Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Based on the high level of understanding of metabolism and toxicity of glycol ethers, it is reasonable to expect the toxicity of methoxypropanol and ethoxypropanol to be similar. Accordingly, it is believed that this information for the reproductive toxicity of methoxypropanol provides a useful indication of the likely effects of ethoxypropanol, which is in turn the rapidly created in vivo metabolite of ethoxypropyl acetate, the substance that is the subject of this dossier. On this basis, the study indicates that ethoxyypropyl acetate is not toxic to reproduction. See summary of toxicokinetics of glycol ethers (7.1.1) for more information. A more extensive justification for read across is contained in the read across justification attached to chapter 13 of this dossier.

Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
other: read across substance
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
not specified
Dose descriptor:
NOAEC
Effect level:
300 ppm
Based on:
other: read across substance
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
not specified
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
1 000 ppm
Based on:
other: read across substance
Sex:
male/female
Basis for effect level:
viability
sexual maturation
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Critical effects observed:
not specified
Dose descriptor:
NOAEC
Generation:
F2
Effect level:
1 000 ppm
Based on:
other: read across substance
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Critical effects observed:
not specified
Reproductive effects observed:
not specified
Executive summary:

In a guideline and GLP study used for read across purposes, the reproductive toxicity of methoxypropanol (a close structural analogue of ethoxypropanol) was studied in male and female SD rats exposed by inhalation to 0, 300 1,000 or 3,000 ppm vapours for 10 days prior to mating and 7 d/wk during mating, gestation and lactation for 2 generations. Marked parental toxicity was seen at 3,000 ppm, as evidenced by changes in various organ and body weights (relative/absolute) of the first and second generation males and females, in particular of the testes and ovaries. In females, toxicity was accompanied by decreased fertility, lengthened oestrous cycle, decreased ovarian weight and histopathological ovarian atrophy. Embryotoxicity and foetotoxicity occurred only at maternally toxic doses. No reproductive/neonatal effects were observed at 1000 ppm, a concentration which caused less marked , but significant body weight effects without sedation. Based on these findings the NOEL for reproductive/neonatal effects was 1000 ppm, and that for parental toxicity was 300 ppm. Equivalent airborne concentrations of ethoxypropanol are 4.25 and 1.275 mg/L, respectively. Equivalent airborne concentrations of ethoxypropanol are 4.25 and 1.275 mg/L, respectively.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There is no data available for the substance ethoxypropyl acetate.

The reproductive toxicity of methoxypropanol (the methyl analogue of ethoxypropanol, which is the in vivo hydrolysis product of ethoxypropyl acetate) was studied in male and female SD rats exposed by inhalation to 0, 300 1,000 or 3,000 ppm vapours for 10 days prior to mating and 7 d/wk during mating, gestation and lactation for 2 generations. Marked parental toxicity was seen at 3,000 ppm, as evidenced by changes in various organ and body weights (relative/absolute) of the first and second generation males and females, in particular of the testes and ovaries. In females, toxicity was accompanied by decreased fertility, lengthened oestrous cycle, decreased ovarian weight and histopathological ovarian atrophy. Embryotoxicity and foetotoxicity occurred only at maternally toxic doses. No reproductive/neonatal effects were observed at 1000 ppm, a concentration which caused less marked , but significant body weight effects without sedation. Based on these findings the NOEL for reproductive/neonatal effects was 1000 ppm, and that for parental toxicity was 300 ppm.

In a continuous breeding study in CD-1 mice, methoxpropanol (methyl analogue of the in vivo hydrolysis product of ethoxypropyl acetate) was administered up to 2% in the drinking water for 2 generations. No effects on fertility or reproduction were observed at 2%, although at this dose level MP was moderately toxic as shown by statistically decreased pup body weight gain from birth to postnatal day 14 in the second generation animals. This effect on pup body weight was seen in the absence of an effect on parental body weight. A NOAEL for this effect cannot be established from this study because lower doses were not evaluated in the second generation animals. Otherwise a NOAEL of 1885mg/kg was established for the substance 2 -methoxypropanol.

This result can be considered representative of the close structural analogue ethoxypropanol, which is in turn the rapidly created in vivo metabolite of ethoxypropyl acetate, the substance that is the subject of this dossier. On this basis, the study indicates that ethoxyypropyl acetate is not toxic to reproduction and by extrapolation on a molar basis, a NOAEL of 3058mg/kg is predicted.


Short description of key information:
Inhalation NOEC for reproductive / neonatal effects (extrapolated from surrogate): ~ 1000 ppm (6.1 mg/L)
Inhalation NOEC for parental toxicity (extrapolated from surrogate): ~ 300 ppm (1.8 mg/L)

Justification for selection of Effect on fertility via inhalation route:
Based on read across substance suitable for extrapolation for systemic effects.

Effects on developmental toxicity

Description of key information
Inhalation NOAEC for developmental effects (extrapolated from surrogate): >~ 2000 ppm (12.2 mg/L)
Inhalation NOAEC for maternal toxicity (extrapolated from surrogate): ~ 100 ppm (0.6 mg/L)
Additional information

There is no data available on the substance ethoxypropyl acetate.

In a developmental toxicity study in rats, whole body inhalation exposure to ethoxypropanol (the in vivo hydrolysis product of ethoxypropyl acetate) vapour at concentrations up to 2000 ppm on Days 6-15 of gestation did not produce evidence of developmental effects (based on uterine and litter data, and foetal development). Reduced weight gain and clinical signs were noted in maternal animals exposed to 450 ppm or 2000 ppm. No effects were noted in maternal animals exposed to 100 ppm. Based on these results the following NOAECs for developmental toxicity in the rat are established for ethoxypropanol vapour: NOAEC (maternal) >= 100 ppm; NOAEC (developmental) >= 2000 ppm.

In a developmental toxicity study in rabbits, whole body inhalation exposure to ethoxypropanol (the in vivo hydrolysis product of ethoxypropyl acetate) vapour at concentrations up to 1200 ppm on Days 6-18 of gestation did not produce evidence of developmental effects (based on uterine and litter data, and foetal development). A slight reduction in mean food consumption and an initial retardation in body weight gain (gestation days 6 – 10) was seen in maternal animals exposed to 1200 ppm. No effects were noted in maternal animals exposed to 100 or 350 ppm. Based on these results the following NOAECs for developmental toxicity in the rabbit are established for ethoxypropanol vapour: NOAEC (maternal) >= 350 ppm; NOAEC (developmental) >= 1200 ppm

Justification for classification or non-classification

The indirect evidence for the reproductive toxicity of ethoxypropyl acetate indicates that reproductive toxicity is likely to be low; based on evidence from structurally similar surrogates it is expected that ethoxypropyl acetate does not meet any of the criteria for classification for this end point.