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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
12 mg/kg bw/day
Additional information

3, ,5 ,5 -trimethylhexan-1-ol was tested in a combined repeated toxicity/reproduction toxicity screening test according to OECD TG 422 under GLP conditions in rats at 0, 12, 60, and 300 mg/kg bw/day (gavage). The repeated dose NOAEL was12 mg/kg bw/day in male and female parental animals (findings of this study are summarized in Chapter 7.5.1).

As to reproduction, the following deviations from normal were seen:

Continuation of anestrus for 8 to 14 days in 4 of the high dose females; pregnancy occurred in 3 of these. The number of implantations was decreased at 60 and 300 mg/kg bw; therefore, the implantation index was significantly reduced (p<0.05) at these dose levels. Maternal toxicity was also seen at 60 and 300 mg/kg bw (cf. summary of the same study in section 7.5.1). Thus, compared to controls, low values for the number of nidations, nidation rate, number of births and the number of live births were seen at 60 mg/kg bw/day and in the 300 mg/kg/day group; a level of significance up to p<0.01 was gained for some of the parameters. Male and female pup weight at birth was slightly reduced at 60 mg/kg bw/day, and statistically significantly reduced at 300 mg/kg bw/day (p<0.5 (males), p<0.01 (females)). Male and female body weights increased and were comparable with that of the controls on day 4 past parturition. The viability index, i.e. survival of pups from birth until day 4 after birth, was significantly reduced in the group at 300 mg/kg bw/day (p<0.01). The authors related this to maternal toxicity during fetal development and during lactation.

No external aberrations were confirmed in any of the cases in necropsies of deaths and newborn pups sacrificed on day 4 of nursing. 

 

The authors derived the following NOAELs related to reproduction:

Males: 300 mg/kg bw/day; basis: no effect on virility

Females: 60 mg; basis: anestrus in 4 of 12 animals at high dose

Pups: 12 mg/kg bw/day; basis: nidation reduced, i.e. significantly reduced implantation index and lower number of fetuses at 60 mg/kg bw.

Overall, toxicity to reproduction was seen at maternal toxic dose levels (Yoshimura, 1997).

 

 

 

Effects on developmental toxicity

Description of key information
Significantly reduced implantation index (p<0.05) at 60 mg/kg bw/day possibly indicates embryotoxicity. Original reference required for assessment.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
12 mg/kg bw/day
Additional information

3, ,5 ,5 -trimethylhexan-1-ol was tested in a combined repeated toxicity/reproduction toxicity screening test according to OECD TG 422 under GLP conditions in rats at 0, 12, 60, and 300 mg/kg bw/day (gavage). The repeated dose NOAEL was12 mg/kg bw/day in male and female parental animals (findings of this study are summarized in Chapter 7.5.1).

As to developmental toxicity, the following deviations from normal were seen: The number of implantations was significantly decreased at 60 and 300 mg/kg bw; therefore, the implantation index was significantly reduced (p<0.05) at these dose levels. Maternal toxicity was also seen at 60 and 300 mg/kg bw (moderat eat 60 mg/Kg bw/day, 33% mortality at the high dose; cf. summary of the same study in section 7.5.1). Thus, compared to controls, low values for the number of nidations, nidation index, number of births and the number of live births were seen at 60 mg/kg bw/day and in the 300 mg/kg/day group; a level of significance up to p<0.01 was gained for some of the parameters. Male and female pup weight at birth was slightly reduced at 60 mg/kg bw/day, and statistically significantly reduced at 300 mg/kg bw/day (p<0.5 (males), p<0.01 (females)). Male and female body weights increased and were comparable with that of the controls on day 4 past parturition. The viability index, i.e. survival of pups from birth until day 4 after birth, was significantly reduced in the group at 300 mg/kg bw/day (p<0.01). The authors related this to maternal toxicity during fetal development and during lactation. No external aberrations were confirmed in any of the cases in necropsies of deaths and newborn pups sacrificed on day 4 of nursing. 

The NOAEL value was 12 mg/kg bw/day for maternal, fetal and embryo toxicity, and 300 mg(kg bw/day for teratogenicity (screen level examinations) in this study. Overall, toxicity to reproduction was seen at maternal toxic dose levels. (Yoshimura, 1997).

 

However, repeated dose/reproduction screening studies provided first insights, but is limited, due to short exposure periods, low animal numbers, and limited histopathological examinations. Moreover, it was shown by Hellwig et al (1997) that QSAR possibilities are very limited. Wistar rats were orally dosed with two different mixtures of "isononyl alcohols" at 144, 720, 1080, or 1440 mg/kg bw*day on days 6 to 15 of gestation. At the top dose, up to 30% mortality was seen in the dams and weak teratogenicity in the fetuses. The two types of isononanol mixtures exerted different patterns regarding maternal and developmental toxicity, and teratogenicity. No maternal toxicity was seen at the low dose. Developmental toxicity occurred only at maternally toxic doses. The authors stretched that each of the 5 long chain alcohols examined exerted a different pattern of maternal and developmental toxicity which disables direct QSAR considerations but requires that each compound is examined separately (Hellwig, 1997).

 

 

Justification for classification or non-classification

Regulation 67/548/EEC: no classification required.

Reason: screening level information is available but insufficient for classification. Embryo- and fetotoxicity could be attributable to maternal toxicity.

Regulation 1272/2007/EC: no classification required.

Reason: adverse effects on reproduction and development (reduced implantation index, reduced pub viability) gained a level of statistical significance 300 mg/kg bw and day. This dose level also caused clear maternal toxicity and mortality (33%), i.e. in accordance with the regulation 1272/2007/EC, No. 3.7.2.4.4 the effects on reproduction cannot be classified.

Reduced implantations, pup delivery and pup viability were also seen at the next lower dose level (60 mg/kg bw and day) without reaching a level of statistical significance. Due to the low animal numbers in screening studies the statistical power is, however, low. It is therefore noted that adverse effects were seen at the intermediate dose level, but it cannot be decided whether the effects did not reach a level of statistical significance, or whether the low statistical power was responsible for failing statistical significance.

Overall It is therefore concluded that the screening level information is insufficient for classification.