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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.23 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
62.5
Dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
14.08 mg/m³
Explanation for the modification of the dose descriptor starting point:

Potential worker exposure would likely occur via the dermal or inhalation routes. The relevant dose-descriptor is a NOAEL of 16 mg/kg bw/day. This is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. The dose descriptor is adjusted for rat 8-hr respiratory volume (0.38 m3/kg bw) and differences in respiratory volumes (6.7 m3/10 m3) in active workers as compared to individuals at rest, as described in REACH guidance R.8.4.2. For route–to-route extrapolation (oral to inhalation), a factor of 2 is appropriate per REACH guidance R.8.4.2:

16 x (1/0.38) x 6.7/10 x (1/2) = 14.08

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is appropriate since the chronic study demonstrated no different or greater toxicity following chronic exposure compared to subchronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via mg/m3(inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
5
Justification:
A factor of 5 is appropriate because of the lack of repeat dose inhalation data warrants an uncertainty factor of greater than
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.32 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Potential worker exposure would likely occur via the dermal or inhalation routes. The starting point is a NOAEL of 16 mg/kg bw/day, this is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. For route–to-route extrapolation, a factor of 1 is appropriate since the animal exposure was via ingestion.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is appropriate since the chronic study demonstrated no different or greater toxicity than the subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.83 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
15
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
The starting point of the DNEL calculation is a LOAEL. As is described in ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the NOAEL/LOAEL ratio is highly dependent on the spacing between the dose. There is a steep dose-response in sensitisation following PPD exposure. However, the EC3 value is an average of 10 separate studies, of which each was conducted similar to OECD TG 429 and each has used a proper dose-spacing including doses below and above the (anticipated) EC3. Hence, the uncertainties of the LOAEL is considered minimal. An assessment factor of 3 for dose-response relationship, which is the minimum advised when the starting point is a LOAEL, is therefore recommended.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via µg/cm2.
AF for other interspecies differences:
1
Justification:
According to the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8, the default value for the AF for interspecies differences (other than allometric scaling) is 10 for skin sensitisation. This is based on the observation that cases are known in the EC3 values and human skin sensitisation thresholds derived from historical predictive testing differ by a 10-fold or more. The default value of 10 may be lowered if there is evidence of a good correlation between the EC3 and human NOAEL/LOAEL. In this case the experimental EC3 (0.11% ) value is considered as the experimental LOAEL for induction (27.5 µg/cm²). The human NOAEL is defined as the dose at which no sensitisation in the exposed people has occurred, while the human LOAEL has been proposed to be the dose at which sensitisation has occurred in 5% or <8% of exposed people.
Marzulli and Maibach performed a HRIPT test and reported 7.2, 11.2 and 53.4% of positive reactions following doses of 0.01, 0.1 and 1%, respectively (Marzulli and Maibach, 1974). Goebel et al converted these doses to respectively 10, 100 and 1000 µg/cm². By the definition mentioned before, it can be stated that the human LOAEL in this study is 10-100 µg/cm² (Goebel et al, 2012). The Mazulli and Maibach study is the only available HRIPT study. However, given the statistical power (88-97 subjects tested per dose) and the selection of doses (a proper dose-spacing and doses below and above the (anticipated) are included EC3), the human LOAEL derived in this study is considered a effect level to compare with the experimental LOAEL. The human LOAEL (10-100 µg/cm²) in the same order as the experimental LOAEL (27.5 µg/cm²), thus demonstrating a good correlation between the EC3 and human LOAEL. It can therefore be stated that the default value of 10 for interspecies differences can be reduced to 1.
AF for intraspecies differences:
5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
AF for remaining uncertainties:
1
Justification:
AF- vehicle or product matrix - workers
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8, an additional AF of 1-10 fold should be considered when a DNEL is derived for skin sensitisation potential, depending on the information available on the vehicle or matrix relevant for human exposure. Workers in formulation plants may be potentially exposed to the substance in pure state (i.e. the powder). Thus, as there is no involvement of a matrix which may enhance the sensitising properties of the substance, the use of a matrix in the LLNA studies is considered worst case and no additional AF is necessary.

AF for different exposure conditions- workers
According to the R8 guidance R.8: “Characterisation of dose [concentration]-response for human health: An assessment factor for different exposure conditions should be considered for the DNEL derivation of skin sensitization. On a case by case basis an additional AF (1 – 10 fold) should be considered to account for differences in exposure condition considerations (that are not considered in the exposure assessment) between the animal/human study and actual human exposure situation (i.e. site of contact, dermal integrity, and occlusion). For workers, only potential exposure to the powder (pure substance) is relevant. Hence, the LLNA conditions are considered worst case and an assessment factor of 1 is applicable.

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

Potential worker exposure would likely occur via the dermal or inhalation routes

This substance is classified as toxic via the oral and inhalation route under REACH regulations and guidance. The rat oral minimum lethal dose is 75 mg/kg bw and the rat inhalation 4-hour LC50 is 0.92 mg/L (920 mg/m3). Based on the weight of evidence from various dermal studies, the test substance is not considered toxic via the dermal route.

Male and female rats were exposed to the test substance via gavage at doses of 2, 4, 8, or 16 mg/kg/day for 13 weeks. Increased mean absolute liver weights(≥8 mg/kg males) and body weight-related liver weights (16 mg/kg bw/day males) and increased mean absolute and body weight-related kidney weights ((≥8 mg/kg bw/day females) were observed. However, there were no associated pathological changes. No effects were observed at 4 mg/kg bw/day. The NOAEL for systemic toxicity effects after 90 days was 16 mg/kg bw/day. The test substance did not cause cancer in a dietary study (with the dihydrochloride) at any dose level tested. Based on this information the NOAEL for significant systemic effects was determined to be 16 mg/kg-bw/day and can be used for development of a long-term DNEL for systemic effects. 

Skin sensitization was observed in acute exposure studies; therefore a short-term DNEL for local effects was derived.

In a local lymph node assay, this substance was found to be positive for dermal sensitization.The EC3 value of 0.11%, which was the average over 10 LLNA studies and was published by Goebel et al, is used as a starting point. As per REACH R.8 Appendix R. 8-10 Skin sensitization, an EC3 value can be considered as a LOAEL for induction (expressed in µg/cm2) and can be used for development of a short-term DNEL for local effects.

References

Goebel C, Diepgen TL, Krasteva M, Schlatter H, Nicolas JF, Blömeke B, Coenraads PJ, Schnuch A, Taylor JS, Pungier J, Fautz R, Fuchs A, Schuh W, Gerberick GF, Kimber I. Quantitative risk assessment for skin sensitisation: consideration of a simplified approach for hair dye ingredients. Regul Toxicol Pharmacol. 2012 Dec;64(3):459-65. doi: 10.1016/j.yrtph.2012.10.004. Epub 2012 Oct 13.

Marzulli FN, Maibach HI. The use of graded concentrations in studying skin sensitizers: experimental contact sensitization in man. Food Cosmet Toxicol. 1974 Apr;12(2):219-27.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.06 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
125
Dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Potential general population exposure would likely occur via the dermal, oral, or inhalation routes. The relevant dose-descriptor is a NOAEL of 16 mg/kg bw/day. This is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. The dose descriptor is adjusted for rat 24-hr respiratory volume (1.15 m3/kg bw), as described in REACH guidance R.8.4.2. For route–to-route extrapolation (oral to inhalation), a factor of 2 is appropriate per REACH guidance R.8.4.2:

16 x (1/1.15) x (1/2) = 7.0 mg/m3

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is appropriate since the chronic study demonstrated no different or greater toxicity following chronic exposure compared to subchronic exposure.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via mg/m3(inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
5
Justification:
A factor of 5 is appropriate because of the lack of repeat dose inhalation data warrants an uncertainty factor of greater than 1.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Potential general population exposure would likely occur via the dermal, oral, or inhalation routes. The starting point is a NOAEL of 16 mg/kg bw/day, this is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. For route–to-route extrapolation, a factor of 1 is appropriate since the animal exposure was via ingestion.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is appropriate since the chronic study demonstrated no different or greater toxicity than the subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.458 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
60
Dose descriptor starting point:
other: LOAEL
AF for dose response relationship:
3
Justification:
The starting point of the DNEL calculation is a LOAEL. As is described in ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the NOAEL/LOAEL ratio is highly dependent on the spacing between the dose. There is a steep dose-response in sensitisation following PPD exposure. However, the EC3 value is an average of 10 separate studies, of which each was conducted similar to OECD TG 429 and each has used a proper dose-spacing including doses below and above the (anticipated) EC3. Hence, the uncertainties of the LOAEL is considered minimal. An assessment factor of 3 for dose-response relationship, which is the minimum advised when the starting point is a LOAEL, is therefore recommended.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via µg/cm2.
AF for other interspecies differences:
1
Justification:
According to the ECHA Guidance on information requirements and chemical safety assessment – Chapter 8, the default value for the AF for interspecies differences (other than allometric scaling) is 10 for skin sensitisation. This is based on the observation that cases are known in the EC3 values and human skin sensitisation thresholds derived from historical predictive testing differ by a 10-fold or more. The default value of 10 may be lowered if there is evidence of a good correlation between the EC3 and human NOAEL/LOAEL. In this case the experimental EC3 (0.11% ) value is considered as the experimental LOAEL for induction (27.5 µg/cm²). The human NOAEL is defined as the dose at which no sensitisation in the exposed people has occurred, while the human LOAEL has been proposed to be the dose at which sensitisation has occurred in 5% or <8% of exposed people.
Marzulli and Maibach performed a HRIPT test and reported 7.2, 11.2 and 53.4% of positive reactions following doses of 0.01, 0.1 and 1%, respectively (Marzulli and Maibach, 1974). Goebel et al converted these doses to respectively 10, 100 and 1000 µg/cm². By the definition mentioned before, it can be stated that the human LOAEL in this study is 10-100 µg/cm² (Goebel et al, 2012). The Mazulli and Maibach study is the only available HRIPT study. However, given the statistical power (88-97 subjects tested per dose) and the selection of doses (a proper dose-spacing and doses below and above the (anticipated) are included EC3), the human LOAEL derived in this study is considered a effect level to compare with the experimental LOAEL. The human LOAEL (10-100 µg/cm²) in the same order as the experimental LOAEL (27.5 µg/cm²), thus demonstrating a good correlation between the EC3 and human LOAEL. It can therefore be stated that the default value of 10 for interspecies differences can be reduced to 1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
AF for remaining uncertainties:
2
Justification:
See "Explanation for hazard conclusion"

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.16 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Value:
16 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Potential worker exposure would likely occur via the dermal, oral, or inhalation routes. The starting point is a NOAEL of 16 mg/kg bw/day, this is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. No route to route extrapolation is needed since the animal exposure was via ingestion.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is appropriate since the chronic study demonstrated no different or greater toxicity than the subchronic study.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Potential general population exposure would likely occur via the oral, dermal or inhalation routes.

This substance is classified as toxic via the oral and inhalation route under REACH regulations and guidance. The rat oral minimum lethal dose is 75 mg/kg bw and the rat inhalation 4-hour LC50 is 0.92 mg/L (920 mg/m3). Based on the weight of evidence from various dermal studies, the test substance is not considered toxic via the dermal route.

Male and female rats were exposed to the test substance via gavage at doses of 2, 4, 8, or 16 mg/kg bw/day for 13 weeks. Increased mean absolute liver weights(≥8 mg/kg bw/day males) and body weight-related liver weights (16 mg/kg bw/day males) and increased mean absolute and body weight-related kidney weights ((≥8 mg/kg bw/day females) were observed. However, there were no associated pathological changes No effects were observed at 4 mg/kg bw/day. The NOAEL for systemic toxicity effects after 90 days was 16 mg/kg bw/day. The test substance did not cause cancer in a dietary study (with the dihydrochloride) at any dose level tested. Based on this information the NOAEL for significant systemic effects was determined to be 16 mg/kg bw/day and can be used for development of a long-term DNEL for systemic effects.

Skin sensitization was observed in acute exposure studies; therefore a short-term DNEL for local effects was derived.

In a local lymph node assay, this substance was found to be positive for dermal sensitization. The EC3 value of 0.11%, which was the average over 10 LLNA studies and was published by Goebel et al, is used as a starting point.. As per REACH R.8 Appendix R. 8-10 Skin sensitization, an EC3 value can be considered as a LOAEL for induction (expressed in µg/cm2) and can be used for development of a short-term DNEL for local effects.

References

Aeby P, Sieber T, Beck H, Gerberick GF, Goebel C. Skin sensitization to p-phenylenediamine: the diverging roles of oxidation and N-acetylation for dendritic cell activation and the immune response.J Invest Dermatol. 2009 Jan;129(1):99-109. doi: 10.1038/jid.2008.209. Epub 2008 Aug 14.

Api AM, Basketter DA, Cadby PA, Cano MF, Ellis G, Gerberick GF, Griem P, McNamee PM, Ryan CA, Safford R. Dermal sensitization quantitative risk assessment (QRA) for fragrance ingredients. Regul Toxicol Pharmacol. 2008 Oct;52(1):3-23. doi: 10.1016/j.yrtph.2007.10.008. Epub 2007 Oct 24. Review. PubMed PMID: 18406028.

Goebel C, Diepgen TL, Krasteva M, Schlatter H, Nicolas JF, Blömeke B, Coenraads PJ, Schnuch A, Taylor JS, Pungier J, Fautz R, Fuchs A, Schuh W, Gerberick GF, Kimber I. Quantitative risk assessment for skin sensitisation: consideration of a simplified approach for hair dye ingredients. Regul Toxicol Pharmacol. 2012 Dec;64(3):459-65. doi: 10.1016/j.yrtph.2012.10.004. Epub 2012 Oct 13.

Hudari FF, de Almeida LC, da Silva BF, Zanoni MVB.Voltammetric sensor for simultaneous determination of p-phenylenediamine and resorcinol in permanent hair dyeing and tap water by composite carbon nanotubes/chitosan modified electrode. Microchem J. 2014;116:261-268.

Marzulli FN, Maibach HI. The use of graded concentrations in studying skin sensitizers: experimental contact sensitization in man. Food Cosmet Toxicol. 1974 Apr;12(2):219-27.

Pot LM, Scheitza SM, Coenraads PJ, Blömeke B. Penetration and haptenation of p-phenylenediamine. Contact Dermatitis. 2013 Apr;68(4):193-207. doi: 10.1111/cod.12032.

SCCS. (2017) Opinion on Skin Sensitisation Quantitative Risk Assessment for 18 Fragrance Ingredients (QRA2). Available at:https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_211.pdf. Accessed May 2018

Zanoni TB, Pedrosa TN, Catarino CM, Spiekstra SW, de Oliveira DP, Den Hartog G, Bast A, Hagemann G, Gibbs S, de Moraes Barros SB, Maria-Engler SS. Allergens of permanent hair dyes induces epidermal damage, skin barrier loss and IL-1 α increase in epidermal in vitro model. Food Chem Toxicol. 2018 Feb;112:265-272. doi: 10.1016/j.fct.2017.12.033.

 

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