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Administrative data

Description of key information

Oral: OECD 407 and OECD 422; 28-day and 1-Gen Screen gavage, rats. NOAEL = 10 mg/kg.  Reliability = 1

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
10 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
OECD Guideline, GLP study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The 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.

Justification for classification or non-classification

In 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.

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 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.

References:

Eichenbaum 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.

Hard GC (2002).Significance of the renal effects of ethyl benzene in rodents for assessing human cancer risk.Toxicol. Sci., 69:30-41.

Hard 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.

Kahn 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.

In 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) No. 1272/2008.