrothorax, which does not occur with the para-compound. All the phenylenediamines produce rise of blood pressure, stimulation of respiration, fall of temperature, tremors, convulsions, coma, and death. With large doses, the animal may die before the edema can develop. Frogs show a narcotic action. In the monograph on cosmetic dermatitis by Louis Schwartz and my- self, published in 1946 (2), we believe to have summarized the most im- portant data concerning toxicity of the para and allied dyes which had appeared up to that time. We stated as follows: Ingram (3) reported three cases of dermatitis due to paraphenylene- diamine proved by patch tests. He states that 4 per cent of the general population have an idiosyncrasy toward it. Close (4) reports a case of nausea, colitis, and nervous symptoms caused by the use of a hair dye containing paraphenylenediamine. Greenbaum (5) reported eye injuries in the United States from para- phenylenediamine. His report was followed by reports of similar cases by Bourbon (6), Hamer (7), Jamieson (8), and Rattner (9). Moran (10) reported bilateral necrosis of the cornea following the use of a paraphen- ylenediamine product. Forbes and Blake (11) reported a case of a sloughing ulcer of the cornea and death caused by an eye make-up preparation containing paraphen- ylenediamine. Goodman (12) said that the symptoms of paraphenylene- diamine poisoning were similar to those produced by histamine. He stated that only a very few of the thousands who dye their hair with paraphen- ylenediamine were affected. Block (13) reported a case of conjunctivitis following eyelash dyeing. In Europe similar cases were reported by Bostroem (14). He stated that patch tests with diacetylaminoazotoluene were negative. Aust (15) reported a case which had had a dermatitis four years before from rabbit fur dyed with paraphenylenediamine, and now developed conjunctivitis from an eyebrow and eyelash dye. Bab (16) reported five cases of aller- gic lesions of the eyelids and conjunctiva from a so-called "henna" dye, but he states that the name "henna" is applied to dyes with various com- positions rather than to pure Egyptian henna. Preparations sold under this name sometimes contain amino compounds and aniline derivatives. Semon (17) makes a similar report of four cases in England. Neuschueler reported four cases from an "eye-stock" the composition of which he did not determine.