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EC number: 221-264-5
CAS number: 3049-71-6
NOAEL 28d oral rat = 1000 mg/kg. No substance
specific changes were observed. (NOTOX, 2006)
NOAEL 28d oral rat = 1500 mg/kg. (Safepharm, 1990)
NOAEL 90d oral rat = 50,000 ppm. (Hoechst, 1967)
These data are based on read across approach to other
GROUP MEAN HAEMATOLOGICAL VALUES AND STANDARD DEVIATIONS (S.D.) - FEMALES
* = significantly different from corresponding control group value p = 0.05
** = significantly different from corresponding control group value p = 0 .01
- = not applicable
The repeated dose toxicity of the test article was investigated in
guideline and GLP compliant 28-day oral toxicity study by daily gavage
in the rat, followed by a 14-day recovery period. Based on the resutls
of a 5-day range finding study and in consultation with the sponsor, the
dose levels for the 28-day toxicity study were selected to be 0, 100,
300 and 1000 mg/kg/day. Each group consisted of 5 males and 5 females.
An extra 5 animals per sex in the control and high dose group were
allowed 14 days of recovery. Formulation analyses were conducted once
during treatment to assess accuracy, homogeneity and stability of
formulations. The following parameters were evaluated: clinical signs
daily; functional observation tests; body weight and food consumption
weekly; clinical pathology at the end of treatment; macroscopy at
termination; organ weights and histopathology on a selection of tissues.
Accuracy, homogeneity and stability over 5 hours of formulations of test
substance in Milli-U water were demonstrated by analyses. No
toxicologically relevant changes were observed in any of the parameters
determined in this study. No evidence for neurotoxicity or
immunotoxicity was obtained in this study. NOAEL was therefore
determined to be 1000 mg/kg.
No studies with repeated administration are available for the test
substance. However, one 90-day and three 28-day studies are available
for other category members (see attached category justification).
In the available 90-day oral repeated dose study performed with a read
across substance from the same category (comparable to OECD guideline
408, but not fully compliant), Sprague-Dawley rats (15/sex/dose) were
fed with the test substance at 10000 and 50000 ppm in the diet (Hoechst
AG, 1967). A control group received normal diet without test compound.
The following parameters were evaluated: clinical signs, body weight,
food consumption, haematology, urinalysis, macroscopy and microscopy.
The following organs were examined histologically: heart, lung, liver,
kidney, adrenal glands, spleen, cerebrum, cerebellum, testes and
ovaries, pancreas, pituitary, thyroid gland, stomach and small
intestine. The general behavior in all animals of all dose groups was
normal throughout the entire trial period and did not differ from that
of the control animals. None of the experimental animals showed signs of
a toxic effect. The pigment was excreted via the feces. The food
consumption and the weight gains of the treated rats were normal and did
not differ from that of the control rats. The haematological
investigations revealed no pathological findings. Investigation of the
urine showed no pathological findings which could be attributed to the
pigment administered. Macroscopic and microscopic examination revealed
no pathological organ damage. A NOAEL of 50000 ppm for male and female
rats was observed for the test article.
In a 28-day oral toxicity study with a second structural analogue used
as read-across entry, Sprague-Dawley rats (5/sex/dose) were
administered the test substance at 750, 3750 and 15000 ppm in the diet
according to OECD 407 and in compliance with GLP (Safepharm Laboratories
Ltd, 1990). These concentrations in the diet are equal to 79, 404 and
1573 mg/kg bw/day for males and 78, 380 and 1501 mg/kg bw/day for
females. The following parameters were evaluated: clinical signs, body
weight, food efficiency, water consumption and compound intake,
haematology, blood chemistry, urinalysis, organ weights and
histopathology. None of the animals died during the study. No clinically
observable signs of toxicity were noted in test or control animals
throughout the study. Bodyweight gain in all test animals was comparable
with that seen in controls. There were no treatment-related changes in
food consumption and food efficiency during the study. Anaemia was
demonstrated in females treated with 15000 ppm, but not in males from
the same dose group, identified by statistically significant reductions
in haemoglobin levels, erythrocyte counts and haemotrocrit. The anaemia
was very slight and apparently completely reversible since no such
changes were seen in satellite high dose females after fourteen days
without treatment. No toxicologically relevant changes were detected in
any of the urine parameters measured. No treatment-related differences
in organ weight were detected between test and control animals. All
morphological changes were those commonly observed in laboratory
maintained rats of the age and strain employed and, since there were no
differences in incidence or severity between control and treatment
groups, all were considered to be without toxicological significance.In
conclusion,a NOEL of 3750 ppm / 380 mg/kg bw/day for
females was established based on slight anaemia which was completely
reversible. The NOAEL was therefore set at the highest dose level, i.e.,
at 15000 ppm / 1573 and 15000 ppm / 1501 mg/kg bw/day for male and
female rats, respectively.
Two more 28-day studies are available for two additional
substances from the same category (Notox, 2006 and RTC, 2006). Both
studies were compliant with GLP and OECD guideline 407. In both studies,
the test article was administered to groups of 5 rats per sex and group
at dose levels of 100, 300 and 1000 mg/kg bw. Control animals were
treated with the vehicle alone. Five additional animals for each sex
were included in the high and control groups for recovery assessment
over a period of two consecutive weeks. The following parameters were
evaluated: clinical signs daily, functional observation tests, body
weight and food consumption weekly, clinical pathology at the end of
treatment, macroscopy at termination, organ weights and histopathology
on a selection of tissues. No toxicologically relevant changes were
observed in any of the parameters determined in these studies.
Consequently, a NOAEL of 1000 mg/kg body weight was established for both
Conclusion: No data from repeated dose studies with the test article are
available. But according to the category approach, the data available
for other category members is used to assess the toxicity of the test
article. Based on the available and reliable data obtained in long term
application studies with four category members, no classification for
repeated dose toxicity is warranted. The established NOAELs for the
tested substances were all above 1000 mg/kg. Therefore, a NOAEL of 1000
mg/kg bod weight was also established for the test article based on this
read across/category approach.
Classification, Labeling, and Packaging Regulation (EC) No.
The available experimental test data are reliable and suitable for the
purpose of classification under Regulation (EC) No.1272/2008. Based on
the data, classification for repeated dose toxicity is not warranted
under Regulation (EC) No.1272/2008.
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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