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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Diisopropyl ether as well as the surrogate ethyl tert.-butyl ether were assessed in one generation reproductive toxicity studies (application by whole body inhalation exposure) for effects on fertility and developmental toxicity with exposure up to 20.000 mg/m³ (tested in gasoline as diluent, equivalent to 3560 mg/m³ DIPE) and no effects of fertility or sexual performance were seen. The two studies in DIPE and ETBE showed absolutely comparable results in absence of reproductive effects and slight parental findings with respect to increased liver weights, leading to a NOAEC of 2000 mg/m³ for parental effects and 20.000 mg/m³ (highest dose group) for reproductive effects.

In addition, ethyl tert.-butyl ether (ETBE) had been assessed in a two-generation reproductive toxicity study in rats by oral exposure with doses up to 1000 mg/kg bw/d and no effects on fertility were seen in this study. Changes in absolute and relative kidney weights lead to a parental NOAEL of 250 mg/kg bw/d in this study, showing slight toxicity to parental animals, but no effects on mating, fertility, gestation, fecundity or delivery on sperm parameters were observed. The identical findings of DIPE in gasoline and ETBE in gasoline as well as the structural similarity of the two substances, both being ethers of identical molecular weight and very similar phys-chem properties, do support ETBE being a reliable surrogate for DIPE and the finding in the two-generation reproductive toxicity study, showing no effects on reproductive parameters support the absence of necessity to investigate further on reproductive toxicity of DIPE.

Link to relevant study records

Referenceopen allclose all

Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
no effects observed
Description (incidence and severity):
There were no remarkable clinical observations reported
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Light hydrocarbon nephropathy was strongly indicated in all studies by the presence of hyaline droplets in kidneys of 20,000 mg/m³ male rats, an effect already known for decade attributable to the hydrocarbon carrier.
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Estrus cyclicity parameters were comparable between exposed and concurrent control groups.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Semen parameters were comparable between exposed and concurrent control groups.
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no differences in male and female fertility or reproductive performance with exposure to any test material.
No treatment related macroscopic or microscopic changes were seen in male or female reproductive organs.
Dose descriptor:
NOAEC
Effect level:
2 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other: Parental effect
Dose descriptor:
NOAEC
Effect level:
20 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Remarks on result:
other: Reproductive parameters
Remarks:
No effects
Dose descriptor:
NOAEC
Effect level:
356 mg/m³ air (analytical)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other: Parental effects
Remarks:
calculated as DIPE
Dose descriptor:
NOAEC
Effect level:
3 560 mg/m³ air (analytical)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no effects
Remarks on result:
other: Reproductive parameters
Remarks:
calculated as DIPE
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No adverse effects were seen on offspring organ weights
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no findings of malformations
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
The NOAEL was the highest exposure tested for G/DIPE as no differences from controls were seen for fertility, days to mating, estrus cycle length, sperm counts or morphology or developmental parameters in pups.
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
20 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Reproductive effects observed:
no
Conclusions:
In this one generation reproductive toxicity study with a gasoline blend supplemented by 17.8% di-isopropyl ether (measured in vapour phase), no developmental effects or decreases in fertility were observed and thus the NOAEC in this study was set to the highest does tested being 20.000 mg/m³. The addition of di-isopropylether in significant amounts had no impact on reproductive toxicity of oxygenated fuels and hence it is concluded that DIPE as such does not have negative developmental/reproductive effects.
Executive summary:

Vapour condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000 mg/m³, 6 h/day, 7 days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study.

Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME off-spring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000 mg/m³ for all vapour condensates except for lower offspring NOAELs of 10,000 mg/m³ for G/TBA and 2000 mg/m³ for G/TAME.

Thus, it can be concluded that di-isopropyl ether did not impact reproductive toxicity in this one-generation reproductive toxicity study. Similar finding were made with other ethers used in the same study setup such as methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), and t-amyl methyl ether (G/TAME).

Endpoint:
one-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
There were no remarkable clinical observations reported
Dermal irritation (if dermal study):
not examined
Description (incidence and severity):
Inhalation exposure, therefore, dermal effect not monitored
Mortality:
no mortality observed
Description (incidence):
There were no significant effects of treatment on survival in the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant reduction in weight gain during the premating period was observed in females exposed to 20,000 mg/m³ BGVC (P0) G/MTBE (P0 and F1), G/ETBE and G/TBA. No effects on maternal body weight gains occurred during gestation (GD 0 – 20) and lactation (LD 1 – 28). Among males, decreased body weight changes were seen in parental animals in G/ETBE and G/TBA.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was comparable to concurrent controls
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No remarkable histopathologic changes were reported in the study.
Histopathological findings: neoplastic:
no effects observed
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Light hydrocarbon nephropathy was strongly indicated in all studies by the presence of hyaline droplets in kidneys of 20,000 mg/m³ male rats, an effect already known for decade attributable to the hydrocarbon carrier.
Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Estrus cyclicity parameters were comparable between exposed and concurrent control groups.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Semen parameters were comparable between exposed and concurrent control groups.
Reproductive performance:
no effects observed
Description (incidence and severity):
There were no differences in male and female fertility or reproductive performance with exposure to any test material.
No treatment related macroscopic or microscopic changes were seen in male or female reproductive organs.
Dose descriptor:
NOAEC
Effect level:
2 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Remarks on result:
other: Parental effect
Dose descriptor:
NOAEC
Effect level:
20 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Remarks on result:
other: Reproductive parameters
Remarks:
No effects
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No adverse effects were seen on offspring organ weights
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no findings of malformations
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
The NOAEL was the highest exposure tested for G/DIPE and G/ETBE as no differences from controls were seen for fertility, days to mating, estrus cycle length, sperm counts or morphology or developmental parameters in pups.
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
20 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Reproductive effects observed:
no
Conclusions:
In this one generation reproductive toxicity study with a gasoline blend containing 16.3% ethyl tert.-butyl ether (ETBE), no developmental effects or decreases in fertility were observed and thus the NOAEC in this study as set to the highest does tested being 20.000 mg/m³.
Executive summary:

Vapour condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000 mg/m³, 6 h/day, 7 days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study.

Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME off-spring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000 mg/m³ for all vapour condensates except for lower offspring NOAELs of 10,000 mg/m³ for G/TBA and 2000 mg/m³ for G/TAME.

Thus, it can be concluded that ethyl tert.butyl ether (ETBE) did not impact reproductive toxicity in this one-generation reproductive toxicity study. The findings using DIPE supplemented gasoline (17.8 % (v/v)) at ETBE supplemented gasoline (16.3 % (v/v)) were fully comparable, supporting the ypproach to use reproductive toxicity data from ETBE as read-across source to DIPE.

Endpoint:
two-generation reproductive toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
Inhalation exposure, therefore, dermal effect not monitored
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No remarkable histopathologic changes were reported in the study.
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
No treatment related macroscopic or microscopic changes were seen in male or female reproductive organs.
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: statistically significant reduction in body weight gain in F0 males, absolute and relative kidney weight increased in F0 and F1 males and absolute and relative liver weights in F1 males
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
The NOAEL was the highest exposure tested for ETBE as no significant differences from controls were seen for F1 generation.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Discussed together with details on results (F1) - see above!
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Reproductive effects observed:
no
Conclusions:
The results from the study on ETBE can nominally be converted to DIPE as molecular weights of the two substances are identical. The NOAEL (P1) was set to 250 mg/kg bw/d, based on statistically significant reduction in body weight gain in F0 males, absolute and relative kidney weight increased in F0 and F1 males and absolute and relative liver weights in F1 males. The NOAEL for fertility was set to 1000 mg/kg bw/d (highest dose applied) due to lack of effects on mating, fertility, gestation, fecundity, delivery or sperm parameters. No effects were observed on the progeny from delivery until weaning. The NOEL for F1 and F2 generation were set to 1000 mg/kg bw/d, as no treatment-related or statistically significant changes were seen in pups found dead or sacrificed early, or in pups subject to scheduled necropsy at weaning.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3 560 mg/m³
Study duration:
subchronic
Species:
rat
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In accordance with column 2 of REACH Annex VIII, the reproductive toxicity screening study (required in section 8.7.1) does not need to be conducted as a pre-natal developmental toxicity study is available.

A 13-week repeated dose toxicity study by Dalbey and Feuston (1996) noted that the number of sperm and spermatids were not changed; however, there was a significant change in number of abnormal sperm at 7100 ppm. The authors noted that the change in number of abnormal sperm was not considered to be biologically significant. No information is available for the effects on sexual function and fertility in adult females from this study.

Recently, results from one- and two-generation studies assessing effects of oxygenates, supplemented to gasoline, were published. In this study, baseline gasoline and one representative (methyl tert.-butyl ether MTBE) were assessed in a two-generation reproductive toxicity study design, whereas other gasoline blend with oxygenates (ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA)) were investigated in a one-generation study design, applying exposure via inhalation (whole body, 6h/day, 7 days/week). In these investigations no effects on fertility or developmental toxicity were found when dosed up to 20.000 mg/m³, equivalent to 3560 mg/m³ pure DIPE. ETBE, investigated in the same study, also did not show any effects on fertility and developmental toxicity, which supports the validity of the read-across hypothesis to use ETBE reproductive toxicity data as surrogate data to assess DIPE reproductive toxicity. Thus, the results from a two-generation reproductive toxicity study in rats by oral exposure with doses up to 1000 mg/kg bw/d and no effects on fertility seen in this study, can be used for read-across to DIPE too. Changes in absolute and relative kidney weights lead to a parental NOAEL of 250 mg/kg bw/d in this study, showing slight toxicity to parental animals, but no effects on mating, fertility, gestation, fecundity or delivery on sperm parameters were observed. The identical findings of DIPE in gasoline and ETBE in gasoline as well as the structural similarity of the two substances, both being ethers of identical molecular weight and very similar phys-chem properties, do support ETBE being a reliable surrogate for DIPE and the finding in the two-generation reproductive toxicity study, showing no effects on reproductive parameters support the absence of reproductive effects of DIPE and indicate no necessity to investigate further on reproductive toxicity of DIPE.

Effects on developmental toxicity

Description of key information

An inhalation prenatal development toxicity study of di-isopropyl ether (DIPE) in rats, equivalent to OECD guideline 414, did not report a NOAEC.  However, based on a review of the data, the NOAEC for maternal and developmental toxicity was considered to be 430 ppm (1800 mg/m³).  A concentration-related increase in the incidence of fetal rudimentary 14th ribs was noted at maternal toxic doses of DIPE.  The study authors indicated that the rib findings were not indicative of teratogenicity.  There were no embryotoxic effects reported.

Results from one- and two-generation studies assessing effects of oxygenates, supplemented to gasoline, also do support the absence of developmental effects in rats. In this study, baseline gasoline and one representative (methyl tert.-butyl ether MTBE) were assessed in a two-generation reproductive toxicity study design, whereas other gasoline blend with oxygenates (ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA)) were investigated in a one-generation study design, applying exposure via inhalation (whole body, 6h/day, 7 days/week). In these investigations no effects on fertility or developmental toxicity were found when dosed up to 20.000 mg/m³, equivalent to 3560 mg/m³ pure DIPE. ETBE, investigated in the same study, also did not show any effect on fertility and developmental toxicity, which supports the validity of the read-across hypothesis to use ETBE reproductive toxicity data as surrogate data to assess DIPE reproductive toxicity.

A study investigating the developmental toxicity to rabbits via oral exposure from ETBE (ethyl tert.-butyl ether) also did not indicate any developmental toxicity, and as outlined above, ETBE is a suitable surrogate for assessing developmental toxicity of DIPE. Thus, it can be concluded that generation of additional data for developmental toxicity in a second species (besides rats) can be omitted for animal welfare reasons.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: Rats were approximately 9 weeks old when received and approximately 11 weeks old when breeding began
- Weight at study initiation: Not reported
- Fasting period before study: None
- Housing: Individually housed in 1 cubic metre (H-1000) inhalation chambers.
- Diet (e.g. ad libitum): Certified Purina Rodent Chow 5002 ad libitum except during exposure period
- Water (e.g. ad libitum): Ad libitum except during exposure period
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22 ºC
- Humidity (%): 40 to 60%
- Air changes (per hr): At least 12/hour
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: H-1000 1 cubic-metre chambers
- Source and rate of air: HEPA-filtered room air; rate of air flow = 290 lpm
- Temperature, humidity, pressure in air chamber: Mean temperature within the chambers was in the range of 23 to 24 ºC and relative humidity was 60 to 67%. Pressure was not reported.
- Air flow rate: 290 lpm
- Air change rate: 12 changes/hour
- Treatment of exhaust air: Air exiting the chambers was cleaned by passage through charcoal beds


TEST ATMOSPHERE
- Brief description of analytical method used: Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy.

VEHICLE (if applicable)
- Justification for use and choice of vehicle: No vehicle
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. Analyzed concentrations included both DIPE and total hydrocarbons. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy. Time points of analysis were not reported.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Not reported
- Proof of pregnancy: sperm plug/sperm in the vaginal lavage fluid referred to as day 0 of pregnancy
Duration of treatment / exposure:
6 hours/day on Days 6 to 15 of gestation
Frequency of treatment:
6 hours/day on Days 6 to 15 of gestation
Duration of test:
Approximately 5 weeks (acclimation = 2 weeks and study duration = approximately 3 weeks)
Dose / conc.:
430 ppm (analytical)
Remarks:
equivalent to 1800 mg/m³, basis analytical conc.
Dose / conc.:
3 095 ppm (analytical)
Remarks:
equivalent to 12940 mg/m³, basis analytical conc.
Dose / conc.:
6 745 ppm (analytical)
Remarks:
equivalent to 28200 mg/m³, basis analytical conc.
No. of animals per sex per dose:
22 females/group
Control animals:
yes, concurrent no treatment
yes, sham-exposed
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on Days 0, 6, 13, 16, and 20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Publication states that "all organs were examined grossly;" however, specific organs were not reported.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No data
Statistics:
ANOVA, Fisher's exact, or Dunnett's tests were used
Indices:
None reported
Historical control data:
None reported
Details on maternal toxic effects:
Maternal toxic effects: yes

Details on maternal toxic effects:
Lacrimation and salivation were noted in a few DIPE-exposed females at the highest concentration during, or immediately following, exposures. The animals returned to normal appearance shortly after cessation of each daily exposure.

In general, animals housed in chambers gained less weight and consumed less food during the exposure period than the untreated controls (statistically significant at 6745 ppm relative to both of the control groups).

No treatment-related effects were noted at the time of macroscopic examination.

Serum chemistry endpoints were not adversely affected by exposure to DIPE vapors.

Statistically significant decrease in body weight gains were seen on gestation days 6 to 16 at all dose levels (compared to untreated controls for the low- and mid-dose groups and compared to both controls at the high-dose group).

Statistically significant decrease was seen in food consumption on gestation days 6 to 16 at the mid- and high-dose groups (compared to untreated controls on gestation days 6 to 13 and compared to both control groups on gestation days 13 to 16).

Reproductive parameters (i.e., number of pregnant females, percent preimplantation loss, percent resorptions, and litter sizes) were not affected by exposure.
Dose descriptor:
NOEC
Effect level:
430 ppm (analytical)
Based on:
test mat. (dissolved fraction)
Basis for effect level:
other: maternal toxicity
Remarks on result:
not determinable
Remarks:
no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Fetal development (i.e., fetal body weight) was not affected by exposure.

Evaluations of fetal skeletons revealed a significant increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs in fetuses exposed to DIPE at concentrations of 3095 and 6745 ppm. All of the observed 14th ribs were rudimentary except for 2 fetuses from each of the mid- and high-dose groups that had either bilateral short 14th ribs or bilateral short and rudimentary 14th ribs. No other exposure-related findings were noted at the time of fetal evaluations. The study authors have stated that "the observed increase in the incidence of rudimentary 14th ribs does not appear to be indicative of an adverse effect on development" at the concentrations tested.
Dose descriptor:
NOEC
Effect level:
430 ppm (analytical)
Based on:
test mat. (dissolved fraction)
Sex:
male/female
Basis for effect level:
other: slight skeletal effects
Remarks on result:
other: no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No developmental effects in the absence of maternal toxicity were observed. The NOAEC in this study for maternal effects as well as developmental effects can be set to 430 ppm.
Executive summary:

A NOAEC was not reported by the study authors. Review of the study data suggests that a NOAEC of 430 ppm can be derived for maternal toxicity based on the decrease in body weight gain and food consumption at higher concentrations, and a NOAEC of 430 ppm can be derived for foetal toxicity based on increases in rudimentary/short 14th ribs at higher concentrations (although the authors argue that this "variation" is not conclusive evidence of developmental toxicity).

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across: supporting information
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fetotoxicity
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
the study is supported by equivalent finding (no effects at 1000 mg/kg bw/d) in rats (OECD 414) study
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
1 800 mg/m³
Species:
rat
Quality of whole database:
the study is supported by equivalent finding (no effects at 3560 mg DIPE/m³) in rats (one generation reproductive toxicity study).
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The effect of diisopropyl ether (DIPE) on fetal development was evaluated in a prenatal development toxicity study that was similar to OECD test guideline 414 (Dalbey and Feuston, 1996). The GLP-compliance of the study was not specified in the publication. DIPE was administered by whole body inhalation to timed-pregnant Wistar rats at concentrations of 0 (untreated), 0 (sham exposed), 430, 3095, or 6745 ppm (1800, 12940, or 28200 mg/m3) for 6 hours a day from gestation days 6 through 15 (n = 22/group). Decreased body weight gain was reported in DIPE and sham-treated animals compared to controls. Maternal body weight gain was statistically significantly decreased at 6745 ppm compared to both control groups. Maternal food consumption was statistically significantly decreased in the 3095 and 6745 ppm dose groups compared to both control groups. There were no effects of DIPE on embryotoxicity parameters or on fetal body weight. An increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs was reported in fetuses in the 3095 and 6745 ppm groups. Given that no other teratogenic findings were observed when the dose was doubled from 3095 to 6745 ppm, the authors argued that these findings were not indicative of teratogenicity. The authors of the publication did not identify a NOAEC for maternal or developmental toxicity; however, based on these data, the NOAEC for maternal and developmental toxicity in rats was considered to be 430 ppm (1800 mg/m³).

Additionally, data on gasoline vapour exposure of rats, supplemented by di-isopropyl ether (17.8% v/v) and ethyl tert.-butyl ether (16.3% v/v) in a one-generation reproductive toxicity study design showed, that no effects on fertility were seen, but also no effects on developmental toxicity. The NOAEL in these studies for developmental toxicity were 20.000 mg/m³ (equivalent to 3560 mg DIPE/m³). An oral developmental toxicity study, performed by gavage exposure of rabbits during GD 6 - 29 to ETBE up to 1000 mg/kg bw/d also did not indicate any developmental toxicity effects.

In summary, it can be concluded that all available studies on developmental toxicity, resulting from OECD 414 studies on rats and rabbits, as well as resulting from OECD 416 studies on rats, do indicate that no developmental toxicity is to be expected from oral or inhalation exposure to di-isopropyl ether.

Justification for classification or non-classification

The fertility and developmental toxicity studies indicate that DIPE does not affect reproductive toxicity. All available studies on reproductive toxicity do indicate no reproductive toxicity from oral or inhalation exposure to di-isopropyl ether. As a result, data is conclusive not to classify DIPE according to Regulation (EC) No 1272/2008, Annex I section 3.7 for reproductive toxicity.

Additional information