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Effects on fertility

Description of key information

All in all, fertility effects, if any, were observed only in the presence of parental toxicity and it remains unclear whether they can be considered specific or not.

  

Based on the data submitted to the US EPA HPV program (2000), the reproductive effects were summarized as follows:

“Adverse reproductive effects of Dioxolane were reported at high dose levels in the drinking water reproduction (one-generation) studies. Most notable effects were the apparent reduced female mating index, live birth index and pup survival index at the high dose level (1.0% in drinking water) for the F1a litter in which the females were exposed during mating and gestation. Examination of the data suggests that effects occurred at the 0.5% drinking water level and were more severe at the higher dose. The other drinking water study, at lower concentrations, was below the NOAEL. It could not be clearly determined which was the affected sex due to the study design. The LOAEL for reproductive effects may also be an effect level for maternal toxicity.

There was clear maternal toxicity at the 1.0% level and mild effects on body weight gain at the 0.5% level. This same strain of rats was also examined in a 4-week “pilot” study where only body-weight gains and water consumption was recorded. In this study, body weight gain was reduced over the 4-weeks of the study for female rats by 15, 28 and 56 percent at 0.5, 1.0 and 2.0 percent drinking water levels, respectively. Although the reduced body weight gain was not statistically significant at the two lower doses (due to an n of only 5), it appears that 0.5% represents a maternally toxic concentration in drinking water.

 

Adverse effects on reproduction thus are considered to occur at maternally toxic doses. After consideration of the data and the information that higher gavage or inhalation doses do not cause dominant lethal effects […], it can be concluded that the affected sex in this study was probably the female. […]

 

Another consideration in assessing the potential reproductive toxicity of Dioxolane is histopathologic changes in the reproductive organs. Three repeat-dose or subchronic GLP-studies conducted careful examinations of male and female reproductive organs from exposed rats and in only one study was there any finding associated with reproductive organs. In the 14-day gavage study at doses up to 2000 mg/kg/day, two of ten high-dose males displayed multifocal testicular degeneration which was described by the pathologist as ‘the affected tubules had a decreased amount of spermatogenic cells with evidence of degeneration and formation of multinucleated giant cells. Other males at this dose-level were not affected or were females (regarding their reproductive organs) or any lower-dose animals. In the 14-day inhalation study at concentrations up to 5132 ppm (inhalation of approximately 1700 mg/kg over 6 hours) no male or female demonstrated reproductive organ effects. And, in the 90-day inhalation study at concentrations up to 3010 ppm (inhalation of approximately 1000 mg/kg over 6 hours), neither males nor females were found with adverse changes to reproductive organs. Taken together, this is strong evidence that Dioxolane is not a significant reproductive toxicant.

 

Summary: Dioxolane has an effect on reproductive parameters only at maternally toxic doses.

The clear NOAEL for these effects was 0.1% in drinking water.

 

Recommendation: Reproductive effects of Dioxolane are characterized sufficiently for the purpose of hazard and risk assessment. No additional studies are recommended.”

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
149 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Studies were reviewed by US EPA HPV Program, and found to be "Reliable with Restrictions". Also, the NOAEL of 149 mg/kg BW/ day has been estimated based on the NOAEL of 0.1% from two studies, two one-generation studies (see calculations under remarks in WOE Morrow - 2-gen Drinking Water - Rat (1976)
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
379 mg/m³
Study duration:
subchronic
Species:
rat

Effects on developmental toxicity

Description of key information

Information regarding Toxicity to Reproduction for 1,3-dioxolane comes from a number of studies, including a Pre-Natal Developmental study (Hoberman, 1991), three One-Generation Reproductive Toxicity (Gerstner [F0 and F1a], 1976; Gerstner [F0 and F1b], 1976; Morrow, 1976), two of which are actually connected through the F0/F1a generations (the F0 females for the second study (Gerstner [F0 and F1b], 1976) were actually derived from the F1a generation of the first study (Gerstner [F0 and F1a], 1976).  There is also a published study on Developmental Toxicity (Sitarek, et al., 1992).  In addition to traditional Repro and Developmental studies, there is also information available on reproductive organs/tissues from repeated dose toxicity studies. In preparation for conducting a developmental toxicity study, a dose range finding test (DRF) was conducted on pregnant female New Zealand White rabbits at dose levels of 46.88, 187.5, 500 and 700 mg/kg bw /day.  The developmental findings at dose levels of 187.5, 500 and 750 mg/kg bw/day include spine bifida, limb hyperflexion, exencephaly and missing digits or tail. Neither the control nor low dose groups were affected.

In addition, a developmental toxicity study (OECD 414) was conducted in rabbits by oral route (Barnett, 2017). The study reports “the maternal NOAEL for 1, 3-dioxolane was established at 60 mg/kg/day, based on mortality, clinical observations (thin body condition and decreased fecal output), reductions in body weight gain and reductions in food consumption observed at 200 and 500 mg/kg/day during the study. The developmental NOAEL is 200 mg/kg/day due to decreases in fetal body weight, hyperextension of the forepaws, skeletal variations and delayed skeletal ossification observed at 500 mg/kg/day. The delayed ossification was considered to be related to the reduction in fetal body weight observed in the 500 mg/kg/day dose group. This change in ossification at 500 mg/kg/day was considered not to be adverse because it is a minor, reversible delay in skeletal ossification and was observed in the presence of maternal toxicity.”

However, maternal toxicity was not strong enough to explain the observed fetal effects. While it is common to observe an increased incidence of malformations in fetuses of low FBW, it is incorrect to suggest that the low FBW due to the slight maternal toxicity causes the malformations. Severe malformations affect the growth of the fetus and these result in low FBW (Holson et al., 2006).  If the decreased in FBW was the cause of hyperflexion of the forepaws, this would require all or at least the majority of the pups of similar FBW have hyperflexion of the forepaws.

 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat

Toxicity to reproduction: other studies

Description of key information

No effects could be detected in female gonads in doses up to and including 2000 mg/kg/day (Hoberman, 1991). In males, no effects were observed on gonads in doses up to and including 750 mg/kg/day. Adverse effects on male gonads were limited to testes showing multiple areas of degeneration of seminiferous tubules in the top dose group only. The relevance of results in this group is strongly limited due to severe general toxicity incl. mortality and the dose being far beyond the limit dose for this type of study.

Consequently, the available data do not indicate any effects on male or female fertility in doses relevant for classification and labelling.

These data are also supported by a 13-week inhalation study in Fisher rats using 0, 300, 1000 or 3000 ppm. Although parental toxicity was observed in 1000 and 3000 ppm groups, no effect could be detected on male or female gonads (Dow, 1989).

In addition, drinking water exposure of rats at 0.5 or 1.0% produced clear adverse effects on reproduction. In the F1a mating, it could not be determined if effects were attributable primarily to exposure of males, females or both. Survival of high dose pups was especially affected, but this is not an expression of an effect on fertility).

In the second exposure using untreated proven male breeders, the effects were less severe suggesting that there was a male contribution to the reproductive toxicity. This conclusion is clouded, however, since the females were not exposed to test article during mating, gestation or lactation during the production of this second litter. It is clear that the females were still affected and therefore the female was an affected sex regarding reproductive toxicity of dioxolane.

 

In order to confirm the results from the drinking water studies, an analogous study design was applied for an inhalation one-generation study in rats using a single dose of 125 ppm (Industrial Bio-Test Laboratories, 1976c, 1976d).

Also, in an inhalation study, the same endpoints were investigated as in the drinking water studies. No effects were seen on any of these endpoints, thus confirming the lack of any effects on fertility in doses not causing paternal toxicity.

Based on all the available reproductive toxicity data, it is possible to conclude that fertility effects, if any, were observed only in the presence of parental toxicity and it remains unclear whether they can be considered specific or not.

Justification for classification or non-classification

The C&L assessment for 1,3-dioxolane under the GHS system meets the criteria for reproductive toxicity Category 1B based on pregnancy loss, incidence of hyperflexion of forepaws, decreases in FBW and increased skeletal variations/ decreased ossification in rabbits and decreased FBW and increased incidence of septal heart defects and vertebral malformations in rats.