Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
3 122 mg/kg bw/day
Species:
rat
Additional information

Secondary butanol, in a modified two-generation reproductive toxicity study in rats, produced a reduction in fertility when administered at 3% in drinking water, a concentration which clearly exceeded the maximum tolerated dose level, causing significant maternal toxicity and reduced pup survival (Cox, 1975). The non-specific systemic effects on the dams and pups noted at 3% (4571 mg/kg/day) included significant maternal body weight loss, kidney and liver histopathology, reduced fetal body weight and pup survival and reduced fertility. When the highest concentration was lowered to 2% (equivalent to 3384 and 3122 mg/kg/day for males and females, respectively) for 2 subsequent matings (P and F1), no effect on fertility or reproduction was observed. Adult rats exposed to 2.0% SBA showed significant kidney histopathology; however, no adverse systemic effects were found at a dose of 1% (equivalent to 1644 and 1771 mg/kg/day for males and females, respectively). Thus, the overall NOAEL for the study was 1644 mg/kg/day. This study was conducted prior to the GLPs and was similar to OECD test guideline 416.


Short description of key information:
Secondary butanol has been studied for effects on fertility through two generations in rats, and through a second P mating leading to a teratology study via drinking water exposures up to 3% (approximately 4571 - 5089 mg/kg/day). A number of non-specific systemic effects on the dams and pups were noted at 3% (4571 mg/kg/day), including significant maternal body weight loss, kidney and liver histopathology, reduced fetal body weight and pup survival and reduced fertility. No evidence for specific reproductive impairment was seen at a concentration of 2% (3122 mg/kg/day). Adult rats exposed to 2.0% SBA showed significant kidney histopathology; however, no adverse systemic effects were found at a dose of 1% (equivalent to 1644 and 1771 mg/kg/day for males and females, respectively). The overall NOAEL for the study was 1644 mg/kg/day.
There are no selective effects on offspring during the lactational phase at dose levels which are not also maternally toxic.

Effects on developmental toxicity

Description of key information
Secondary butanol (SBA) was studied for developmental toxicity by the oral and inhalation routes of exposure in prenatal development toxicity studies similar in design to OECD Guideline 414.  An oral prenatal development toxicity study in rats, predating the GLPs, identified a NOAEL for maternal and developmental toxicity of 1644 mg/kg bw/day (1% in drinking water).  An inhalational prenatal development toxicity study of SBA in rats reported a NOAEL for developmental toxicity of 3,500 ppm (10605 mg/m3).  A maternal NOAEL was not identified in the inhalational study on the basis of decreased maternal food consumption and reduced body weight gain at all dose levels.  
Supportive information was available from an inhalational study conducted with the read across substances, methyl ethyl ketone (MEK) in mice and isopropanol (IPA) in rabbits. No evidence of teratogenicity or was observed in these studies in mice, rats or rabbits. Embryotoxic and fetotoxic effects only occurred at maternal toxic doses in these studies.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 644 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
10 605 mg/m³
Species:
rat
Additional information

The effects of orally administered secondary butanol (SBA) on development were evaluated in a prenatal development toxicity study that is comparable in design to OECD Guideline 414, and predates the GLPs (Cox, 1975). This study was part of a multi-generation reproductive toxicity study. Both F1 males and female Wistar rats were treated with 0 (water), 0.3, 1.0, or 2.0% SBA in drinking water pre-mating through to gestation day 20. Increased maternal kidney weight and renal pathology including tubular casts, tubular degeneration, and eosinophilia at 2% (3122 mg/ bw kg/day) were reported. Fetal body weights were also reduced at 2%. No treatment-related skeletal or visceral malformations or variations were seen at any dose. No treatment-related maternal or developmental toxicity was observed at an SBA concentration of 1% (NOAEL = 1644 mg/kg/day).

The effect of inhaled SBA on development was evaluated in a prenatal development toxicity study similar in design to OECD Guideline 414 (GLP status not provided) (Nelson et al., 1989). Sprague-dawley rats were exposed to SBA concentrations of 0, 3500, 5000, or 7000 ppm 7 hours/day from gestation days 0 through 20. Maternal toxicity (evidenced by reduced food intake and reduced body weight gain) was noted at all dose levels. An increase in resorptions and reduced fetal weight were seen at 5000 and 7000 ppm, respectively. There were no teratogenic effects reported at any dose level. The NOAEC for embryotoxicity and fetotoxicity was 3500 ppm (10,605 mg/m3). An estimated internal absorbed dose of 350 mg/kg/day was calculated to correspond to the 3500 ppm concentration in the study. No NOAEC was identified for maternal toxicity in the study.

Supportive information was provided by a study conducted with the read across substance, methyl ethyl ketone (MEK)

(see "Read-across justification" attachment in Section 13 of dossier).

An inhalation teratology study of MEK in Swiss mice reported slight maternal toxicity in form of increased relative liver and kidney weights and fetotoxicity in form of reduced male fetal weights and increased incidence of the variation misaligned vertebrae at 3000 ppm (Schwetz, 1991). Some additional variations and malformations occurred in the study that were not normally encountered in contemporary controls, but there was no clear dose-response relationship for these findings. The NOAEC for fetotoxic and maternal toxicity in this study was 1000 ppm (2940 mg/m3).

Another supporting study in a non-rodent species was available for the read-across substance, isopropanol (IPA) (see "Read-across justification" attachment in Section 13 of dossier). In this study, pregnant rabbits were orally administered 0, 120, 240 or 480 mg/kg/day IPA, once daily on gestation days 6 -18 (Tyl et al, 1994). Treatement-related maternal mortality was reported (26.7% at 480 mg/kg dose). Other adverse maternal effects included reduced weight gain, food consumption and clinical signs indicative of alcohol intoxication. No developmental effects were observed in the fetus. The authors concluded that the NOAEL for developmental toxicity was 480 mg/kg/day in rabbits.

Overall, the data suggests that SBA is not teratogenic and it does not cause fetotoxicity at doses that do not also cause maternal toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:
<10% decrease in fetal weight at highest dose (2% or 3122 mg/kg)

Justification for selection of Effect on developmental toxicity: via inhalation route:
NOAEC of 3500 ppm (10605 mg/m3) selected as a result of fetotoxicity (increased resorptions and reduced fetal weight) associated with maternal toxicity.

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