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Oral: OECD 407 and OECD 422; 28-day and 1-Gen Screen gavage, rats. NOAEL = 10 mg/kg. Reliability = 1
test substance was administered by gavage to male and female rats at
doses of 0, 10, 50, or 200 mg/kg/day for 28 days, with an additional
28-day recovery period, to evaluate the potential repeated-dose
toxicity. Additional groups of rats were treated through the 28-day
premating period, during cohabitation, gestation, and lactation up
through day 3. Treatment-related microscopic findings occurred in the
kidneys of male rats at 50 and 200 mg/kg/day and in the nose of both
sexes at 200 mg/kg/day. In the kidneys of males, there was an increase
in hyaline droplets in cortical tubules (primarily the proximal tubules)
of mild severity at 200 mg/kg/day and minimal severity at 50 mg/kg/day.
The droplets were variably sized, round, densely eosinophilic, and were
consistent with alpha-2u globulin, a urinary protein. Increased hyaline
droplet accumulation was not present in the recovery males. However, the
presence of a slight increase in severity of chronic progressive
nephropathy in two recovery males, one with minimal granular casts,
suggests that the increased droplets at 200 mg/kg/day were adverse.
Accumulation of hyaline droplets composed of alpha-2u globulin in renal
tubules is a common finding in male rats following exposure to many
different compounds and is not considered relevant to human risk
assessment. Kidney effects at 50 mg/kg/day were considered non-adverse.
In the 28-day subset, minimal to mild degeneration/atrophy of olfactory
epithelium was present in the nose of 2/5 animals in both the male and
female groups administered 200 mg/kg/day with minimal changes in 1/5
females in the 50 mg/kg/day group. In the reproductive subset, minimal
to mild degeneration/atrophy of nasal olfactory epithelium was present
in 3/10 and 2/10 rats in the 50 and 200 mg/kg/day female groups,
respectively; in one 200 mg/kg/day group female, the lesions was severe
. Although not clearly dose-related across the affected groups, these
changes were consistent with those observed in the animals from the
28-day subset and were likely test substance-related. In males, single
occurrences of usually minimal olfactory degeneration/atrophy were
observed in all groups, including controls, and were thus considered to
be incidental findings. Olfactory lesions were reversible as no test
substance-related changes were present in the nose of the 200 mg/kg/day
recovery groups. In the 50 mg/kg group, nasal effects occurred in only
1/5 females in the 28-day subset; the effects were minimal in that
single animal; and there was not a proportional increase in occurrence
or severity at a dose 4 times higher. Overall, the no-observed adverse
effect level (NOAEL) for systemic toxicity was 10 mg/kg/day based on
histopathologic effects that were observed in the noses of female rats
at 50 mg/kg/day.
the kidneys of males, increased hyaline droplets consistent with alpha-2µ
globulin were present in cortical tubules at 50 and 200 mg/kg/day. A
slight increase in severity grade for rat chronic progressive
nephropathy (CPN) was present in the 200 mg/kg/day recovery group males
and was considered a sequella of the hyaline droplet accumulation
observed at the end of the exposure period. Both alpha-2µ
nephropathy and CPN have been shown to be unique to rats, especially
male rats with no counterpart in humans.As
such, these rat-specific lesions are not considered to be relevant to
humans (Kahn et al.2013; Hard, 2002; Hard et al., 2013). For these
reasons, the kidney effects in rats were not considered to be relevant
for humans and therefore not relevant for STOT – RE classification.
the 28-day subset, minimal to mild degeneration/atrophy of olfactory
epithelium was present in the nose of 2/5 animals in both the male and
female groups administered 200 mg/kg/day and in 1/5 females in the 50
mg/kg/day group. In the affected 50 mg/kg female, the nasal effects were
minimal and there was not a proportional increase in occurrence or
severity at a dose 4 times higher. Overall, the nasal effects in males
were of low incidence, minimal or mild severity, and appeared in all
groups (including controls), indicating these were incidental,
background findings. In females, nasal lesions were of comparable
incidence but of slightly greater severity than males. Although there
was one female with severe olfactory degeneration at 200 mg/kg, it’s
conceivable this might be test substance related but attributable to the
gavage technique and therefore administration route specific (Eichenbaum
et al., 2010). Regardless, given the low incidence and the absence of
effects on food consumption (an indirect indicator olfactory function)
in any group, the nasal effects in females were not considered to be
adverse for purposes of GHS classification for STOT-RE.
G, Damsch S, Looszova A, Vandenberghe J, Van den Bulck K, Roels K,
Megens A, Knight E, Hillsamer V, Feyen B, Kelley MF, Tonellin A, and
Lammens L (2011).Impact
of gavage dosing procedure and gastric content on adverse respiratory
effects and mortality in rat toxicity studies.J
Appl. Toxicol., 31:342-354.
of the renal effects of ethyl benzene in rodents for assessing human
cancer risk.Toxicol. Sci., 69:30-41.
GC, Banton MI, Bretzlaff RS, Dekant W, Fowles JR, Mallett AK, McGregor
DB, Roberts KM, Sielken Jr. RL, Valdez-Flores C, and Cohen SM (2013).Consideration
of rat chronic progressive nephropathy in regulatory evaluations for
carcinogenicity. Toxicol. Sci., 132(2): 268–275.
KNM, Hard GC, and Alden CL (2013). Chapter 47: Kidney, in Toxicologic
Pathology, 3rdedition, WM Haschek, CG Rousseaux, and MA
Wallig et al., eds. Elsevier, Amsterdam, pp. 1751.
summary, the kidney effects were not considered to be relevant to humans.The
nasal effects were not considered to represent significant organ
specific toxic effects or to have resulted in significant organ
dysfunction. Therefore, the test substance does not need to be
classified for repeat dose toxicity according to EU Classification,
Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC)
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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