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Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
31 680 mg/m³
Additional information

In a key reproduction toxicity study the effect of inhalation of commercial hexane (52% n-hexane) on reproduction in rats was determined (Daughtrey, 1994; Klimisch score =1). Groups of 25 male and 25 female rats were exposed to nominal concentrations of 0, 900, 3000, or 9000 ppm of commercial hexane for 10 weeks pre-breeding, Reproductive parameters were similar in exposure groups and control groups. There was reduced body weight in the F1 and F2 generation in both sexes in the 9000 ppm exposure group in both adults and offspring. The NOAEC is therefore 3000 ppm (10560 mg/m3), and the LOAEC is 9000 ppm (31680 mg/m3). Since there were no adverse effects in offspring without adverse maternal effects, the NOAEC for reproduction is 9000 ppm (31680 mg/m3).


Short description of key information:
One key toxicity to reproduction study was read across for inhalation exposure; the study evaluated commercial hexane.

The toxicity to reproduction NOAEC for both male and female rats (adults and offspring) was 3000 ppm (10560 mg/m3). The LOAEC for these groups was 9000 ppm based on reduced body weight. There were no adverse effects to reproduction, therefore the NOAEC for reproduction is 9000 ppm (31680 mg/m3).

Effects on developmental toxicity

Description of key information
Two key developmental studies were read across from commercial hexane. In the developmental toxicity study in mice, the maternal NOAEC was 900 ppm, and the maternal LOAEC was 3000 ppm (10560 mg/m3) based on color changes in the lungs.  The developmental NOAEC was 3000 ppm and the LOAEC was 9000 ppm(31680 mg/m3) in mice.  
In rats, the maternal NOAEC was 3000 ppm (10560 mg/m3), and the maternal LOAEC was 9000 ppm (31680 mg/m3) based on color changes in the lungs, reduced body weight gain, and reduced food consumption. The developmental NOAEC 9000 ppm (31680 mg/m3) in rats.
Two additional developmental studies were read-across from cyclohexane. No developmental effects were reported in rat or rabbit fetuses exposed in utero to concentrations up to 7000 ppm (21000 mg/m3).
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
31 680 mg/m³
Additional information

In a key developmental toxicity study of commercial hexane (52% n-hexane) , groups of 30 pregnant female mice were exposed to concentrations of 0, 900, 3000, or 9000 ppm for 6 hrs/day during gestational days 6 -15 (API, 1989; Klimisch score =1). The animals were then sacrificed on GD 18. During the study, the animals were examined for clinical signs, mortality, food and water consumption, and body weights taken. After sacrifice, the internal organs were examined, and the uterus was examined for viable fetuses, number of resorptions, and number of corpora lutea. Fetuses were examined for malformations. Necropsy revealed color changes in the lungs of females in the 3000 and 9000 ppm groups. Fetuses in from dams in the 9000 ppm group had a statistically significant increase in some skeletal abnormalities. The maternal NOAEC in mice was 900 ppm (3168 mg/m3), and the LOAEC 3000 ppm based on lung color changes. The developmental NOAEC in mice was 3000 ppm (10560 mg/m3) and the LOAEC 9000 ppm (31680 mg/m3) based on skeletal abnormalities.

In the developmental toxicity of commercial hexane (52% n-hexane) in rats, groups of 25 pregnant female rats were exposed to concentrations of 0, 900, 3000, or 9000 ppm for 6 hrs/day during gestational days 6 -15 (API, 1989; Klimisch score =2). The animals were then sacrificed on GD 21. During the study, the animals were examined for clinical signs, mortality, food and water consumption, and body weights taken. After sacrifice, the internal organs were examined, and the uterus was examined for viable fetuses, number of resorptions, and number of corpora lutea. Fetuses were examined for malformations. Necropsy revealed color changes in the lungs of females in the 9000 ppm groups along with reduced body weight gain, and reduced food consumption. No treatment related abnormalities was seen in the fetuses. The maternal NOAEC in rats was 3000 ppm (10560 mg/m3), and the LOAEC 9000 ppm based on lung color changes, reduced body weight gain, and reduced food consumption. The developmental NOAEC in rats was 9000 ppm (31680 mg/m3).

The developmental toxicity of cyclohexane was evaluated in two species (Kreckman et al., 2000) in a prenatal development study equivalent to OECD study guideline 414. Pregnant Sprague- Dawley-derived rats (25/concentration) and pregnant rabbits were exposed to 0, 500, 2000 or 7000 ppm cyclohexane vapor for gestation days 6-15 and 6-18 respectively. There was a statistically significant decrease in mean body weight gain for rats exposed to 7000 ppm cyclohexane suggesting a potential for maternal toxicity at high dose although no other adverse clinical parameters were noted. No compound- related effects were noted for pregnancy rate, resorption rate, abortion rate, mean number of implantations per litter, mean number of live fetuses per litter and early delivery rate. There was a statistically significant decrease in mean number of implantations but this was not considered substance- related since implantations occurred before exposure start. NOAEC was determined to be 2000 ppm for maternal effects and 7000 ppm for fetal effects.

With regard to rabbits, there were no treatment-related maternal or fetal effects. A statistically significant decrease in mean number of corpora lutea for females in the 2000 and 7000 ppm concentration groups was not considered treatment-related since implantation and ovulation occurred before exposure was initiated. NOAEC was 7000 ppm for maternal and fetal effects.

Justification for classification or non-classification

n-hexane is classified as toxic to reproduction category 3 in EU 67/548/EEC Annex 1 and as a Category 2 reproductive toxicant in CLP Annex VI, based on fertility effects.