Registration Dossier

Administrative data

Description of key information

Disazocondensation red pigments were found to non toxic upon acute oral toxicity testing in rat with doses being tested in the range of 2000 and 10000 mg/kg bw. They are non toxic upon acute skin contact based on experimental data with Pigment Red 144 obtained with rabbits and based on the physico-chemical properties which indicate absent or very low skin permeability.  

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw
Quality of whole database:
Reliable and valid.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Adequate and reliable experimental data on acute oral toxicity in rats is available for all disazocondensation red pigments with one exception (Pigment Brown 41) for which only a summary report on acute toxicity testing is available and therefore read-across is applied. As shown in the overview table below, acute oral toxicity was investigated in studies that are either valid without restrictions or valid with restrictions. No substance-related mortality occurred. In general, tested doses were between 2000 and 10000 mg/kg bw. The studies are described in detail below, in the order of ascending molecular weight and given in the overview table.

The table also includes acute toxicity data on the benzeneamine components of the pigments. Components A are monoamines and components B are diamines. This information is included to support the read-acros for Pigment Brown 41 and the overall assessment that the pigments are inert and not absorbed or metabolised. Depending on the position and nature of the substituent, aromatic amines may be hazardous and as can be seen in the table, most have LD50 values of less than 2000 mg/kg bw. Nevertheless, the pigments show absence of toxicity at even higher doses. The LD50 values of the amines present in Pigment Brown 41 are in the same range as those for which experimental data is available. Pigment Brown 41 is in the same range for molecular weight and water and octanol solubility. So overall, it is considered acceptable to conclude by read-across that Pigment Brown 41 has an LD50 of > 2000 mg/kg bw in rats. This is consistent with the poorly documented experimental data which indicates that the LD50 in rat is higher than 5000 mg/kg bw.

Acute dermal toxicity was studied with Pigment Red 144 in rabbits (MBRL1978). The study was performed prior to the introduction of GLP, but is reported in adequate detail for evaluation. In deviation to the current OECD testing guideline, only 4 animals (2 male and 2 female) were used and abraded skin was treated in 2 animals. The size of application area is not reported. These differences are minor, and considering survival of all four animals the outcome of the study would not have been different in a fully OECD 402 guideline compliant study. The dose of 2000 mg/kg bw was applied using water for moistioning with occlusive wrapping for 24h. No local effects were observed. One animal with intact skin showed transient clinical signs.

A second study report is available which cannot be assigned as to its validity as it was performed at a CRO which had in part falsified study reports: No acute dermal toxicity was observed for each one single rat tested at 300, 1000 and 3000 mg/kg bw of Pigment Red 221 (IBT 1975). A summary value of > 5000 mg/kg bw is provided for Pigment Brown 41 (Sandoz 1975). It refers to a study for which no details on the experimental procedure are provided and which is assigned a validity score of 4.

The available data is considered representative for all disazo condensation red pigments. The pigments are very large and bulky molecules with calculated diameters of more than 10 Angström. According to ECHA guidance, a reduction in dermal uptake to 10% may be applied if the molecular weight is higher than 500 Da and if the log Pow is less than -1 or higher than 4. The molecular weight ranges from 781.7 g/mol (Pigment Red 262) to 930.5 g/mol (Pigment Red 242) which is well above the threshold of 500 g/mol generally considered for low dermal uptake in the ECHA guidance document. The criterium for log Pow is not fulfilled, but it is not considering helpful for cases where the substances are equally poorly soluble in organic and inorganic solvents. Transport processes require some solubility and these pigments are overall poorly soluble (< 0.1 mg/L) in octanol and water. As the dermal uptake is predicted to be very low and there is no indication of acute oral toxicity up to limit doses, it is safe to assume that no acute dermal hazard exists for all disazo condensation red pigments.

Regarding acute inhalation toxicity, a study with whole-body exposure to Pigment Red 220 was performed at the CRO which was later sued for having falsified study reports (IBT 1972).  This report itself appears to be plausible, since the findings regarding the focal red discoloration and the particle sizes make sense.The test concentration in testing atmosphere was 2.2 mg/l. Details on analytical verification of test atmosphere concentration are not provided.The method of particle size determination is described as follows: A sample of airborne dust was collected from the test atmosphere for the purpose of conducting a microscopic determination of particle size distribution. Particles were counted with respect to three size ranges, viz. 5 µm or smaller (considered to be respirable), 6-25 µm and >25 µm. The smallest particle which could be detected by the light-field technique employed was approximately one µm. The largest particle observed was also recorded. 55% of the particles were in the range of less than 5 µm and 35% were in the range of 6-25 µm. No deaths were noted during the four-hour exposure period or 14-day observation period which followed. Necropsy, performed on all animals at the end of the two-week observation period, revealed slight to moderate diffuse focal red discoloration of the lungs in six rats. There were no other gross pathologic alterations in any of the other tissues and organs examined.

The reported procedure and findings are plausible and would be expected for red inert pigments that are too large for passive permeation through biological membranes.

The pigments are not have irritating or sensitizing properties and are expected to cause effects via excessive deposition at high doses. Based on experience with inert organic pigments, these do not result in mortality in acute inhalation exposure studies. Exposure to inhalable dust must be controlled, and at acceptable levels (3 mg/m3) no substance-specific acute inhalation hazard is expected. Further testing of acute inhalation testing was therefore not performed.  

Table: Overview on the experimental acute toxicity data for disazocondensation red pigments and the respective amines

 

PR 262

PR 166

PR 144

PBr 41

PBr 23

PR 214

PR 220

PR 221

PR 242

79665-24-0

3905-19-9

5280-78-4

68516-75-6

35869-64-8

40618-31-3

68259-05-2

71566-54-6

52238-92-3

Mol. weight

781.7

794.5

828.9

844.5

850.0

863.4

925.8

925.8

930.5

Water solubility

(μg /L)

16.4

<6.5

11.2

0.5 – 1

<20

6.1

14.2

91

18.9

n-octanol solubility

(μg /L)

55.4

<6.5

21.9

56

<20

17.8

<10

24

41

Log Pow

 (calculated from solubilities)

0.53

n.a.

0.29

1.7 - 2.1

n.a.

0.47

<-0.15

-0.57

0.33

acute oral tox (LD50 in mg/kg bw, rat)

> 5000

K1

> 5000

K2

> 10 000

K2

>5000

K4 

> 10 000

K2

> 5000

K1

> 5000

K1

> 5000

K1

> 2000

K1

acute dermal tox (LD50 in mg/kg bw, rat)

 

 

> 5000

K2

>5000

K4 

 

 

 

>3000

K4

 

acute inhalation tox (LC50 in mg/m3, rat)

 

 

 

 

 

 

> 2200

K2

 

 

CAS of amine A

95-79-4

95-82-9

95-82-9

608-27-5

89-63-4

95-82-9

none

none

121-50-6

acute oral tox (LD50 in mg/kg bw, rat)

amine A

700*

1600*

1600*

940*, 2500*

 

1600*

 

 

 

CAS amine B

6393-01-7

106-50-3

615-66-7

2243-62-1

615-66-7

20103-09-7

6393-01-7

20103-09-7

20103-09-7

acute oral tox (LD50 in mg/kg bw, rat)

amine B

27**

ca 300*

ca 1500 (mice)**

>2000*

ca 1500 (mice)**

>5000**

27**

>5000**

>5000**

 

Pigment Red 262 (CAS 79665-24-0, 782 g/mol)

Pigment Red 262 was evaluated in a GLP and OECD 423 compliant study in rats with the limit dose of 5000 mg/kg bw (RCC 1988). Clinical signs involved sedation, dyspnea (males), hunched posture, ruffled fur. All rats recovered within six observation days. No mortality occurred.

Pigment Red 166 (CAS 3905-19-9, 794.5 g/mol)

Pigment Red 166 was tested in valid studies in rats (Ciba-Geigy Ltd 1975), mice (Ciba-Geigy Ltd 1980) and hamsters (Ciba-Geigy Ltd 1980) that were performed prior to the introduction in GLP, but according to procedures similar to OECD guidelines for acute oral toxicity.

The study in rats was performed at doses of 1000, 3000, 10000 and 15000 mg/kg bw in each five male and female rats with a 14-day observation period. Clinical symptoms at lowest dose (1000 mg/kg) was hyperreflexia which resolved within 24h. At the other dose levels (3000, 10000, 15000 mg/kg) additionally transient reduction in spontanous motility, ataxia and irregular respiration occurred. No mortality occurred.

The study in mice was performed at doses of 3000, 4000, 5000 mg/kg bw in each 5 male and female animals with a 14-day observation period. Each one animal in the mid and in the high dose died.Following effects were seen in the first week of observation: sedation - all doses until 5hrs after application, highest dose until 3rd day after application (slight effects); dyspnoea: all doses until 7th day after application (slight effects); ruffled fur: all doses until 6th day after application (slight and moderate effects); diarrhoe: all doses 24 hrs after application until 4th day (slight effects); curved body position: all doses until 5th day after application. No effects seen in the 2nd week of observation. Gross necropsy did not reveal adverse findings.

The study in Chinese hamster was performed at doses of 3000, 4000 and 5000 mg/kg bw in each five male and female animals with a 14-day observation period. Clinical symptoms (sedation, dyspnoea, exophthalmos, ruffled fur, curved body position) were observed from day 1 to 6. No mortality occurred.

Pigment Red 144 (CAS 5280-78-4, 829 g/mol)

Pigment Red 144 was tested in valid studies in rats (Ciba-Geigy Ltd 1972, MBRL1975, Ciba AG 1965) that were performed prior to the introduction in GLP, but according to procedures similar to OECD guidelines for acute oral toxicity.

The first study was performed similar to OECD guideline 401,with the deviations that 30 mL test preparation per kg bw were applied, that the observation period was only 8 days, that individual test results are missing and that no data on necropsy is provided. Each five male and female rats received a single dose of 5000 or 10000 mg/kg bw. The vehicle was an aqueous suspension with 0.5% carboxymethyl cellulose. At 5000 mg/kg bw piloerection was observed, at 10000 mg/kg bw ataxia, sedation, piloerection, inhibition of spontaneous motility, red stained urine and feces were observed.

The second study was performed following the procedure of OECD guideline 401 in each five male and female rats at a single dose of 5000 mg/kg bw. Red diarrhea was observed after 4 hours in 4 animals; chromorhinorrhea after 2 days in 1 animal; ptosis after 12 and 13 days in one animal and chromodacryorrhea after 13 and 14 days in the same animal. Gross necropsy showed purple lung areas in two animals, mottled liver in one animal and mottled kidneys in another animal. Findings in lung indicate a gavage error, although this is not specifically mentioned in the report.

Pigment Brown 41 (CAS 68516-75-6, 844 g/mol)

Poorly documented experimental data is available (Sandoz 1975). It reports that the LD50 for acute oral and dermal toxicity in rat is greater than 5000 mg/kg bw without further details on method, species or sex. The order and the reporting dates lie 2 month apart.

Pigment Brown 23 (CAS 35869-64-8, 850 g/mol)

Pigment Brown 23 was tested in a valid study in rats (Ciba-Geigy Ltd 1973) that was performed prior to the introduction in GLP, but according to procedures similar to OECD guidelines for acute oral toxicity. The design included only a 7-day observation period and body weights determined only at study start. Each five male and female rats received a single dose of 6000 or 10000 mg/kg bw. Within 2 hours after treatment the rats of both dosage groups showed dyspnoea, exophthalmus, curved position and ruffled fur. These symptoms became more accentuated as the dose was increased. The animals had recovered within 3 to 6 days. No mortality occurred. No substance related gross organ changes were seen at necropsy.

Pigment Red 214 (CAS 40618-31-3, 863 g/mol)

Pigment Red 214 was tested in two valid studies in rats (RCC 1989 and 2006). Both studies are GLP and OECD 423 compliant. No animal died at the limit dose of 2000 mg/kg bw. In the more recent study, all animals expressed a slightly ruffled fur throughout the day of dosing. In addition, a hunched posture was noted in three animals at the 3-hour reading. Red staining of the feces was noted for all animals on days 2 and 3 and for the first dosing group already at the 5-hour reading.No macroscopic findings were recorded at necropsy. In the other study, all rats had recovered within three observation days from sedation and unsteady gait and ruffled fur. The results are consistent with poorly documented information indicating an LD50 of greater than 15000 mg/kg bw (Andrysova 1978).

 

Pigment Red 220 (CAS 68259-05-2, 926 g/mol)

Pigment Red 220 was studied for acute oral toxicity in four studies of which only one is reliable and adequate (Ciba-Geigy Ltd 1987). The study was performed according to GLP and OECD guideline 401 with a limit dose of 5000 mg/kg bw. No mortality occurred. Dyspnea, exophthalmos, ruffled fur, and curved body position were seen, being common symptoms in acute tests. Additionally, a red discoloration of the body was observed from day 1 to 4 after administration. The animals recovered within 11 days. The information is consistent with poorly documented data from 1965 and a study run at CRO that was known to have falsified study reports (IBT 1972).

Pigment Red 221 (CAS 71566-54-6, 926 g/mol)

Pigment Red 221 was studied for acute oral toxicity in three studies of which two are reliable and adequate (Ciba-Geigy 1974, Centre de Recherches Biologiques 1983).

The study performed in 1974 has the deficiencies of an observation period of only 7 days. Tested doses were 2150, 3170 and 4640 mg/kg bw/day. Within 2 hours after treatment the rats in all dosage groups showed dyspnoea, exophthalmus, curved position, and ruffled fur. All animals had recovered within 4 to 7 days. No mortality occurred.

The study performed in 1983 had the deficiency that no necropsy was performed at the end of the study. All animals survived the single dose of 5000 mg/kg bw.Immediately following application, piloerection and apathy were observed; these symptoms however disappeared rapidly during the course of the observation period.

Pigment Red 242 (CAS 52238-92-3, 931 g/mol)

A GLP and OECD 401 compliant study was performed with rats (Sandoz 1991). A single dose of 2000 mg/kg was tolerated by all rats without showing clinical signs or any other adverse effect.

 

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance is not considered to be classified for acute oral or dermal toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance is not considered to be classified for acute oral or dermal toxicity under Regulation (EC) No. 1272/2008, as amended for the third time in Directive EC 618/2012.