**4.3 Nickel**

Nickel is one of the metal impurities which is inevitably found in several natural ingredients used in cosmetic products. Most of the salts containing nickel are green in color, hence also its potential use as a colorant. However, nickel is considered to be a contact allergen that may provoke dermal sensitization, allergies, and dermatitis [100] by direct and often prolonged exposure. Persons have been diagnosed with Ni allergy due to its presence in topical cosmetic products and jewelry [101]. Nickel may also affect the respiratory system which may result in nasal and lung cancer [98]. Despite of the potential use of cosmetics to maintain the skin in a rejuvenating state, Ni in such products may lead to oxidative stress and hence promote skin aging [25]. This may be due to the overexpression of collagenases in the skin leading to the weakening of the skin matrix and a subsequent loss in elasticity [102]. The International Agency for Research on Cancer (IARC) has classified metallic Ni as a potential

carcinogen to humans (Group 2B) and its compounds as carcinogenic (Group 1) [103]. Nickel may be found occurring naturally in soil and volcanic dust. This may be acquired from industrial dust and fumes. Due to the potential skin sensitization, limits for Ni presence in products have been proposed. Limits of 5 ppm [88] and 1 ppm [104] were suggested for certain household products and detergents, respectively. Likewise, in cosmetics, a Ni limit was also proposed particularly aimed for sensitized persons. Most "nickel-free" products on the market, contain less than 1 ppm of Ni [31, 105, 106]. The permissible level is 0.20 ppm according to [107] for oral consumption. Nickel and a number of its salts are prohibited in any cosmetic product within the EU [5]. These include nickel monoxide, dinickel trioxide, nickel dioxide, trinickel disulphide, tetracarbonynickel, nickel sulphide, nickel dihydroxide, nickel carbonate and nickel sulphate.

Due to its possible implications in allergenic reactions, the content of Ni in a number of cosmetic products was reported by a number of research groups (**Tables 1**–**3**). The risks associated with Ni intoxication is more possible with cosmetics that are potentially ingested. Lipsticks and lip products are amongst these candidates. Most lipstick products investigated by research groups rarely contained less than 0.20 ppm of Ni for oral consumption. Due to the short-term duration of lipstick on the lips, these products are applied frequently by consumers. This may pose a further exacerbation if ingested. The maximum levels in most studies range from 1.61 to 22.8 ppm of Ni in lipsticks [18, 45, 56, 61, 64, 66, 70]. However, in one study it was reported that the mean Ni content was 0.10 ± 0.14 ppm [62]. It was demonstrated that the price has no impact on Ni content of lipsticks (high-priced 8.24 ± 3.29 ppm and low-priced 5.15 ± 4.19 ppm) [60]. Oral consumption may be due to the accidental swallowing of toothpaste. Studies have shown the range of Ni content in most toothpaste is between 0.02 and 2.54 ppm [80, 81] but another study reported maximum levels of 18.535 ppm [82]. Dermal sensitization has been associated with eye cosmetic products. In this situation the 1 ppm threshold is applicable. Several studies have reported levels of Ni which exceed 1 ppm. Only two studies show that the minimum level of Ni in eye-shadows was less than 1 ppm [19, 31]. In several studies, maxima for Ni levels ranged between 4.133 and 359.4 ppm [61, 62, 71, 72, 74]. Nickel has been found in a green eye liner which provoked a form of contact dermatitis in a 47-year-old woman [76] whereas another study reported contact allergy to a Ni-containing mascara [77]. A study reported a mean Ni content of 6.31 ± 4.21 ppm in eyebrow pencils [62]. Most make-up foundation products seem to contain high amounts of Ni, quoting the minimum values above 3 ppm and the maximum values to 13.01 ppm [60, 64]. Only one study reported values being less than the detection limit [61]. In a study on face paints, the average Ni content was 7.6 ppm [79]. However, in other facial formulations such as face washes and creams, the content was reported to be very low with a mean of 0.04 ± 0.11 ppm [14] or not detectable [70] for these formulations respectively. Hair products are of no major concern, as the levels in shampoos and conditions do not exceed 0.06 ppm whereas the highest content of Ni in hair dyes is 4.167 ppm [64]. Body products vary in Ni content. In general, Ni does not exceed 12.37 ppm, but the 1 ppm of Ni is exceeded for most products that include skin lightening creams, sun blocks, tonic creams and body creams [60, 64, 85, 87, 88]. Body lotions and cleansers seem to contain very low Ni contents (<0.08 ppm) [62].

Whereas Ni in mascaras and eye shadows has been implicated in its involvement in allergic chronic dermatitis, several studies have reported that Ni allergy cannot be considered as the main risk factor in patients reporting eye-lid dermatitis [108].
