Registration Dossier

Administrative data

Description of key information

In a read-across study, Fischer 344 rats and CD-1 mice were exposed to 100, 500, 1500 or 5000 ppm IPA, 6 hours/day, 5 days/week for 13 weeks. A sub-group of rats were exposed to 0, 500, 1500 or 5000 ppm IPA for neurobehavioural assessment. This study was equivalent to OECD Test Guideline 413. No systemic or persistent neurobehavioural effects were reported in the study. The NOAEC for the study was determined to be greater than highest concentration tested (5000 ppm). In a supporting 90-day inhalation study in Fischer 344 rats, animals were exposed to the read-across substance methyl ethyl ketone (MEK) at concentrations of 0 (control), 1254 ppm, 2518 ppm, or 5041 ppm for 6 hours/day, 5 days/week for 89 or 90 consecutive days.  This GLP study was equivalent to OECD Test Guideline 413.  The NOAEC for toxic effects was not identified by the study authors.  However, a NOAEC of 5041 ppm can be considered for subchronic inhalation exposure, based on minimal effects such as decreased body weight and increased absolute liver weights and liver to brain weight ratios. Dermal and oral studies have not been conducted. 

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
15 111 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

In the absence of inhalation toxicity data on sBA, the testing requirement for an inhalation subchronic toxicity study was adapted using a read-across analogue. Isopropanol (IPA) was considered a suitable analogue read-across to sBA because it fulfills the read-across criteria as identified in Annex XI, Section 1.5 of the REACH regulation. The read-across justification for the use of IPA is provided in an attachment in section 13 of this dossier ("Read-Across justification").

Burleigh-Flayer et al (1994) conducted a 90 -day inhalation toxicity study in F-344 rats (10/sex/group) and CD-1 mice (10/sex/group) exposed to 0, 100, 500, 1500 or 5000 ppm (0, 245, 1230, 3690 or 12,390 mg/m3) IPA for 6 hours/day, 5 days/week for 13 weeks. An additional 15 rats/sex were included in the 0, 500, 1500 and 5000 ppm groups for neurobehavioral assessment following sub-chronic exposure. All animals survived to the end of the study. Acute central nervous system effects (narcosis, ataxia and/or hypoactivity) were observed in rats and mice of the 1500 and 5000 ppm groups, but only during or immediately after exposures. In rats, no narcosis was observed during exposure after the second week of the study, suggesting enhanced metabolism. Neurobehavioral assessment, using the standard functional observational battery, revealed no persistent neurological effects in any dose groups in rats and neuropathological examination of the brain, spinal cord and peripheral nerves of the exposed rats did not identify any exposure-related lesions. There was a slight increase in motor activity for female rats at 9 and 13 weeks, however no statistically significant differences were observable at study termination. No similar effects were seen in male rats.

With regard to systemic effects, clinical signs observed following exposures included an increase in the incidence of swollen periocular tissue in 5000 ppm female rats and perinasal encrustation in male rats of the 500, 1500 and 5000 ppm groups, an indication of slight irritation of the eyes and mucous membranes. Statistically significant increases in body weight and/or mean body weight gain were observed for rats of the 1500 and 5000 ppm groups. A similar effect was observed for 5000 ppm female mice and these changes generally corresponded with increases in food consumption. Exposure-related changes in tissue weights were restricted to relative liver weight increases in 5000 ppm rats (8 and 5% for male and females respectively). A 10 and 21% increase in relative liver weight was observed for female mice of the 1500 and 5000 ppm groups, respectively; no similar effect was observed in male mice. As noted earlier, these changes in relative liver weight were not associated with changes indicative of liver toxicity and hence could be regarded as adaptive effects of increased metabolic load (Ennulat et al, 2010; Hall et al, 2012; Schulte-Hermann, 1979). The only microscopic changes noted were observations of an increased incidence of hyaline droplets within the kidneys of IPA-exposed male rats compared to chamber controls. This effect has been well documented as species-specific, with no toxicological relevance to humans (Swenberg & Lehman-McKeeman, 1999; USEPA, 1991). Although the authors did not identify a No-Observable-Adverse-Effect-Concentration (NOAEC) in this paper, a subsequent re-evaluation of the study by the same authors identified 5000 ppm as the NOAEC (Kapp et al, 1996).

Metabolic data demonstrate that sBA is rapidly and extensively converted to methyl ethyl ketone via oxidation of the alcohol functional group by alcohol dehydrogenase in the liver. Thus, methyl ethyl ketone may be used as an appropriate surrogate for s-butanol and vice versa considering that exposure to either substance would essentially result in exposure to methyl ethyl ketone (note that justification for the use of MEK as a read-across analogue is also provided in an attachment [Read-across justification] in Section 13 of this dossier). In a whole body 90-day inhalation study in Fischer 344 rats, animals were exposed to the read-across substance methyl ethyl ketone (MEK) at concentrations of 0 (control), 1254 ppm, 2518 ppm, or 5041 ppm for 6 hours/day, 5 days/week for 89 or 90 consecutive days (Cavender, 1981). This GLP study was equivalent to OECD Test Guideline 413. No mortalities were observed during the study. Clinical signs noted (including irritation, swelling, ear tag crustiness, and/or crusty eye in control and treated animals) were not related to the administration of the test article. High-dose (5041 ppm) male and female body weights were transiently depressed starting at week one, while the low-dose male and mid-dose male and female body weights were elevated as the study progressed. There were no test article related changes in ophthalmoscopy and urinalysis. The mean corpuscular hemoglobin (in high-dose males and females) and mean corpuscular haemoglobin concentration (in high-dose females only) were increased compared to controls. The increase in haemoglobin corresponded to a slight (but not significant) decreased in the number of red blood cells. The serum glutamic-pyruvic transaminase (SGPT) activity in the 2500-ppm female rats was elevated while the 5000-ppm female rats exhibited significantly decreased SGPT activity.  Potassium levels in high-dose (5041 ppm) females were statistically higher than control values. In high-dose (5041 ppm) male rats, liver weights, liver/body weight ratio, liver/brain weight ratio and kidney/body weight ratios were significantly elevated. In female rats, a significant dose response was observed in increased liver weight. In high-dose (5041 ppm) female rats, the liver/body weight ratio, liver/brain ratio, and kidney/brain weight ratios were significantly elevated while the brain/body weight ratio was significantly depressed.Liver pathology showed no lesions.Significantly depressed spleen and brain weights were also observed. Only minor macroscopic lesions were observed and none were attributed to test article administration. Any neoplastic lesions observed were not related to test article administration. No changes in neurological function were observed. Although a NOEC was not determined by study authors, based on the data, a NOEC of 5041 ppm can be considered for subchronic inhalation exposure, based on minimal effects such as decreased body weight and increased absolute liver weights and liver to brain weight ratios. This result is complementary to the data obtained with IPA, providing stronger evidence that sBA is not likely to cause systemic effects in rodents with exposure concentrations up to 5000 ppm.

Additional References

Ennulat D, Walker D, Clemo F, Magid-Slav M, Ledieu D, Graham M, Botts S, Boone L (2010) Effects of hepatic drug-metabolizing enzyme induction on clinical pathology parameters in animals and man.Toxicologic pathology 38:810-828

Hall AP, Elcombe CR, Foster JR, Harada T, Kaufmann W, Knippel A, Kuttler K, Malarkey DE, Maronpot RR, Nishikawa A, Nolte T, Schulte A, Strauss V, York MJ (2012) Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes--conclusions from the 3rd International ESTP Expert Workshop.Toxicologic pathology 40:971-994

Schulte-Hermann R (1979) Adaptive liver growth induced by xenobiotic compounds: its nature and mechanism.Archives of toxicology Supplement = Archiv fur Toxikologie Supplement: 113-124

Swenberg JA, Lehman-McKeeman LD (1999) alpha 2-Urinary globulin-associated nephropathy as a mechanism of renal tubule cell carcinogenesis in male rats.IARC Sci Publ: 95-118

USEPA. (1991) Alpha2u-globulin: Association with chemically induced renal toxicity and neoplasia in the male rat. Risk Assessment Forum, USEPA, Washington, DC.

Kapp RW, Jr., Bevan C, Gardiner TH, Banton MI, Tyler TR, Wright GA (1996) Isopropanol: summary of TSCA test rule studies and relevance to hazard identification.Regulatory toxicology and pharmacology : RTP 23:183-192

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for this endpoint, as set out in Regulation (EC) NO. 1272/2008.