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EC number: 224-809-5
CAS number: 4500-29-2
Repeated oral administration of the submission substance at doses of 0, 12, 30 and 75 mg/kg body weight per day for 28 consecutive days to groups of 5 male and 5 female Wistar rats revealed no mortality and no clinical signs of intoxication. Additionally, no adverse effects were noted in functional observation battery, ophthalmoscopic, haematological or blood coagulation parameters. Body weight development was not impaired. Gross macroscopy and histopathology revealed no adverse effects. However, a preceding 14-day dose-range-finder study in rats revealed clinical effects, reduction in food intake and tendencies of reduced body weight gain as well as indications of altered organ weights and secondary inflammatory changes as evidenced by white blood cell counts at doses slightly above the highest dose tested in the main study. Based on all available data, the no-observed-adverse-effect level (NOAEL) of the test item with regard to repeated dose toxicity is considered to be equal or greater 75 mg/kg body weight per day.
The test item was orally administered in graduated doses of 0, 12, 30
and 75 mg/kg body weight per day to 3 groups of male and female Wistar
rats by oral gavage. One group receiving the vehicle sterile water
served as control. The volume of application was 5 mL/kg body weight and
the animals were dosed 7 days per week for a period of 28 days. No
mortality and no clinical signs were recorded in any of the dose groups
during the treatment period of this study. Additionally, no effects with
clinical relevance were observed in any of the parameters of the
functional battery testing and no ophthalmoscopic findings were noted.
Body weight development and food intake were not affected. No relevant
differences were found for haematological and blood coagulation
parameters. Slight deviations in the clinical biochemistry parameters
glucose, total protein, cholesterol and sodium in male or female
treatment groups were within the range of historical controls.
Additionally, deviation observed for relative weight (to terminal body
weight) of kidney in female high dose group animals were not associated
with histopathological findings and hence, were unlikely to be related
to treatment. Based on the data generated the no observed adverse effect
level (NOAEL) of Genamin CH 020 is considered to be equal or greater 75
mg/kg body weight per day.
There are no human data available on repeated dose toxicity of the test
item. Likewise no data from repeated dose studies are available for the
inhalatory or dermal route of exposure. For the oral route of exposure
information from a 14 -day dose-range-finder study as well as from a
guideline compliant subacute 28 -day study is available.
In the 14 -day DRF mortality occurred at the high dose of 500 mg/kg body
weight per day. Clinical signs of intoxication, tendencies of reduced
food intake and body weight gain, and slightly altered organ weights
were observed at the mid-dose of 125 mg/kg body weight. With regard to
the corrosive nature of the test material, these effects may be regarded
to be secondary due to irritative stress mediated by inflammatory
changes as substantiated by differential blood cell count data.
In the 28-day oral toxicity study, doses up to 75 mg/kg body weight per
day were devoid of any distinct adverse effect attributable to the
treatment. There were no mortalities, no influence on food intake or
body weight development and no clinical signs of intoxication. No
relevant effetcs were observed in any parameter from the functional
observation battery before and at the end of the treatment period. There
were also no relevant differences in body temperature between the
groups. Haematology, urinalysis and clinical chemistry revealed no
statistical significant differences between treated and control animals.
With regard to organ weights, there were slight deviations in the
relative kidney weight in females from the high dose group. However,
these were not considered to be treatment related since there were no
structural and/or functional histopathological findings neither in the
kidneys nor in any other organ evaluated. The no-observed-adverse-effect
level (NOAEL) from this 28 -day oral toxicity study was considered to be
75 mg/kg body weight per day.
The results from the available studies with repeated exposure of the
submission substance indicate that the test material is systemically
available following oral administration. Mortalities in male and female
animals were observed at doses of 500 mg/kg body weight per day after
approximately 6 - 8 days of dosing. Decrease in food intake was observed
in male and female animals of the 500 mg/kg and 125 mg/kg dose groups in
the first week of treatment. Haematological findings revealed increases
in white blood cell count in male and females from these two higher dose
groups as well as increased neutrophil counts in males and increased
monocyte, eosinophil and baophil counts in females. These haematological
findings are interpreted to be associated with inflammatory changes
related to treatment. A possible explanation may be seen in the strong
irritative / corrosive properties of the test material which may excert
a cytotoxic potential at any site of contact, e.g. the mucosa of the
gastrointestinal tract. The no-observed-adverse-effect level (NOAEL)
from the subsequent 28 -day subacute oral toxicity study was established
at 75 mg/kg body weight per day.
Based on ECHA guidance on the application of the CLP criteria (version
3.0), substances are classified as specific target organ toxicants
following repeated exposure by the use of expert judgement on the basis
of the weight of all evidence available, including the use of
recommended guidance values. In this respect, the evidence from studies
with repeated dose toxicity studies indicate that the submission
substance has the potential to be harmful to human health following
repeated exposure. Taking into account the guidance values as provided
in annex 184.108.40.206.7 to Regulation (EC) No 1272/2008 (CLP), the respective
dose range showing adverse health effects is indicative of a category 2
classification for the test item. Based on the extrapolated "equivalent"
guidance values from 28 -day oral toxicity studies, the relevant dose
range where adverse effects have to be seen is between 30 and 300 mg/kg
body weight per day. The NOAEL for the test item identified in the 28
-day study is 75 mg/kg body weight per day.Taking into account that
mortality was observed at 500 mg/kg body weight per day and at 125 mg/kg
body weight per day significant changes in body weight development,
organ weights and haematologial parameters occurred, the submission
substance should be classified as
Xn; R48/22 Harmful: Danger of serious damage to health by prolonged
exposure if swallowed (according to DSD)
Warning; STOT-RE Category 2 - H373: May cause damage to the
gastrointestinal tract through prolonged or repeated
exposure via the oral route (according to CLP)
Inclusion of the inhalation route of exposure in the hazard statement
according to CLP is not considered necessary, because of the very low
vapour pressure of the submission substance and because the material is
not a solid and thus exposure to dusts will not occur. In the unlikely
event that the substance becomes airborne as an inhalable aerosol, the
strong irritative properties of the submission substance will exhibite
self-warning effects in the respiratory tract.
Inclusion of the dermal route of exposure in the hazard statement
according to CLP is not considered necessary, because any dermal
exposure has to be minimized due to strong irritative / corrosive
properties of the submission substance and because the gastrointestinal
tract is the primary target organ.
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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