P-Phenylenediamine; 4-Phenylenediamine
(in 724 products)
Banned by Gov or classified as a carcinogen by IARC

Potential Risk Index®:

ISCE InhaleISCE SwallowISCE ContactISCE Environment
PRI Legend

About:

p-Phenylenediamine (PPD) is primarily used as a dye intermediate and as a dye (e.g., hair dyes and dyes used for dyeing furs), as well as a photographic developing agent and a chemical intermediate. p-Phenylenediamine is also used as a vulcanization accelerator and as an antioxidant in rubber compounds. [1]
Recent Findings:
The Hong Kong Consumer Council has labelled p-Phenylenediamine (PPD) as an "extreme sensitiser" and that even "a small amount of sensitisers could trigger allergic skin reactions in some people" despite complying with concentration standards set in Mainland China and the European Union. It has also stated that "p-Phenylenediamine (PPD), m-Phenylenediamine (MPD) and Toluene-2,5-diamine (PTD) were on the Poisons List of Pharmacy and Poisons Regulations". "Consumers should be aware that studies have indicated that some people, particularly women, might develop allergic reactions towards PPD, which may cause pruritus, pricking or burning sensations, or in more severe cases, even complications such as contact urticaria, angioedema, bronchospasms, etc."
The Draize test has shown p-Phenylenediamine (PPD) to be a strong skin sensitizer, with 0.01% PPD eliciting a positive response from 7.2% of the test sample, 0.10% PPD eliciting a response from 11.2% of the test sample and 1.00% PPD eliciting a response from 53.4% of the test samples [2]. In a comparison with other skin sensitizers such as Mafenide, Benzocaine, Bronopol, Formalin, Glutaraldehyde and Captan, it proved to be the strongest skin sensitizer. [2]
Commercially sold hair dyes are also infamous for having high levels of skin sensitizers, where 50% of all 105 hair dye products in Spain contains PPD. [3] A separate study also found PPD to cause an allergic reaction in 7.3% of the hairdresser's clients, [4] while 18.1% of hairdressers themselves. [5] PPD found in henna may also cause an allergic skin reaction, but PPD is banned for use in henna in the US and in the EU. [6] [7] [8]
PPD can be detected in plasma, urine and faeces after topical application though under "normal hair dyeing exposure conditions, <1% of the applied PPD dose penetrates the skin". [7] PPD is also highly unstable, with the body metabolizing PPD into five other metabolites, which may induce skin sensitization though it remains non-carcinogenic. [7] [9] Multiple studies have also confirmed that PPD does not cause bladder cancer. [9] [11] PPD is also readily oxidized by the oxygen in the air. [10] It is also hypothesized that the skin sensitization is caused by the rapid metabolism of PPD in the skin, "presumably by N-acetyltransferase-1 (NAT1)". [11] [12] [13] Testing on reconstructed skin models, EpiDerm™ and EpiSkin® has shown NAT1-mediated metabolism in the skin as a major route of detoxification following dermal exposure. [12] A study has also shown that "applications of PPD applied to the same site repeatedly over 8 days will cause an elicitation reaction approximating to a single-application equivalent to the aggregation of repeated time exposure". [14] This proves the persistence of PPD in the skin and the accumulation of the "allergenic component of PPD". [14] PPD has also been shown to induce hemolytic anemia in Sprague-Dawley rats, decreasing the total RBC count, which then subsequently results in acute renal failure. [15] Accidental oral ingestion of PPD in humans may also lead to "acute renal failure because of rhabdomyolysis. [15]
PPD can commonly be found in hair dyes and in some inks used in henna. It is a highly unstable compound which is predominantly metabolized by the NAT1 enzyme in the skin and also by the oxygen in the air. Skin sensitization is caused by the rapid metabolism of PPD in the skin and also via other PPD metabolites which are able to accumulate through repeated exposure. PPD has been shown to cause renal failure in rats although its effects on humans have yet to be established.
EU CosIng Annex III Restriction Information:
Regulation:
(EC) No 1197/2013
Annex/Ref#:
III/8b
Product Type, body parts:
Products intended for colouring eyelashes
Other:
After mixing under oxidative conditions the maximum concentration applied to eyelashes must not exceed 2 % calculated as free base.
For professional use only.
Wording of conditions of use and warnings:
To be printed on the label: The mixing ratio. “For professional use only. This product can cause severe allergic reactions. Read and follow instructions. This product is not intended for use on persons under the age of 16. Temporary ‘black henna’ tattoos may increase the risk of allergy. Eyelashes shall not be coloured if the consumer: — has a rash on the face or sensitive, irritated and damaged scalp, — has experienced any reaction after colouring hair or eyelashes, — has experienced a reaction to a temporary ‘black henna’ tattoo in the past. Rinse eyes immediately if product comes into contact with them. Contains phenylenediamines. Wear suitable gloves.” ’
SCCS opinions:
0989/06 - Opinion on p-Phenylenediamine
1054/06 - Memorandum on Hair Dye Substances and their Skin Sensitising Properties
1311/10 - Opinion on reaction products of oxidative hair dye ingredients formed during hair dyeing processes
0129/99 - Opinion concerning p-Phenylenediamine
Scientific References:
2. The use of graded concentrations in studying skin sensitizers: Experimental contact sensitization in man. (Food Chem. Toxicol., 12(2), 219–227. doi:10.1016/0015-6264(74)90367-8)
3. p-Phenylenediamine and other hair dye sensitizers in Spain. (Contact Derm., 66(1), 27–32. doi:10.1111/j.1600-0536.2011.01979.x)
4. Contact dermatitis in hairdressers’ clients. (Contact Derm., 26(2), 108–111. doi:10.1111/j.1600-0536.1992.tb00893.x)
5. Contact allergy to hairdressing allergens in female hairdressers and clients – current data from the IVDK, 2003–2006. (JDDG, 5(11), 993–1000. doi:10.1111/j.1610-0387.2007.06511.x)
6. Allergic Contact Dermatitis Caused by Skin Painting (Pseudotattooing) With Black Henna, a Mixture of Henna and p-Phenylenediamine and Its Derivatives. (Arch. Dermatol., 136(12). doi:10.1001/archderm.136.12.1515)
7. Penetration and haptenation of p-phenylenediamine. (Contact Derm., 68(4), 193–207. doi:10.1111/cod.12032)
8. Identification and Quantification of para-Phenylenediamine in a Temporary Black Henna Tattoo. (Am. J. Contact Dermat., 13(1), 15–18. doi:10.1053/ajcd.2002.30466)
9. Urinary acetylated metabolites and N-acetyltransferase-2 genotype in human subjects treated with a para-phenylenediamine-containing oxidative hair dye. (Food Chem. Toxicol., 42(11), 1885–1891. doi:10.1016/j.fct.2004.07.009)
10. Skin Sensitization to p-Phenylenediamine: The Diverging Roles of Oxidation and N-Acetylation for Dendritic Cell Activation and the Immune Response. (J. Invest. Dermatol., 129(1), 99–109. doi:10.1038/jid.2008.209)
11. Plasma/blood pharmacokinetics and metabolism after dermal exposure to para-aminophenol or para-phenylenediamine. (Food Chem. Toxicol., 44(3), 371–379. doi:10.1016/j.fct.2005.08.009)
12. Dermal penetration and metabolism of p-aminophenol and p-phenylenediamine: Application of the EpiDerm™ human reconstructed epidermis model. (Toxicol. Lett., 188(2), 119–129. doi:10.1016/j.toxlet.2009.03.019)
13. Characterization of N-Acetyltransferase 1 Activity in Human Keratinocytes and Modulation by para-Phenylenediamine. (J. Pharmacol. Exp. Ther., 334(1), 318–326. doi:10.1124/jpet.110.167874)
14. Intermittent exposure to low-concentration paraphenylenediamine can be equivalent to single, higher-dose exposure. (Contact Derm., 56(5), 262–265. doi:10.1111/j.1600-0536.2007.01072.x)
15. Repeated topical application of Para-phenylenediamine induces renal histopathological changes in rats. (Toxicol. Int., 19(2), 132. doi:10.4103/0971-6580.97206)
16. Epidemiological data on consumer allergy top-phenylenediamine. (Contact Derm., 59(6), 327–343. doi:10.1111/j.1600-0536.2008.01427.x)
17. p-Phenylenediamine allergy: the role of Bandrowski’s base. (Clin. Exp. Allergy, 36(10), 1289–1293. doi:10.1111/j.1365-2222.2006.02561.x)
Regulatory References:
1. CANADA INGREDIENT HOTLIST, List of Ingredients that are Prohibited for Use in Cosmetic Products [2019]
- p-Phenylenediamine and its salts
2. South Korea - Ministry of Food and Drug Safety - Prohibited/Restricted Chemicals
- Ref: 1180
3. CANADA INGREDIENT HOTLIST, List of Ingredients that are Restricted for Use in Cosmetic Products [2019]
- Coal tar dye
4. EU CosIng Annex III, SUBSTANCES WITH RESTRICTIONS IN COSMETIC PRODUCTS [2018]
- Ref: III/8b
5. US CARB Identified Toxic Air Contaminants
- p-Phenylenediamine
7. WHO International Agency for Research on Cancer (IARC) - Group 3 [2018]
- para-Phenylenediamine
8. Hong Kong Consumer Council 2015-2016 Annual Report
- Report: Improving Product Quality and Safety, p26

Safety and Hazards (UN GHS):

1. Toxic if swallowed (H301)
2. Toxic if swallowed, in contact with skin or if inhaled (H301+H311+H331)
3. Toxic in contact with skin (H311)
4. Causes skin irritation (H315)
5. May cause an allergic skin reaction (H317)
6. Causes serious eye irritation (H319)
7. Toxic if inhaled (H331)
8. May cause allergy or asthma symptoms or breathing difficulties if inhaled (H334)
9. Causes damage to organs (H370)
10. Causes damage to organs through prolonged or repeated exposure (H372)
11. Causes damage to organs through prolonged or repeated exposure (H373)
12. Very toxic to aquatic life (H400)
13. Very toxic to aquatic life with long lasting effects (H410)

Potential Health Concerns For:

1. Angioedema (PubMed ID:18405138)
2. Chromosome Aberrations (PubMed ID:30439388)
3. Dermatitis, Allergic Contact (PubMed ID:11298694)
4. Dermatitis, Contact (PubMed ID:11531941)
5. Micronuclei, Chromosome-Defective (PubMed ID:30439388)
6. Necrosis (PubMed ID:26784575)
7. Renal Insufficiency (PubMed ID:18405138)
8. Rhabdomyolysis (PubMed ID:18405138)

User Comments:

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