N,N'-(2-chloro-1,4-phenylene)bis[4-[(2,5-dichlorophenyl)azo]-3-hydroxynaphthalene-2-carboxamide]

Endpoint summary

Description of key information

The substance is considered to be too large to be taken up after ingestion or after dermal uptake. This consideration is based on the physico-chemical properties and the findings of the subacute oral toxicity studies. It is insoluble in both hydrophilic and lipophilic solvents and cannot accumulate in tissues.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic assessment is mainly based on the absence of adverse findings upon acute and subacute oral toxicity testing and on physic-chemical properties. It concludes that the pigments are inert and are not taken up by the body. Therefore, there is no potential for bioaccumulation. The assessment covers the following substances, for which a data matrix (Tables A and B) is given below:

 

COLOUR INDEX NAME                   CAS NUMBER                      

Pigment Brown 23                             35869-64-8                

Pigment Brown 41                             68516-75-6

Pigment Red 144                              5280-78-4                              

Pigment Red 166                              3905-19-9                              

Pigment Red 214                              40618-31-3                            

Pigment Red 220                              68259-05-2                            

Pigment Red 221                              71566-54-6                            

Pigment Red 242                              52238-92-3                            

Pigment Red 262                              79665-24-0                            

 

An overview on the structures is given in the attached document as chemical structures cannot be inserted into the freetext fields of IUCLID. The attachment also contains experimental data on dynamic dissolution particle reactivity showing that all of the above listed pigments are insoluble unreactive particles.

The high molecular weights ranging from 781.7 g/mol (Pigment Red 262) to 930.5 g/mol (Pigment Red 242) are just below the general threshold of 1000 g/mol for cellular uptake. Both water and octanol solubility is less than 0.1 mg/L which impedes transport in both aqueous and non-aqueous compartments. None of the groups are ionisable at physiological pH; specifically no increased solubility or degradation in stomach acid is possible.

Modelling of the molecular dimensions shows that the substances are large and bulky; all dimensions are larger than 10 Angström for Pigment Red 262, which has the lowest molecular weight (BASF 2012). As the pigments completely consist of conjugated systems, the molecule is not flexible which again hinders uptake.

 

All the disazocondensation red pigments included in this category contain azo and amide bonds which according to textbook knowledge on xenobiotic metabolism are susceptible to enzymatic cleavage. This would in all cases result in the formation of aromatic mono- and p-di-amines. Available toxicity data on these amines is summarized in table C below. Their hazard potential depends on the electron-donating or withdrawing character of the substituent as well as its position on the ring. For example, if Pigment Red 166 would be metabolized, p-phenylene diamine would be released and for this substance, a NOAEL of 16 mg/kg bw for subchronic oral exposure was obtained (ECHA dissiminated dossier on CAS 106-50-3).

Therefore, absence of systemic toxicity upon subacute oral exposure to Pigment Red 220 and 166 is a strong argument against systemic uptake and consequential metabolism of disazocondensation red pigments.

Also, azo-pigments which are smaller in size and soluble in stomach acid such as Pigment Red 57:1 (CAS 5281-04-9) cause signs of systemic effects upon subacute gavage exposure. For details it is referred to the dissiminated REACH dossiers.

 Release of aromatic amines would also have been detected via genotoxicity in the in-vivo study for unscheduled DNA synthesis with Pigment Brown 23 and in the in-vivo micronucleus assays with Pigment Brown 23, Pigment Red 166 and Pigment Red 221. However, all of these tests were negative, as were the in-vitro tests both with and without Prival modification for azo compounds. Pigment Red 144 and 166 were tested with the Prival modification. Absence of uptake into cells and the body is consistent with the physico-chemical properties. Indeed, the red chromophore of the pigment remains intact during the passage through the gastrointestinal tract, as indicated by the red color of the feces of orally treated rats.

 

 

Table A: Overview of physico-chemical data of the disazocondensation red pigments

	PBr 23	PBr 41	PR 144	PR 166	PR 214	PR 220	PR 221	PR 242	PR 262
	35869-64-8	68516-75-6	5280-78-4	3905-19-9	40618-31-3	68259-05-2	71566-54-6	52238-92-3	79665-24-0
Mol. weight	850.0	844.5	828.9	794.5	863.4	925.8	925.8	930.5 (max)	781.7(min)
Melting point	Decomp. above 370°C	nd	> 350°C	Decomp. above 349°C	Decomp. above 300°C	> 350°C	Decomp. above 300°C	nd	nd
Relative densitiy	1.57	1.58	1.51	1.49	1.54	1.4	1.39	1.61	1.4
Water solubility (μg /L)	<20	0.5 – 1	11.2	<6.5	6.1	14.2	91	18.9	16.4
n-octanol solubility (μg /L)	<20	56	21.9	<6.5	17.8	<10	24	41	55.4
Log Pow  (calculated from solubilities)	n.a.	1.7 - 2.1	0.29	n.a.	0.47	<-0.15	-0.57	0.33	0.53

 

Table B: Overview of the toxicity data of the disazocondensation red pigments

	PBr 23	PBr 41	PR 144		PR 166	PR 214		PR 220	PR 221	PR 242	PR 262
	35869-64-8	68516-75-6	5280-78-4		3905-19-9	40618-31-3		68259-05-2	71566-54-6	52238-92-3	79665-24-0
Skin and eye irritation	not irritating K2		not irritating K2		not irritating K2	not irritating K1		not irritating K4	not irritating K2	not irritating K1	not irritating K1
skin sensitzation			not sensitizing K1			not sensitizing K1		not sensitizingK2	not sensitizingK2	not sensitizing K1
acute oral tox (LD50 in mg/kg bw)	> 10 000 K2		> 10 000 K2		> 5000 K2	> 5000 K1		> 5000 K1	> 5000 K1	> 2000 K1	> 5000 K1
acute dermal tox (LD50 in mg/kg bw)			> 5000  K2
acute inhalation tox (LC50 in mg/m3)	ongoing							>2200 K4
28-day gavage study (OECD 407)				NOAEL = 1000 (lymph nodes in males at 1000) K1
Combined reproductive and toxicity screening gavage study (OECD 422)	ongoing (100, 300 and 1000 mg/kg bw)				ongoing (100, 300 and 1000 mg/kg bw)			NOEL = 1000 mg/kg bw K1	ongoing (100, 300 and 1000 mg/kg bw)
Bacterial mutagenicity	not mutagenic* K1 non-Prival	not mutagenic K1 Non Prival	not mutagenic K1 Prival and Non Prival		not mutagenic* (K1, Prival and non-Prival)	not mutagenic K1 Non Prival, Prival		not mutagenic K2, non Prival and K1 Prival	not mutagenic K1, non Prival	not mutagenic K1 Non Prival	not mutagenic K1 Non Prival
Clastogenici-ty in vitro	Not clastogenic K1		Not clastogenic K1			Not clastogenic K1				Not clastogenic K1
Mutagenicity in mammalian cells in vitro			Not mutagenic K1		not mutagenic (hprt + MLA) K1	Not mutagenic K1
Clastogenic-ity in vivo (MN)	Non clastogenic K1				Non clastogenic K2				Non clastogenic K1
Mutagenicity in mammalian cells in vivo (UDS)	not mutagenic K1
Mutagenicity in mammalian cells in vivo (Comet)	ongoing

* Single positive Ames tests due to impurity.

Table C: Overview of toxicity data on the amine components (data sources *OECD QSAR Toolbox v2.3, **ECHA Dissimination view, accessed Oct 30, 2012 or ***company data)

	PBr 23 amine a	PBr 41 Amine a	PB 41 Amine b	PR 144, 166, 214 Amine a	PR 144, PB 23 Amine b	PR 166 Amine b	PR 220 amine a	PR 221 amine a	PR 242 Amine a
CAS	89-63-4	608-27-5	2243-62-1	95-82-9	61702-44-1, 615-66-7, 6219-71-2	106-50-3	No CAS available	No CAS available	121-50-6
Acute oral toxicity (LD50, mg/kg bw)		940**,  2500**	634**	1600**	ca.1500 in mice, (BG-Chemie MN study, 1999)***	Ca 300 (minimum lethal dose = 75)**
Acute dermal toxicity (LD50)			>2000**
Combined reproductive and toxicity screening gavage study (OECD 422)	NOEL = 60 mg/kg bw (haematology)*
Bacterial mutagenicity	Mutagenic*	Not mutagenic**	Mutagenic*	Not mutagenic*	Mutagenic*	Equivocal*			Not mutagenic*
Clastogenicity in vitro
Mutagenicity in mammalian cells in vitro		Negative** (UDS)
Clastogenic-ity in vivo (MN)		Negative**
Subchronic or chronic toxicity in rats	NOAEL < 50 mg/kg bw (spleen, liver, kidney)*		(mortality at 0.3% in the diet, range-finder study)**			NOAEL = 16 mg/kg bw (OECD 408). NOAEL < 25 mg/kg bw (chronic) (Spleen, liver and kidney) *
Toxicity to reproduction
carcinogenicity			Carcinogenic**			Not carcinogenic*

 

Table C, continued:

	PR 214, 221, 242 Amine b	PR 262 Amine a	PR 220, 262 Amine b
	20103-09-7	95-79-4	6393-01-7
Acute oral toxicity (LD50, mg/kg bw)	>5000 (Ciba, 1983)***	700**	27 (Clayton, 1979)***
Acute dermal toxicity (LD50 mg/kg bw)
Bacterial mutagenicity		Negative*, ambiguous**	Negative**
Clastogenicity in vitro		Negative**
Mutagenicity in mammalian cells in vitro		Negative**
Genotoxicity in vivo
Repeated dose toxicity
Toxicity to reproduction
Carcinogenicity		Carcinogenic*