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EC number: 223-460-6
CAS number: 3905-19-9
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.
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.
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
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.
reported procedure and findings are plausible and would be expected for
red inert pigments that are too large for passive permeation through
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
0.5 – 1
(calculated from solubilities)
1.7 - 2.1
acute oral tox (LD50 in mg/kg bw, rat)
> 10 000
acute dermal tox (LD50 in mg/kg bw, rat)
acute inhalation tox (LC50 in mg/m3, rat)
CAS of amine A
CAS amine B
ca 1500 (mice)**
Red 262 (CAS 79665-24-0, 782 g/mol)
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.
Red 166 (CAS 3905-19-9, 794.5 g/mol)
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.
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.
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.
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.
Red 144 (CAS 5280-78-4, 829 g/mol)
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
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.
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
Brown 41 (CAS 68516-75-6, 844 g/mol)
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.
Brown 23 (CAS 35869-64-8, 850 g/mol)
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
Red 214 (CAS 40618-31-3, 863 g/mol)
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
Red 220 (CAS 68259-05-2, 926 g/mol)
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
Red 221 (CAS 71566-54-6, 926 g/mol)
221 was studied for acute oral toxicity in three studies of which two
are reliable and adequate (Ciba-Geigy 1974, Centre de Recherches
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.
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
following application, piloerection and apathy were observed; these
symptoms however disappeared rapidly during the course of the
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.
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
Classification, Labelling, and Packaging Regulation (EC) No.
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.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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