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Effects on fertility

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

The reproductive toxicity of isopropanol (IPA) was assessed in a GLP-compliant study equivalent to the OECD test guideline 415 (one-generation reproduction toxicity study). Wistar rats were administered IPA at concentrations of 0 (tap water), 1.25, or 2.0% in drinking water (Faber, 2008). Based on water intake, these dose concentrations corresponded to IPA dose levels of 383, 686, and 1107 mg/kg bw/day during the premating period; and 347, 625, and 1030 mg/kg bw/day for 18 weeks of treatment in males. In females, IPA intake was calculated to be 456, 835, and 1206 mg/kg bw/day during the premating period; 668, 1330, and 1902 mg/kg bw/day during the gestation period; and 1053, 1948, and 2768 mg/kg bw/day during the post partum phase. F0 Generation: There were no mortalities, abortions, or early deliveries reported. Adult male food consumption was decreased in all dose groups compared to controls. This corresponded with decreased body weights in the 2.0% dose group, and a transient slight decrease in body weight in animals treated with 0.5 and 1.0% IPA. Water intake was decreased in male rats treated with IPA; however, intake returned to normal levels in the 0.5% group. Food consumption also was decreased in adult females treated with 1.0 and 2.0% IPA; however, decreases noted in the 1.0% group had recovered by the second day of gestation. Body weights in IPA-treated adult females were lower than those reported for the control group at the start of gestation, but had recovered during gestation except in the 2.0% group. Following parturition, body weights for all dose groups were initially similar to controls; however, decreased body weights were noted in the 2.0% dose group on and after post-natal day 4. Water consumption was initially decreased in females treated with 1.0 and 2.0% IPA, but had returned to control levels in the 1.0% IPA group by the third day of treatment.

A slight-dose dependent decrease in red blood cells in the 2.0% group adult males and 1.0 and 2.0% adult females was noted. For males, a slight increase in mean cell volume in the mid- and high-dose groups was observed. Increased absolute and relative kidney weights, and relative liver and spleen weights were noted in high-dose F0 males. Statistically significant increased absolute liver and kidney weight, and relative liver weight were noted in the 2.0% F0 females.

There were no effects of IPA exposure on fertility. The number of pups per litter on post-natal day 1 was decreased in the 2.0% group. This increase was attributed to the cannibalism of the pups by the Dam and decreased pup survival, as a decrease in litter size was not observed in the embryotoxicity study. In the embryotoxicity study, increased preimplantation loss, a decrease in mean litter weight, and a decrease in mean fetal body weight was noted in the 2.0% group.

F1 Generation: Average pup weight was decreased in the 2.0% group on post-natal day 7. Increased mean relative liver weight was reported in F1 males and females at the 2.0% dose level. High-dose F1 males also had higher relative kidney weights. Slight increases in absolute brain weight and increased relative empty caecum weight were noted in high-dose F1 males and females. There were no gross abnormalities noted in the F1 generation at necropsy.

Based on a review of the data it is proposed that the NOAEL for parental toxicity be considered to be 347 mg/kg bw/day (based on the lowest calculated parental IPA intake for 0.5% IPA in drinking water). The proposed NOAEL for reproductive toxicity is 853 mg/kg bw/day (based on the lowest calculated maternal IPA intake for 1.0% IPA in drinking water) on the basis of effects noted on pre-implantation loss, mean litter and fetal body weight, and fetal survival at the 2.0% dose level.

 

A supportive oral gavage, GLP, multi-generation study equivalent to the OECD test guideline 416 (Beyer, 1992) reported a NOAEL for parental toxicity of 500 mg/kg bw/day due to increased organ weights at 1000 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day due to reduced body weights and increased mortality at 1000 mg/kg bw/day.

 

A supportive GLP-compliant pilot study equivalent to the OECD test guideline 415 in rats served as a range finding study. This study did not identify a NOAEL at IPA dose concentrations of 0, 1.25, 2.0, or 2.5% in drinking water (Gaunt, 1986). Decreased adult food and water consumption, decreased adult and pup body weight gain, evidence of embryotoxicity (i.e., fewer live pups, increase in pup mortality, and reduction in pup body weight gain), signs of anaemia, and increased liver and kidney weights were noted. These effects were mainly seen at the 2.0 and 2.5% dose concentrations compared to the control.

Short description of key information:
A GLP-compliant study in rats has provided information on the reproductive toxicity of IPA. The oral gavage study, equivalent to the OECD test guideline 416, reported a NOAEL for parental toxicity of 500 mg/kg bw/day. The NOAEL for reproductive effects was 1000 mg/kg bw/day. The NOAEL for offspring toxicity was 500 mg/kg bw/day.
Additionally, the reproductive toxicity of IPA was assessed in a GLP, one-generation study in rats, equivalent to the OECD test guideline 415. Based on a review of the data, it is proposed that the NOAEL for parental toxicity was 347 mg/kg bw/day (the lowest calculated parental IPA intake for 0.5% IPA in drinking water) and that the NOAEL for reproductive effects was 853 mg/kg bw/day (the lowest calculated maternal IPA intake for 1.0% IPA in drinking water). From the available data, it can be concluded that IPA does not affect male mating ability of fertility at doses up to approx. 1000 mg/kg bw/day.
A one-generation study involving administration of IPA at concentrations ranging from 1.25 to 2.5% in drinking water did not identify a NOAEL.

Effects on developmental toxicity

Description of key information
A GLP prenatal development study in rats, equivalent to OECD Test Guideline 414, identified an oral NOAEL of 0.5% (596 mg/kg bw/day) for maternal and developmental toxicity.  There were no teratogenic effects reported.  Supportive GLP developmental toxicity studies, similar to OECD Guideline 414, in New Zealand White rabbits and rats showed that isopropanol was not teratogenic at the dose levels administered.  In rabbits, the reported maternal and developmental NOAELs were 240 and 480 mg/kg bw/day, respectively.  In rats, the NOAEL for maternal and developmental toxicity was considered to be 400 mg/kg bw/day.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
596 mg/kg bw/day
Additional information
The developmental toxicity of isopropanol (IPA) was assessed in a GLP, prenatal development toxicity study equivalent to the OECD test guideline 414 (Faber, 2008). Wistar rats were administered 0 (tap water), 0.5, 1.25, or 2.5% IPA in drinking water. These dose levels were equivalent to 0, 596, 1242, and 1605 mg/kg bw for the low-, mid-, and high-dose groups, respectively. There were no mortalities reported. Reduced food and water consumption was noted at the 1.25 and 2.5% dose levels. A slight decrease in water consumption was observed in the 0.5% dose group on the first day of dosing, but this did not achieve statistical significance. Body weight loss was noted from gestation days 6 to 8 in the 2.5% dose group, and decreased body weight gain was noted thereafter during the dosing period. Decreased body weight gain was noted in the low dose group on the first day of treatment, and for the first two days of treatment in the mid-dose group. After cessation of treatment, the dams in the 2.5% dose level reported increased weight gain comped to controls. Overall, body weights of the 2.5% dose group were lower than those reported for control animals from gestation day 7 through to termination. There were no effects on embryotoxic pameters. A slight dose-dependent decrease in fetal litter weight was observed. Statistically significant decreased mean fetal weight was noted at the 1.25 and 2.5% dose levels. A statistically significant increase in variations was reported in treated animals, and was indicative of a lower degree of ossification. These changes may have been secondy to decreased water and food consumption, secondary to palatability problems. The authors proposed that fetotoxicity, as manifested by reduced fetal body weights, only occurred at dose levels that also caused maternal toxicity (decreased food and water consumption).

 

A NOAEL was not reported by the study authors. It is proposed that the NOAEL for maternal toxicity be considered to be 0.5% (596 mg/kg bw/day) due to decreased food and water consumption, and corresponding effects on body weight at higher dose levels. The NOAEL for fetal toxicity is proposed to be 0.5% (596 mg/kg bw/day) on the basis of reduced body weights at higher dose levels.

 

Supportive studies have shown that there is no evidence of fetotoxicity or teratogenicity following IPA administration. A GLP-compliant, oral gavage, prenatal development study in rats, equivalent to the OECD Test Guideline 414 (Tyl et al., 1990a, cited in Faber et al. 2008) identified a NOAEL for maternal and developmental toxicity of 400 mg/kg bw/day in rats. The basis of this NOAEL was maternal mortality noted at doses up to 1200 mg/kg bw/day. In another GLP-compliant developmental toxicity study similar to the OECD Guideline 414 in New Zealand White rabbits (Tyl et al., 1990b, cited in Faber et al. 2008), maternal mortality, reduced body weight gain, reduced food consumption and severe clinical signs of toxicity were noted at 480 mg/kg bw/day. These findings were mild and nonspecific at lower dose levels. There was no evidence of fetotoxicity or teratogenicity at any dose tested.  The NOAEL for maternal toxicity was determined to be 240 mg/kg bw/day and the NOAEL for developmental toxicity was 480 mg/kg bw/day.

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.