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Effects on fertility

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Referenceopen allclose all

Endpoint:
two-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
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
hydrocarbons C6 and C8, aliphatic and olefinic are an important component in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of 12 - 15% (<35%) by weight. Thus, aliphatic and olefinic components cannot be ignored when assessing the reproductive toxicity of “2-propanol and 2-butanol production, distn. residues”, also considering their volatility (inhalation study) and absorption rate, present in the distillation residue.
Thus, in combination with other data on reproductive toxicity of identified components in “2-propanol and 2-butanol production, distn. residues” such as ethers and alcohols, the reproductive toxicity can be assessed in a weight of evidence approach considering the baseline gasoline vapour condensates (BGVC) reproductive toxicity in combination with the reproductive toxicity of ethers and alcohols present.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical baseline gasoline vapour condensates (BGVC) was tested as such but also in combination with ethers and alcohols (oxygenated hydrocarbon streams) as used in gasolines. BGVC consists mainly of a aliphatic but also olefinic components in the range of C4 - C8. Some of the hydrocarbons C4-C8 in the baseline gasoline vapour condensate are components in the target compound “2-propanol and 2-butanol production, distn. residues” (C4, C5 and C7 components were not found therein and so the BGVC may be seen as a worst case surrogate of the aliphatic and olefinic components) and thus results do contribute to the assessment of reproductive toxicity of the target substance following a weight of evidence approach based on components of the distillation residues. Additionally, as the final use of “2-propanol and 2-butanol production, distn. residues” is to become a component in fuels, the study performed by inhalation route of exposure provides a real life scenario of the products final use.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
The hydrocarbons C4-C8 (BGVC) used in the study, as shown above, are important components in sum typically in the range of 12% and thus using data from reproductive toxicity studies on these components in a weight of evidence approach together with data from other components (ethers and alcohols) provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
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:
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) only. No effects on maternal body weight gains occurred during gestation (GD0 – 20) and lactation (LD1 – 28).
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
Description (incidence and severity):
All test material exposure caused a statistically significant increase in male kidney weights in the 10,000 and 20,000 mg/m³ groups consistent with light hydrocarbon nephropathy (light hydrocarbons as carrier).
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological findings upon exposure to BGVC were reported
Neuropathological findings:
no effects observed
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:
10 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other: Parental toxicity
Remarks:
The BGVC parental NOAEC was based on decreased body weight gains during the premating period in P0 females and F1 males and increased P0 female kidney weight which had no histopathologic correlate.
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
Critical effects observed:
no
Lowest effective dose / conc.:
20 000 other: mg/m³
Organ:
kidney
Clinical signs:
no effects observed
Description (incidence and severity):
See F1 generation
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
See F1 generation
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See F1 generation
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:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
See F1 generation
Gross pathological findings:
no effects observed
Description (incidence and severity):
See F1 generation
Neuropathological findings:
no effects observed
Description (incidence and severity):
See F1 generation
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Dose descriptor:
NOAEC
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
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):
no effects observed
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:
no effects observed
Description (incidence and severity):
Expressions of sexual maturation (vaginal opening and preputial gland separation) were not altered by exposure to BGVC. Additionally there were no decrements in reproductive performance when the F1 animals (1/sex/litter) were bred to produce the second generation.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Lower spleen weights were seen in F1 offspring of BGVC exposed rats; however the effect was not expressed to the F2 offspring and was unlikely to be a toxicologically significant adverse finding. No other 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
Description (incidence and severity):
Neuropathology and GFAP assessments were performed on randomly selected F1 pups from BGVC exposed rats. No adverse neuropathology was observed and there were no differences between control and BGVC F1 offspring in brain length or width. Exposure to BGVC did not cause changes in GFAP levels in any brain region examined with the exception of a single decrease in the BGVC F1 male thalamus at 20,000 mg/m³ that was not considered biologically significant by the investigator. Overall, GFAP results indicated that none of these substances induced gliosis in the brain regions examined.
Developmental immunotoxicity:
not examined
The NOAEL was the highest exposure tested for BGVCE 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:
other: The NOAEL was the highest exposure tested for BGVC as no differences from controls were seen for fertility, days to mating, oestrous cycle length, sperm counts or morphology or developmental parameters in pups.
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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Dose descriptor:
NOAEC
Generation:
F2
Effect level:
20 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Remarks on result:
other: The NOAEL was the highest exposure tested for BGVC as no differences from controls were seen for fertility, days to mating, oestrous cycle length, sperm counts or morphology or developmental parameters in pups.
Reproductive effects observed:
no
Conclusions:
In this two generation reproductive toxicity study with a gasoline blend, no developmental effects or decreases in fertility were observed and thus the NOAEC in this study was set to the highest dose tested being 20.000 mg/m³. Thus, the mix of aliphatic and olefinic hydrocarbons (C4 - C8) had no impact on reproductive toxicity and thus reproductive toxicity of "2-propanol and 2-butanol production, distn. residues" is also not expected to be affected by aliphatic and olefinic components (C6 - C8) therein.
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 aliphatic and olefinic hydrocarbons (C4 - C8) in BGVC did not impact reproductive toxicity in this two-generation reproductive toxicity study and thus it can be concluded that the similar and/or same hydrocarbons (aliphatic and olefinic C6 - C8) as components in "2-propanol and 2-butanol production, distillation residues" also do not contribute to reproductive toxicity or effects on fertility.

Endpoint:
screening for reproductive / developmental 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
Remarks:
Acceptable, well-documented study report similar or equivalent to OECD 421. GLP.
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Hydrocarbons C6 and C8 are minor components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <10% by weight. Thus, this substance is one of those expected to have an impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, present in the distillation residue.
Thus, in combination with other data on teratogenicity and reproductive toxicity of identified components in “2-propanol and 2-butanol production, distn. residues” the reproductive toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical hydrocarbons C4-C8 is one of the minor components in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do contribute to the assessment of reproductive of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Hydrocarbons C4-C8, as shown above, are minor components in sum typically below 10% and thus using data from reproductive toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
no effects observed
Description (incidence and severity):
No apparent treatment-related clinical signs were observed during the exposures orat other times during the study.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No parental animals died or were prematurely killed.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Parental body weights were not significantly affected during the premating, mating, gestation, and lactation periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The consumption of food was not markedly affected by exposure to LAND.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
In the males, the only remarkable findings at necropsy were a small right epididymis and testisseen in one mid-dose male and an abscess on the right epididymis of a high-dose male. In both cases, the dams that had been bred to these males produced normal litters. Besides the one dam in the mid-dose group that had a single nonviable fetus, the only other remarkable finding observed in the females at necropsy was a threadlike uterine horn observed for the low-dose dam that had diffi
culty delivering.
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Description (incidence and severity):
There was no statistical difference in the mean number of corpora lutea per dam between the control and treated groups.
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No clinical signs indicative of systemic toxicity were observed during the study.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Inhalation exposure had no effect on parental food consumption, body weight or fertility, up to and including the 24.7 mg/l dose level.
REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): No treatment-related effects.
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No treatment-related effects.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): There were no differences in the mean number of corpora lutea, implantation sites and live pups per litter. Pups born from treated mothers showed comparable birth weights and weight gains. On postnatal day 4, all groups had a viability index >97%.
GROSS PATHOLOGY (PARENTAL ANIMALS): No treatment-related effects.
ORGAN WEIGHTS and HISTOPATHOLOGY (PARENTAL ANIMALS): Evaluation of the parental reproductive organs (ovaries, testes and epididymides) did not reveal any weight or microscopic changes attributable to exposure.

Any pups that were found dead at the time of observations on post-partum d 0 were recorded as stillborn. The low-dose group had a statistically lower live birth index than the control, due primarily to one dam that had difficulty delivering because all 12 of her implants were in 1 uterine horn. Only six of her pups survived. There was no statistical difference in the mean number of corpora lutea per dam between the control and treated groups. Pup observations were generally unremarkable. All groups showed comparable pup birth weights and weight gain. At 4 d postpartum the viability index for all of the groups was >97%. One dam in the mid-dose group that did not deliver was found at necropsy to have a single nonviable fetus, which was wedged in the vaginal canal and left uterine horn. This dam had only one implant site.

No apparent test material-related microscopic changes were observed in the testes or epididymides of the male rats or in the ovaries of the female rats exposed to LAND. A sperm granuloma was observed in one epididymis of a high-dose rat. This single case was regarded as a non-specific finding in male rats and not related to LAND.
Dose descriptor:
NOAEL
Effect level:
>= 24 690 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed, even at highest dose group
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
At 4 d postpartum the viability index for all of the groups was >97%. One dam in the mid-dose group that did not deliver was found at necropsy to have a single nonviable fetus, which was wedged in the vaginal canal and left uterine horn. This dam had only one implant site.
Body weight and weight changes:
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Necropsies of the pups did not reveal any marked test material-related findings.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 24 690 mg/m³ air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed, even at highest dose group
Reproductive effects observed:
no
Conclusions:
Exposure to vapours of Light alkylate naphtha distillate (LAND) did not result in marked systemic, reproductive, or developmental toxicity with exposures approximating 25000 mg/m³. The no-adverse-observed-effect level for LAND is thus greater than 24690 mg/m³. Thus, it can be concluded that the hydrocarbons present typically below 10% in "2-propanol and 2-butanol production, distn. residues" will not negatively impact reproductive toxicity of the UVCB substance.
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
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
2,2'-oxydipropane (DIPE) is the most abundant component in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of 30% and above (<60%) by weight. Thus, this substance is one of those expected to have a major impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, present in the distillation residue.
Thus, in combination with other data on reproductive toxicity of identified components in “2-propanol and 2-butanol production, distn. residues” the reproductive toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical that was tested is an oxygenated hydrocarbon stream as used in gasolines and consists mainly of a baseline gasoline vapour condensate blended with di-isopropyl ether as oxygenated component (such components are used to improve octane numbers in gasolines). Some of the hydrocarbons C4-C8 in the baseline gasoline vapour condensate as well as the DIPE are components in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do contribute to the assessment of reproductive toxicity of the target substance following a weight of evidence approach based on components of the distillation residues. Additionally, as the final use of “2-propanol and 2-butanol production, distn. residues” is to become a component in fuels, the study performed by inhalation route of exposure provides a real life scenario of the products final use.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Di-isopropyl ether (DIPE) but also the hydrocarbons C4-C8 used in the study as carrier, as shown above, are important components in sum typically below 60% and thus using data from reproductive toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
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
Description (incidence and severity):
All test material exposure caused a statistically significant increase in male kidney weights in the 10,000 and 20,000 mg/m³ groups consistent with light hydrocarbon nephropathy (light hydrocarbons as carrier); increased liver weight in males exposed to G/DIPE. Increases in epididymal absolute weights at 10,000 and 20,000 mg/mymal absolute weights at 10,000 and 20,000 mg/m³ and seminal vesicles/coagulating gland absolute weight and relative to body and brain weights at 20,000 mg/m³ were present in G/DIPE males. None of these organ weight increases were accompanied by adverse histopathology findings. The minor differences to male organ weights in the G/DIPE studies did not occur in a dose-responsive manner and were interpreted as unlikely to be due to exposure or of toxicological (adverse) relevance.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Discolored (tan) foci was observed macroscopically in greater incidence in the lungs of adult females exposed to G/DIPE. This observation was not accompanied by changes in lung weight or histopathology.
Neuropathological findings:
not examined
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
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 as set to the highest does tested being 20.000 mg/m³. Thus, the addition of di-isopropylether in significant amounts had no impact on reproductive toxicity of oxygenated fuels.
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) and thus it can be concluded that the absence of reproductive toxicity is also attributable to di-secondary butyl ether (DSBE) the second major component in "2-propanol and 2-butanol production, distillation residues".

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
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
2-methylpropan-2-ol (tertiary butyl alcohol, TBA) is the most abundant alcoholic component in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of ~10 - 15% (<20%) by weight. Thus, this substance is one of those expected to have a major impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, present in the distillation residue.
Thus, in combination with other data on reproductive toxicity of identified components in “2-propanol and 2-butanol production, distn. residues” the reproductive toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical that was tested is an oxygenated hydrocarbon stream as used in gasolines and consists mainly of a baseline gasoline vapour condensate blended with TBA as oxygenated component (such components are used to improve octane numbers in gasolines). TBA is also an important component in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results of the source study do contribute to the assessment of reproductive toxicity of the target substance following a weight of evidence approach based on components of the distillation residues. Additionally, as the final use of “2-propanol and 2-butanol production, distn. residues” is to become a component in fuels, the study performed by inhalation route of exposure provides a real life scenario of the products final use.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Tertiary butyl alcohol (TBA) but also the hydrocarbons C4-C8 used in the study as carrier, as shown above, are important components in sum typically below 30% and thus using data from reproductive toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
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
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 G/TBA. The lactation weight gain of G/TBA dams of 19 g was significantly higher than the concurrent control of 5 g and the highest concurrent control value range of 13 g in P0 dams. Neither of these weight gain changes during lactation was considered biologically significant. Among males, decreased body weight changes was seen in parental animals in the G/TBA study.
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
Description (incidence and severity):
All test material exposure caused a statistically significant increase in male kidney weights in the 10,000 and 20,000 mg/m³ groups consistent with light hydrocarbon nephropathy (light hydrocarbons as carrier); Statistically significantly decreased spleen weights were seen in G/TBA male rats at the mid and high dose and in females at all dose levels.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Discolored (tan) foci were observed macroscopically in greater incidence in the lungs of adult animals, significantly in G/TBA both sexes. These observations were not accompanied by changes in lung weight or histopathology.
Neuropathological findings:
not examined
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. A slight non-significant lengthening in the number of days of pairing until mating occurred in animals exposed to 20,000 mg/m³ G/TBA, due to 7 of 23 pairs that failed to mate during the first or second estrus opportunity. However, there were no differences in acyclics, persistent estrus or irregular cycles and the lengthening did not translate to observed effects on endpoints of reproductive performance.
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 NOAEC
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 NOAEC
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Postnatal growth of pups was transiently reduced by exposure to G/TBA. In offspring of females exposed to G/TBA there was a slight but statistically significant decrease in pup weight gains early in lactation up to LD14 but weights were comparable to controls by LD21 and postnatal day 28.
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:
effects observed, treatment-related
Description (incidence and severity):
Reduced spleen weights in both sexes from the G/TBA exposed group were observed at 20000 mg/m³. Spleen weights were also reduced in the G/TBA parental rats.
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
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
10 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
Critical effects observed:
yes
Lowest effective dose / conc.:
20 000 other: mg/m³
System:
immune system
Organ:
spleen
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Reproductive effects observed:
no
Conclusions:
In this one generation reproductive toxicity study with a gasoline blend supplemented by 16.5% TBA (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 dose tested being 20.000 mg/m³. Thus, the addition of TBA (2-methylpropan-2-ol) in significant amounts had no impact on reproductive toxicity of oxygenated fuels.
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 2 -methylpropan-2 -ol (TBA) ether did not impact reproductive toxicity in this one-generation reproductive toxicity study. Similar finding were made with another alcohol (ethanol) used in the same study setup and thus it can be concluded that the absence of reproductive toxicity is also attributable to secondary butylalcohol (SBA) and isopropyl alcohol (IPA) the minor alcoholic components in "2-propanol and 2-butanol production, distillation residues".

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

The reference substance “2-propanol and 2-butanol production, distillation residues” consists of the following components:

Group

Component(s)

Conc.

Typical conc.

C3 ether

mainly 2,2'-oxydipropane (DIPE)
and minor 2-propoxypropane

5 – 70%

~30% w/w

C4 ether

 2,2'-oxybisbutane (DSBE)

5 – 50%

~30% w/w

C4 alcohols

mainly 2-methylpropan-2-ol (TBA)
and some butan-2-ol (SBA)

0 – 35%

~24% w/w

C3 alkohol

propan-2-ol (IPA)

0 – 20%

<10% w/w

C6 alkane

2-methylpentane and 3-methylpentane

0 – 15%

<10% w/w

C6 alkene

2,3-dimethylbut-1-ene,
4-methylpent-2-ene,
2-methylpent-1-ene,
2-methylpent-2-ene,
4-methylpent-1-ene,
(2Z)-3-methylpent-2-ene,
(E)-3-methylpent-2-ene

0 – 15%

<10% w/w

C8 alkene

2-hexene, 3,4-dimethyl-

0 – 5%

<1% w/w

 

The “2-propanol and 2-butanol production, distillation residues” do result from collection of various distillation streams resulting from manufacturing sites for 2-propanol and 2-butanol that can be described as follows:

During the synthesis of isopropanol and secondary butanol from the corresponding olefins and water side reactions like etherification, dimerization and isomerisation occur.

A major by-product in the isopropanol synthesis from propylene and water is di-isopropyl ether, which is formed by dehydration of two isopropanol or from the reaction of propylene and isopropanol. Other by products are formed by dimerization of propylene to 2-methyl pentene and isomerisation of 2-methyl pentene to other hexane or hexane isomers. Further side reactions to form hexanols and higher olefins take place in a very small range.

Analogue to this di-secondary-butyl ether, octane and octane isomers, octanols and higher olefins result as by-products of secondary butanol synthesis from butylene and water.

After separation of isopropanol or secondary butanol, respectively, the by-product streams remain as a combination of ethers, olefins and alcohols in various distillation residues derived during synthesis and purification of 2-propanol (IPA) and 2-butanol (SBA) and do become combined in one central tank on-site for further use. In total, three different production lines, all belonging to the same legal entity, collect their distillation residues in this tank and each production line typically includes three to five individual distillation steps, some connected to buffer tanks for safety reasons. As a result, the composition in this central tank is subject to variation, e.g. in case one production line is in buffer mode or not producing, which explains the concentration range of individual components.

Rather than disposing of such residues by incineration, due to their high content of oxygenated components they can be used as components in gasolines as it is known that oxygenated solvents do increase octane numbers in gasoline. Therefore, the “2-propanol and 2-butanol production, distillation residues” are to be supplied to the gasoline manufacturing industry as blending components for their gasoline production, thus substituting primary fuel sources in line with the circular economy concept of the EU.

Such blends of gasoline with oxygenated solvents have been assessed for their reproductive toxicity in various studies and some of the main components were subject to these investigations.

In a publication by Gray et. al (2014) a hydrocarbon stream (Baseline Gasoline Vapour Condensate (BGVC)) and combinations thereof with various alcohols and ethers, amongst them di-isopropyl ether (DIPE) and tertiary butanol (TBA), were assessed in one- and two generation reproductive toxicity studies by inhalation exposure. None of the ethers or alcohols used as supplements to the baseline gasoline vapour condensate (BGVC, as prescribed by the US EPA for use), including DIPE and TBA being main components in "2-propanol and 2-butanol production, distillation residues" had significant impact on fertility and reproductive toxicity and the baseline gasoline vapour condensate itself, containing amongst others also C6 and C8 alkanes and alkenes as the “2-propanol and 2-butanol production, distillation residues”, did not have negative effects on fertility or developmental toxicity either.

As a result, it is concluded that "2-propanol and 2-butanol production, distillation residues" will not impact fertility. The testing of alcohols and ethers in combination with baseline gasoline vapour condensates very well reflects the sole use of the target substance, becoming a supplement in gasolines to improve octane value therein, and inhalation exposure to simulate exposure during refuelling of cars is the appropriate route of exposure. It is noteworthy that also other ethers such as methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), and ethanol

(G/EtOH) have been assessed and none of them did impact fertility or showed other reproductive effects.

Effects on developmental toxicity

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well conducted and reported study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Isopropyl alcohol (IPA, propan-2-ol) is one of the main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <20% by weight. Thus, this substance is one of those expected to have a significant impact on systemic toxicity based on its amount in the distillation residues but also based on absorption rate, being considered higher for alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical Isopropyl alcohol (IPA) is one of the main components (beside di sec-butyl ether, di-isopropyl ether, tert. butanol and sec. butanol) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Isopropyl alcohol (IPA), as shown above, is one of the three alcohol components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Moreover, this study performed with rabbits rather than with rats (see other studies used in the weight of evidence approach) allows insight into developmental effects of alcohols present in the substance towards a second species.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
At 240 and 120 mg/kg/day, the only findings were transient, relatively mild and nonspecific clinical signs of toxicity. At 480 mg/kg bw/d relatively severe clinical signs of toxicity.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Profound maternal toxicity at 480 mg/kg/day, expressed as 26.7% mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Profound maternal toxicity at 480 mg/kg/day, expressed as 26.7% mortality, reduced body weight gain during the treatment period and for the gestational period corrected for the contribution of the gravid uterus, reduced food consumption during the treatment period and relatively severe clinical signs of toxicity.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Profound maternal toxicity at 480 mg/kg/day, expressed as 26.7% mortality, reduced body weight gain during the treatment period and for the gestational period corrected for the contribution of the gravid uterus, reduced food consumption during the treatment period and relatively severe clinical signs of toxicity.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day
Based on:
test mat.
Remarks:
IPA
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No gross abnormalities were observed.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Description (incidence and severity):
There were no effects related to IPA exposure in postimplantation loss, mean number of implantation sites or live fetuses.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: There was no demonstrable developmental toxicity at a dose resulting in significant maternal toxicity (480 mg/kg/day) or at doses with only relatively mild and transient clinical signs of toxicity (240 and 120 mg/kg/day).
Dose descriptor:
NOAEL
Effect level:
480 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no developmental effects observed
Remarks on result:
other:
Remarks:
480 mg/kg bw/d was the high dose group in this study with severe maternal toxicity effects.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
In a teratogenicity study with propan-2-ol applied via gavage to rabbits no fetal toxicity was observed at the high dose group of 480 mg/kg bw/d which was set as the NOAEL for developmental toxicity in this study.
At the high dose group significant maternal toxicity occured (26.7% mortality). No teratogenic effects were seen. Results on IPA, being one of the main components of 2-propanol and 2-butanol production, distn. residues, are important for the assessment on this UVCB substance and this study with rabbits provides insight on teratogenic effects via a second species (rabbits rather than rats).
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Di-isopropyl ether is one of the two main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of 30% by weight and above. Thus, this substance is one of those expected to have a high impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, being considered higher for ethers and alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical di-isopropyl ether is one of the two main components (beside di sec-butyl ether) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Di-isopropyl ether (DIPE), as shown above, is one of the two main components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
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.
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In general, animals housed in chambers consumed less food during the exposure period than the untreated controls (statistically significant at 6745 ppm relative to both of the control groups). 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).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment-related effects were noted at the time of macroscopic examination.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
Reproductive parameters (i.e., number of pregnant females, percent preimplantation loss, percent resorptions, and litter sizes) were not affected by exposure.
Dose descriptor:
NOAEC
Basis for effect level:
other: maternal toxicity
Remarks on result:
other: maternal toxicity
Remarks:
no NOAEC identified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
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. 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.
Visceral malformations:
not specified
Other effects:
not specified
Dose descriptor:
NOAEC
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Developmental effects observed:
yes
Lowest effective dose / conc.:
3 095 ppm
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
no
Conclusions:
No developmental effects in the absence of maternal toxicity were observed. The NOEC in this study for maternal effects as well as developmental effects can be set to 430 ppm, nad effects seen at higher doses were considered non-adverse by the study authors.
Executive summary:

A NOAEC was not reported by the study authors. Review of the study data suggests that a NOEC 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 NOEC 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:
weight of evidence
Study period:
1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Well conducted and reported study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Isopropyl alcohol (IPA, propan-2-ol) is one of the main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <20% by weight. Thus, this substance is one of those expected to have a significant impact on systemic toxicity based on its amount in the distillation residues but also based on absorption rate, being considered higher for alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical Isopropyl alcohol (IPA) is one of the main components (beside di sec-butyl ether, di-isopropyl ether, tert. butanol and sec. butanol) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Isopropyl alcohol (IPA), as shown above, is one of the three alcohol components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Despite mortality (2 females (8%) died in the 1200 mg/kg bw/day group and one female (4%) died in the 800 mg/kg bw/day group) there were no treatment related clinical signs apparent in maternal animals exposed to isopropyl alcohol.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
Two females (8%) died in the 1200 mg/kg bw/day group and one female (4%) died in the 800 mg/kg bw/day group.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Maternal body weights were equivalent across all groups and for all timepoints. The statistically reduced maternal weight gain (Gestational Days 0 - 20) in the 1,200 mg/kg bw/day group was likely due to significantly reduced gravid uterine weights.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Maternal food consumption was statistically equivalent across all groups for all intervals evaluated although a significant downward trend for Gestational Days 6 - 9 and 6 - 15 (treatment period) with no significant pairwise comparisons was evident.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Description (incidence and severity):
No pregnant surviving female aborted, delivered early or was removed from study.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Remarks:
IPA
Basis for effect level:
clinical signs
mortality
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No gross abnormalities were observed.
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: No effects

Details on embryotoxic / teratogenic effects:
A total of 22 - 25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Remarks:
IPA
Sex:
male/female
Basis for effect level:
changes in litter size and weights
other: no developmental effects observed
Abnormalities:
not specified
Developmental effects observed:
no
Conclusions:
In a teratogenicity study with propan-2-ol applied via gavage to rats during major organogenesis resulted in maternal and developmental toxicity at 800 and 1,200 mg/kg bw/day, with no indication of teratogenicity at any dose tested. The "no observable adverse effect level" (NOAEL) for maternal and developmental toxicity of isopropanol in rats is therefore 400 mg/kg bw/day under the conditions of this study.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Well conducted and reported study in the peer-reviewed literature
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Isopropyl alcohol (IPA, propan-2-ol) is one of the main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <20% by weight. Thus, this substance is one of those expected to have a significant impact on systemic toxicity based on its amount in the distillation residues but also based on absorption rate, being considered higher for alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical Isopropyl alcohol (IPA) is one of the main components (beside di sec-butyl ether, di-isopropyl ether, tert. butanol and sec. butanol) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Isopropyl alcohol (IPA), as shown above, is one of the three alcohol components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
All animals given 1.25% or 2.5% IPA showed reduced feed and water consumption. Administration of 2.5% IPA in drinking water resulted in an immediate reduction in water intake, and this was statistically significant throughout the treatment period. A statistically significant increase occurred on the first day (GD 16 – 17) following the end of treatment for all dose levels. Although the mid-dose group also showed a similar but less marked reduction in water intake, the values were only statistically significant during GD 6 – 9. Except for a slight decrease on the first day of treatment, water consumption in the low-dose group was similar to the control group values. Feed consumption patterns paralleled the water consumption during and after treatment in the mid and high-dose groups.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality was observed in the main study on pregnant rats.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
From GD 6 – 8, those animals consuming 2.5% IPA in the drinking water lost weight; for the remainder of the treatment period, those animals gained weight at a lower rate than the control group. After cessation of treatment (GD 17 – 20), weight gain was greater in the group consuming 2.5% IPA in the drinking water than the control group value. Overall, mean body weights of animals in the 2.5% IPA group were lower than the control group from GD 7 to termination.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
All animals given 1.25% or 2.5% IPA showed reduced feed and water consumption. Administration of 2.5% IPA in drinking water resulted in an immediate reduction in water intake, and this was statistically significant throughout the treatment period. A statistically significant increase occurred on the first day (GD 16 – 17) following the end of treatment for all dose levels. Although the mid-dose group also showed a similar but less marked reduction in water intake, the values were only statistically significant during GD 6 – 9. Except for a slight decrease on the first day of treatment, water consumption in the low-dose group was similar to the control group values. Feed consumption patterns paralleled the water consumption during and after treatment in the mid and high-dose groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
All animals given 1.25% or 2.5% IPA showed reduced feed and water consumption. Administration of 2.5% IPA in drinking water resulted in an immediate reduction in water intake, and this was statistically significant throughout the treatment period. A statistically significant increase occurred on the first day (GD 16 – 17) following the end of treatment for all dose levels. Although the mid-dose group also showed a similar but less marked reduction in water intake, the values were only statistically significant during GD 6 – 9. Except for a slight decrease on the first day of treatment, water consumption in the low-dose group was similar to the control group values. Feed consumption patterns paralleled the water consumption during and after treatment in the mid and high-dose groups.
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
596 mg/kg bw/day
Based on:
test mat.
Remarks:
IPA
Basis for effect level:
food consumption and compound intake
water consumption and compound intake
Remarks on result:
other: Authors did not report a NOAEL, but based on findings low dose group (596 mg/kg bw/d) was identified as NOAEL
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significant findings included a slight dose-dependent decrease in mean litter weight and a statistically significant decrease in mean fetal weight in groups consuming 1.25% and 2.5% IPA in the drinking water.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Significant findings included a slight dose-dependent decrease in mean litter weight and a statistically significant decrease in mean fetal weight in groups consuming 1.25% and 2.5% IPA in the drinking water.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No gross abnormalities were observed. The only major skeletal changes were an absence of caudal vertebrae and short forelimb and hindlimb bones in a single control fetus.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
A statistically significant increase in variations was indicative of a lower degree of ossification in the treated animals. There was a dose-dependent decrease in the number of fetuses with the 4th sacral arch and a dose-dependent increase in the number of fetuses with less than 2 caudal arches. The sternum also showed reduced ossification because there were increased numbers of fetuses with small, absent, or incompletely ossified sternebrae. A reduction in ossification of bones of the skull was only observed in the 0.5% IPA group, and there were more fetuses in the mid-dose group with forelimb proximal phalanges, less than 3 metacarpals or unilateral sternebrae. In both the low and mid-dose group, there were increased numbers of fetuses with dumbbell shaped sternebrae or 14 pairs of ribs.
Visceral malformations:
no effects observed
Other effects:
not specified
Description (incidence and severity):
There were no effects related to IPA exposure in postimplantation loss, mean number of implantation sites or live fetuses.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: There were no effects related to IPA exposure in postimplantation loss, mean number of implantation sites or live fetuses.
Dose descriptor:
NOAEL
Effect level:
596 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
In a teratogenicity study with propan-2-ol applied via drinking water fetal toxicity was only observed at high doses showing also maternal toxicity and thus no teratogenic effects could become clearly attributed. Results on IPA, being one of the main components of 2-propanol and 2-butanol production, distn. residues are important for the assessment on this UVCB substance.
Executive summary:

The authors of this publication did not identify a NOAEL for developmental toxicity following exposure to IPA from drinking water. Based on a review of this drinking water study, both maternal and fetal NOAELs are proposed being 596 mg/kg bw/d (0.5% in drinking water), whereas effects at higher doses (1.25% and 2.5% in drinking water) were mainly driven by reduced water and food intake and unspecific. There were no effects related to IPA exposure in post-implantation loss, mean number of implantation sites or live fetuses. Significant findings included a slight dose-dependent decrease in mean litter weight and a statistically significant decrease in mean fetal weight in groups consuming 1.25% and 2.5% IPA in the drinking water.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The target substance “2-propanol and 2-butanol production, distn. residues” consists of ethers, alcohols and hydrocarbons (aliphatic and olefinic) derived as residues form various distillation processes during production of 2-propanol and 2-butanol. The distillation residues are collected from different distillation columns from one 2-butanol and two 2-propanol production facilities belonging to one legal entity and are combined in one tank for use as fuel supplement in an external facility. As it is known that oxygenated components as present in “2-propanol and 2-butanol production, distn. residues” have an additive effect in octane number improvement of motor fuels, this “waste” from 2-propanol and 2-butanol production can be used as recyclable fraction within the motor fuel industry due to its content of alcohols and ethers, known to improve the properties of fuels.
Oxygenated motor fuels have been subject to toxicological investigations to assess their impact on health upon exposure during fuelling of passenger cars and have shown not to contribute to health risks of motor fuels.
To that extent, gasoline blends, agreed upon with the US EPA as model compounds/mixtures have been assessed for toxicological properties in rather intense toxicological assessments and studies and upon proposal of the US EPA beside baseline gasoline also highly supplemented oxygenated fuels have been artificially created to assess the impact of addition of ethers and alcohols to gasoline, amongst others tertiary butyl alcohol (TBA) and di-isopropylether (DIPE). In these artificial blends TBA and DIPE were deliberately dosed extremely high to vapour concentrations of 17.8 vol% for DIPE and 16.5 vol% for TBA, respectively.
Besides hydrocarbons present in the target compound “2-propanol and 2-butanol production, distn. residues”, also found in the baseline gasoline vapour condensate (BGVC) used as fuel surrogate in the studies, also DIPE is the most abundant ether in the target compound and TBA the most abundant alcohol.
Thus, the studies used as sources here do represent all component groups of the target compound (ethers, alcohols and hydrocarbons, aliphatic and olefinic), consisting of typical C3 and C4 units and their combinations, and hence are representative for the toxicity of the target compounds. Additionally, the route of exposure by inhalation does reflect the most likely route of exposure of the target substance, given that the use as fuel additive is the only used relevant for the target substance.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source studies do consist of a study on BGVC (a blend of aliphatic and olefinic hydrocarbons in the range of C4 to C8 mainly - compare to the C6 and C8 hydrocarbons, aliphatic and olefinic, in the target compound at 10 – 15%), a study on BGVC blended with 17.8 vol% DIPE (G/DIPE) which is also the most abundant ether in the target compound (present at approx. 30%), as well as a study on BGVC blended with 16.5 vol% TBA (G/TBA), the major alcoholic component in the target substance present at approx. 12 – 15 % therein, all investigating developmental toxicity of these streams towards rats by exposure via inhalation at doses up to 20’000 mg/m3 air, which is several magnitudes above the potential exposure of a person refuelling his car. Thus, the three source studies do represent in total 50 – 60% of target compounds components and remaining components in the target compound are di-secondary butyl ether (DSBE), structurally very similar to DIPE, secondary butanol (SBA), structurally very similar to TBA and traces of isopropyl alcohol (IPA), also very similar to TBA.
Thus, the source studies do provide direct information on the majority of components present in the target compound and surrogate information on developmental toxicity of the remaining components. Noteworthy to mention is that not only DIPE and TBA were assessed in the studies in combination with BGVC but also other alcohols (ethanol, ETOH) and other ethers (methyl-t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME)), not explicitly recorded as source robust study summaries, but all with similar observations shown to be non-teratogenic. The findings in details are mentioned in the source robust study summaries in tables of findings).
The purity and composition of BGVC as well as of the oxygenated blends investigated are tracked in the source robust study summaries, reflecting the composition as analytically determined in the atmosphere to which test animals were exposed too.
Additionally, as the final use of “2-propanol and 2-butanol production, distn. residues” is to become a component in fuels, the study performed by inhalation route of exposure provides a real-life scenario of the products final use.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach the individual main components of “2-propanol and 2-butanol production, distn. residues” are assessed individually to draw up a picture of the developmental toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2 - 5% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Di-isopropyl ether (DIPE) and tertiary butyl alcohol (TBA) but also the hydrocarbons C4-C8 used in the study as carrier but also as such, as shown above, are the most important components in the target substance of their respective groups (ethers, alcohols and hydrocarbons) in sum typically ~60% and thus using data from developmental toxicity studies on these individual components in a weight of evidence approach provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No significant clinical signs were observed during any of the studies on BGVC, G/DIPE and G/TBA. Low incidences of alopecia were seen in the abdominal areas and limbs among treated and control animals in each study. Red nasal discharge and chromodacryorrhea were observed at higher doses in various animals in all studies and were considered a common reaction to inhalation exposure and mild stress in rats.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All females survived to study termination.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Exposure to BGVC resulted in no effects.
In the G/DIPE study, transient reduction in maternal weight gain during the early days of the exposure period at 20,000 mg/m³ was partially resolved by GD 21.
Maternal toxicity was reflected in decreased body weight (G/TBA), decreased body weight gain (usually during the first days of exposure), and/or decreased food consumption at 20,000 mg/m³ in all studies and also at 10,000 mg/m³ for G/TBA.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Exposure to BGVC resulted in no effects.
Reduction in food consumption, although statistically significant intermittently, did not exceed 10% during the exposure period to G/DIPE.
Decreased food consumption at 20,000 mg/m³ in all studies and also at 10,000 mg/m³ for G/TBA was observed. In the G/TBA study, maternal toxicity during the first half (GD 5–14) of the exposure period was seen in decreased food consumption in the 10,000 and 20,000 mg/m³ groups and reduced weight gain and maternal body weights throughout gestation at the 10,000 and 20,000 mg/m³ exposure levels.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Exposure to BGVC resulted in no effects.
A decrease in uterine weight to 96% of concurrent control value upon exposure to G/DIPE was not statistically significant but likely contributed to the decrease in the overall GD 5–21 body weight interval at 20,000 mg/m³.
The gravid uterine weight at 20,000 mg/m³ upon exposure to G/TBA was statistically significantly lower than the concurrent control. However the lower gravid uterine weight may have been due to the non-significant reduction in average litter size performance for G/TBA animals.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Number of abortions:
no effects observed
Description (incidence and severity):
Implantation sites, resorptions, mean litter size, fetal number of viable fetuses and fetuses per litter were comparable to concurrent controls in each study.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implantation sites, resorptions, mean litter size, fetal number of viable fetuses and fetuses per litter were comparable to concurrent controls in each study.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Implantation sites, resorptions, mean litter size, fetal number of viable fetuses and fetuses per litter were comparable to concurrent controls in each study.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The number of pregnant animals was similar in all studies. Only one female was non-pregnant in the G/DIPE group which was not considered test material significant in the 20,000 mg/m³ group as other groups contained one or more non-pregnant animal each.
Other effects:
no effects observed
Description (incidence and severity):
No treatment related statistically significant differences between test material treated groups and concurrent controls were seen for uterine data
Details on maternal toxic effects:
Maternal NOAELs were based primarily on reduced body weight, body weight changes and food consumption, most of which occurred in the GD 5 – 8, GD 8 – 11, and/or GD 11 – 14 intervals which sometimes carried through the entire exposure period and were reflected in the GD 5 – 21 body weight interval and/or the GD 5 – 20 food consumption interval. These effects were relatively mild (in exposure to BGVC, G/MTBE, G/TAME, G/ETBE, G/DIPE, and G/ETOH), resulting in significant differences in maternal body weight only for G/TBA, for which the decrements were less than 10% from control values.
Dose descriptor:
NOAEC
Effect level:
2 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Basis for effect level:
body weight and weight gain
Abnormalities:
effects observed, treatment-related
Localisation:
other: reduced body weight and weight gain
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean combined fetal weights of all BGVC – exposed groups were decreased relative to concurrent controls. However, this difference was considered to be a spurious finding because fetal weights in all of the BGVC exposure groups were within the laboratory control group range of 5.3 – 5.48 g for the other studies in the test program, no dose-response occurred, and the mean litter size in this control group (15.0) was smaller than the litter sizes for the exposed groups [15.5, 15.6, 16.2 in 2000, 10,000 and 20,000 mg/m³ groups, respectively]. Fetal body weight in G/DIPE 20,000 mg/m³ litters was statistically significantly lower for females (5%) and combined sexes (3.3%) compared to concurrent controls. Exposure to G/TBA resulted in 3% decreases in fetal body weight at 20,000 mg/m³. In the G/TBA study fetal body weight did not differ between groups when analysed with litter size or litter size and fetal sex as covariates but showed statistically significant reduction at 20,000 mg/m³ when mean corpora lutea count was added as a covariate. Thus, it is not clear whether exposure to G/TBA at 20,000 mg/m³ is directly linked to decreased fetal body weight.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No significant increases in fetal external variations were seen in any study. Random occurrences of malrotated paw, cleft palate, kinked tail, exencephaly and exophthalmos were reported at various dose levels.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Exposure did not induce skeletal malformations. No skeletal malformations were reported in any study with the exception of 1 fetus/1 litter at 20,000 mg/m³ G/DIPE with a vertebral anomaly in which the right exoccipital and cervical arch #1 were fused, and the thoracic centra #13 and lumbar centrum #1 were absent. G/TBA 20,000 mg/m³ litters showed a statistically significant increase in skeletal variations on a per fetus basis primarily due to increased rudimentary ribs (16/24 litters, 67% compared to control 12/25 litters, 48%).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Few visceral variations or malformations occurred in any study. Reported incidental findings included retinal folds, hydroureter, hydronephrosis, hydrocephaly, and umbilical artery on left side of bladder. None were attributed to the test article exposures.
Details on embryotoxic / teratogenic effects:
NOAECs of 10,000 mg/m³ for G/TAME, G/DIPE and G/TBA were based on reduced fetal body weights and thus rather unspecific correlated with maternal effects. BGVC and other ethers and alcohols had NOAECs of 20,000 mg/m³.
Dose descriptor:
NOAEC
Effect level:
10 000 mg/m³ air (nominal)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: rib
Description (incidence and severity):
only slightly signifcant upon exposure to TBA, not upon exposure to ethanol; no corresponding effects seen in exposure to ethers or BGVC.
Developmental effects observed:
yes
Lowest effective dose / conc.:
20 000 mg/m³ air (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
not specified

Incidence of total skeletal variations in litter of rats exposed from GD 5 to 20 to vapour condensates of gasoline or gasoline/oxygenate blends.

Exposure level

Litters with fetal skeletal variations

 

BGVC

G/MTBE

G/TAME

G/ETBE

G/DIPE

G/ETOH

G/TBA

20,000 mg/m³

 

 

 

 

 

 

 

Litters affecteda

14/24

14/24

16/24

18/24

12/22

15/24

20/24c

% Affectedb

58.3

66.7

66.7

75

54.5

62.5

83.3

10,000

mg/m³

 

 

 

 

 

 

Litters affecteda

11/24

15/24

16/24

18/24

14/24

21/24c

13/23

% Affectedb

45.8

62.5

66.7

75

58.3

87.5

56.5

2000 mg/m³

 

 

 

 

 

 

 

Litters affecteda

16/24

16/24

16/23

16/23

8/23

12/22

13/23

% Affectedb

66.7

66.7

69.6

69.6

34.8

54.5

56.5

Control

 

 

 

 

 

 

 

Litters affecteda

12/24

13/24

19/25

17/25

13/23

15/25

15/25

% Affectedb

50

54.2

76

70.8

56.5

60

60

aLitters affected = litters with affected fetuses/total litters.

b% Affected = affected litters/total litter.

cStatistically significant at p < 0.05 on a per fetus basis.

 

Developmental toxicity: reproduction and fetal data of rats exposed from GD 5 – 20 to gasoline or gasoline/oxygenate vapour condensates at 20,000 mg/m³

 

BGVCa

G/MTBEa

G/TAMEa

G/ETBEa

G/DIPEa,b

G/EtOHa

G/TBAa

No. of females mated

25 (25)

25 (25)

25 (25)

25 (25)

24 (24)

25 (25)

25 (25)

No. of pregnant females

24 (24)

24 (24)

24c(25)

24 (25)

22 (23)

24 (25)

24 (25)

No. pregnancies aborted

0

0

0

0

0

0

0

No. early deliveries

0

0

1c

0

0

0

0

No. litters with viable foetuses

24 (24)

24 (24)

25 (25)

24 (25)

22 (23)

24 (25)

24 (25)

Corpora lutea

17.6 ± 2.6

16.7 ± 3.2

16.3 ± 1.8

15.1 ± 2.2

15.2 ± 2.6

16.1 ± 2.4

15.1 ± 2.7e

 

(16.4 ± 3.4)

(16.0 ± 1.9)

(16.0 ± 3.2)

(15.9 ± 1.5)

(14.9 ± 2.8)

(16.4 ± 3.0)

(16.3 ± 2.0)

Implantation sites

16.7 ± 1.8

15.6 ± 2.2

15.9 ± 1.8

14.6 ± 2.3

14.0 ± 2.4

15.5 ± 3.3

14.7 ± 2.1

 

(15.5 ± 3.2)

(15.5 ± 1.8)

(15.7 ± 3.1)

(14.6 ± 3.0)

(13.5 ± 2.7)

(15.9 ± 2.9)

(15.7 ± 1.8)

Preimplantation loss – %

4.6 ± 6.9

5.1 ± 10.5

2.2 ± 3.9

3.2 ± 4.4

7.6 ± 9.1

4.6 ± 15.8

2.3 ± 4.1

 

(5.1 ± 12.6)

(3.0 ± 3.9)

(1.6 ± 2.7)

(7.9 ± 17.7)

(9.3 ± 13.5)

(3.0 ± 3.9)

(3.7 ± 5.3)

Resorptions mean ±SD

0.42 ± 0.72

0.33 ± 0.56

0.67 ± 1.13

0.33 ± 0.48

0.7 ± 0.6

0.29 ± 0.46

0.29 ± 0.55

 

(0.58 ± 0.83)

(0.63 ± 0.77)

(0.72 ± 0.84)

(0.4 ± 0.58)

(0.5 ± 0.7)

(0.32 ± 0.56)

(0.28 ± 0.6)

Number of viable foetuses

390 (359)

366 (358)

366 (374)

342 (353)

292 (300)

365 (389)

345 (385)

Mean litter size

16.2 ± 1.8

15.2 ± 2.1

15.2 ± 2.1

14.2 ± 2.3

13.3 ± 2.6

15.2 ± 3.3

14.4 ± 2.1

 

(15.0 ± 3.1)

(14.9 ± 2.2)

(15.0 ± 3.1)

(14.1 ± 3.1)

(13.0 ± 2.6)

(15.6 ± 2.9)

(15.4 ± 1.8)

Mean number of fetuses/litter

 

 

 

 

 

 

 

Males ±SD

8.6 ± 1.6

7.0 ± 2.6

7.4 ± 2.6

7.1 ± 2.1

6.1 ± 2.1

7.3 ± 3.1

6.4 ± 1.5

 

(7.5 ± 2.9)

(7.2 ± 2.6)

(7.4 ± 2.5)

(6.9 ± 2.4)

(6.3 ± 1.7)

(7.9 ± 2.6)

(7.8 ± 2.1)

Females ±SD

7.7 ± 2.3

8.3 ± 2.6

7.8 ± 2.3

7.1 ± 2.1

7.1 ± 2.5

7.9 ± 2.9

8.0 ± 2.1

 

(7.4 ± 2.6)

(7.8 ± 2.3)

(7.6 ± 2.4)

(7.2 ± 2.2)

(6.7 ± 2.0)

(7.6 ± 2.4)

(7.5 ± 2.2)

Fetuses/implantation

0.98 ± 0.04

0.98 ± 0.04

0.96 ± 0.07

0.98 ± 0.03

0.95 ± 0.06

0.98 ± 0.03

0.98 ± 0.04

 

(0.97 ± 0.05)

(0.96 ± 0.05)

(0.95 ± 0.07)

(0.95 ± 0.1)

(0.96 ± 0.1)

(0.98 ± 0.04)

(0.98 ± 0.04)

Resorptions/implantation

0.02 ± 0.04

0.02 ± 0.04

0.04 ± 0.07

0.02 ± 0.03

0.05 ± 0.03

0.02 ± 0.03

0.02 ± 0.04

 

(0.04 ± 0.05)

(0.04 ± 0.05)

(0.05 ± 0.07)

(0.04 ± 0.1)

(0.04 ± 0.05)

(0.02 ± 0.03)

(0.02 ± 0.04)

Postimplantation loss – %

2.5 ± 4.1

2.1 ± 3.6

4.2 ± 7.0

2.5 ± 3.3

5.2 ± 5.2

2.1 ± 3.0

2.3 ± 3.8

 

(3.3 ± 5.4)

(4.2 ± 5.4)

(5.1 ± 6.7)

(4.6 ± 10.2)

(3.4 ± 4.7)

(2.0 ± 3.4)

(1.9 ± 3.8)

Fetal deaths mean ±SD

0

0

0

0.04 ± 0.2

0

0.04 ± 0.2

0

 

 

 

 

(0.04 ± 0.2)

 

(0)

(0.04 ± 0.2)

Mean body weight ±SD

 

 

 

 

 

 

 

Male foetuses

5.5 ± 0.4

5.6 ± 0.5

5.2 ± 0.5

5.4 ± 0.5

5.7 ± 0.3

5.5 ± 0.4

5.3 ± 0.5

 

(5.8 ± 0.4)

(5.5 ± 0.4)

(5.4 ± 0.3)

(5.5 ± 0.4)

(5.9 ± 0.3)

(5.6 ± 0.4)

(5.4 ± 0.4)

Female foetuses

5.2 ± 0.4

5.3 ± 0.4

5.0 ± 0.5

5.1 ± 0.4

5.4 ± 0.3c

5.2 ± 0.4

5.0 ± 0.3

 

(5.5 ± 0.3)

(5.2 ± 0.4)

(5.2 ± 0.4)

(5.2 ± 0.4)

(5.6 ± 0.3)

(5.4 ± 0.3)

(5.2 ± 0.4)

Combined weightsf

5.36d,g(5.62)

5.42 (5.38)

5.10d(5.31)

5.25 (5.33)

5.54d(5.71)

5.37 (5.48)

5.16 (5.32)

Preimplantation loss = (corpora lutea minus implants)/corpora lutea.

Postimplantation loss = (implants minus live fetuses)/implants.

aConcurrent study control value for each endpoint in parenthesis.

bStudy performed at Huntingdon Life Sciences; 24 presumed pregnant animals at study initiation.

cG/TAME early delivery GD20, not included in calculations.

dstatistically significantly lower compared to concurrent controls at p < 0.01].

estatistically significantly lower compared to concurrent controls at p < 0.05.

fCombined fetal body weight is least squares mean fetal weight adjusted for litter size in individual studies.

gBGVC all dose levels showed similar changes from controls and effect was not considered biologically significant.

Body weights and weight changes in pregnant rats exposed to vapour condensates of gasoline or gasoline/oxygenate blends at 20,000 mg/m³.

Gestation days (GD)

BGVCaNh=24

G/MTBEaNh=24

G/TAMEaNh= 25

G/ETBEaNh= 24

G/DIPEaNh= 22

G/EtOHaNh= 24

G/TBAaNh= 23

Group mean maternal body weights (grams ±std. deviation)b

GD 0

272.8 ± 16.5

266.5 ± 14.8

270.3 ± 14.8

269.9 ± 13.7

NDf

265.2 ± 13.4

260.4 ± 14.3

 

(273.3 ± 17)

(265.9 ± 13)

(269.7 ± 17.1)

(270 ± 14.6)

 

(265.2 ± 13.3)

(260.6 ± 16.7)

GD 5

302.7 ± 15.8

291.8 ± 24.3

300.7 ± 17.2

295.5 ± 19.1

245 ± 15.2

296.4 ± 18.2

288.9 ± 14.7

 

(303.3 ± 18.3)

(297.8 ± 12.7)

(299.5 ± 19.4)

(299.2 ± 16.7)

(244 ± 14.6)

(297.6 ± 16.0)

(293.5 ± 18.8)

GD 8

308.2 ± 15.3

303.5 ± 17.2

302.7 ± 14.1

298.9 ± 18.5

256 ± 16.3

303.1 ± 20.1

288.9 ± 14.7d

 

(311.6 ± 19.7)

(305.4 ± 12.2)

(306.5 ± 18.9)

(305.4 ± 18.1)

(259 ± 12.8)

(305.8 ± 18.0)

(302.9 ± 20.3)

GD 11

319.8 ± 15.8

312.9 ± 16.4

310.8 ± 16.8

307.3 ± 19.1

275 ± 19.5

314.6 ± 21.6

298.2 ± 15.2c

 

(323.7 ± 20.9)

(320.1 ± 12.6)

(316.0 ± 22.6)

(317.2 ± 19.3)

(281 ± 14.9)

(320 ± 19.1)

(316.7 ± 21.5)

GD 14

332.0 ± 16.3

325.7 ± 18.0

318.8 ± 18.8

317.6 ± 19.3

290 ± 19.5

327.9 ± 25.1

309.9 ± 15.9c

 

(336.7 ± 22.8)

(334.3 ± 14.8)

(328.9 ± 25.3)

(330.6 ± 21.4)

(301 ± 17.0)

(334.2 ± 19.3)

(330 ± 23.7)

GD 17

365.8 ± 17.3

358.1 ± 22.4

348.5 ± 20.2

347.5 ± 20.8

321 ± 24.9

358.6 ± 27.7

340.0 ± 18.0d

 

(367.0 ± 24.4)

(363.3 ± 16.9)

(356.6 ± 28.0)

(358.8 ± 27.1)

(332 ± 22.2)

(366.5 ± 20.5)

(360.1 ± 25.8)

GD 20

416.4 ± 20.5

409.1 ± 28.8

395.3 ± 22.3

394.8 ± 22.9

365 ± 27.1

410.1 ± 32.9

385.5 ± 20.7d

 

(416.8 ± 29.5)

(410.4 ± 20.3)

(405.0 ± 33.6)

(404.2 ± 33.1)

(378 ± 26.3)

(418.8 ± 26.4)

(409.4 ± 30.9)

GD 21

439.5 ± 20.5

427.3 ± 29.0

414.3 ± 25.3

413.5 ± 26.9

374 ± 27.4

423.7 ± 29.7

404.3 ± 22.4d

 

(439.1 ± 33.3)

(430. 3 ± 22.1)

(422.6 ± 34.7)

(420.9 ± 35.7)

(388 ± 28.6)

(441 ± 27.7)

(428.4 ± 33.2)

Uterus wt.

118.8 ± 11.4

114.4 ± 14.8

108.3 ± 12.3

104.8 ± 14.9

96 ± 15.7

112.9 ± 22.3

104.1 ± 10.7c

 

(115.5 ± 19.9)

(111.6 ± 12.7)

(110.9 ± 21.4)

(104.8 ± 21.9)

(101 ± 19.4)

(119.5 ± 21.4)

(114.3 ± 13.0)

GD 21Ce

320.7 ± 16.0

312.9 ± 18.3

306.0 ± 21.2

308.8 ± 20.7

273 ± 15.9

310.8 ± 23.8

300.2 ± 19.1

 

(323.6 ± 21.4)

(318.7 ± 16.1)

(311.7 ± 25.7)

(315.5 ± 20.8)

(286 ± 18.1)

(321.5 ± 18.8)

(314.2 ± 23.0)

Group mean maternal body weight changes (grams ±std. deviation)b

GD 0 – 5

29.9 ± 7.7

25.3 ± 18.9

30.5 ± 8.5

25.6 ± 9.9

NDf

31.2 ± 7.7

28.5 ± 6.1

 

(30.0 ± 7.2)

(31.9 ± 8.5)

(29.8 ± 7.1)

(29.2 ± 6.5)

(32.4 ± 7.1)

(32.5 ± 8.5)

 

GD 5 – 8

5.5 ± 6.1

11.7 ± 14.7

2.0 ± 7.9d

3.4 ± 7.7

11 ± 4.7c

6.8 ± 5.6

0 ± 5.9c

 

(8.3 ± 5.5)

(7.6 ± 5.7)

(7.0 ± 5.1)

(6.2 ± 5.2)

(15 ± 4.5)

(8.2 ± 5)

(9.8 ± 6.1)

GD 8 – 11

11.7 ± 5.2

9.4 ± 6.7d

8.1 ± 4.2

8.4 ± 3.4d

20 ± 5.5

11.5 ± 5.1

9.3 ± 3.6c

 

(12.1 ± 4.2)

(14.8 ± 4.6)

(9.6 ± 6.2)

(11.8 ± 4.6)

(22 ± 4.7)

(14.3 ± 4.7)

(13.8 ± 4.4)

GD 11 – 14

12.2 ± 5.1

12.8 ± 4.4

8.0 ± 6.6c

10.4 ± 3.8

15 ± 4.0c

13.3 ± 4.7

11.8 ± 5.4

 

(13.0 ± 4.7)

(14.2 ± 5.4)

(12.9 ± 5.1)

(13.4 ± 4.7)

(20 ± 4.2)

(14.2 ± 4.3)

(13.2 ± 4.1)

GD 14 – 17

33.8 ± 6.4

32.4 ± 6.3

29.7 ± 5.5

29.9 ± 6.4

31 ± 6.8

30.7 ± 6.1

30.1 ± 5.7

 

(30.3 ± 5.8)

(29.0 ± 5.5)

(27.7 ± 7.4)

(28.2 ± 9)

(31 ± 7.3)

(32.2 ± 7.8)

(30.2 ± 5.3)

GD 17 – 20

50.5 ± 8.2

51.0 ± 8.0

46.7 ± 11.0

47.3 ± 6.2

44 ± 7.7

51.5 ± 8.9

45.5 ± 6.4

 

(49.7 ± 9.0)

(47.1 ± 8.7)

(48.4 ± 8.6)

(45.4 ± 10)

(46.6 ± 7.6)

(52.4 ± 9.6)

(49.3 ± 6.9)

GD 20 – 21

23.1 ± 6.3

18.1 ± 4.6

19.0 ± 7.0

18.8 ± 5.8

8.0 ± 5.1

17.7 ± 6.6d

18.8 ± 4.6

 

(22.4 ± 8.3)

(19.9 ± 8.6)

(17.6 ± 6.3)

(17.4 ± 9.5)

(10.0 ± 5.2)

(22.2 ± 5.6)

(19.0 ± 4.4)

GD 5 – 21

136.8 ± 11.4

135.5 ± 21.0

113.1 ± 20.1

118 ± 17.1

129.0 ± 16.0

129.2 ± 21.3d

115.4 ± 15.7c

 

(135.8 ± 21.0)

(132.5 ± 17.5)

(123.1 ± 21.8)

(104.5 ± 91.0)

(144 ± 20.6)

(143.4 ± 21.1)

(135.3 ± 20.3)

GD 0 – 21

166.6 ± 12.4

160.8 ± 21.4

144.0 ± 20.0

143.6 ± 18.8

NDf

159.4 ± 20.8

143.8 ± 15.4c

 

(165.9 ± 22.9)

(164.4 ± 18.1)

(152.9 ± 2.5)

(151.3 ± 24.9)

 

(175.8 ± 23.9)

(167.8 ± 23.2)

GD 0 – 21Ce

47.9 ± 12.6

46.4 ± 13.5

35.8 ± 14.3

38.9 ± 24

NDf

46.5 ± 15.9

39.8 ± 13.9c

 

(50.4 ± 11.5)

(52.8 ± 13.0)

(42 ± 15.2)

(46 ± 11.7)

 

(56.3 ± 11.7)

(53.5 ± 15.6)

GD 5 – 21Ce

NCg

NCg

NCg

NCg

29 ± 10.6c

NCg

NCg

 

 

 

 

 

(43 + 11.1)

 

 

aConcurrent study control value for each endpoint in parenthesis.

bExposure period is GD 5 – 20.

cStatistically significantly lower compared to concurrent controls at p < 0.01.

dStatistically significantly lower compared to concurrent controls at p < 0.05.

eGD 21 C (day 21 corrected) – day 21 body weight minus uterine content.

fND – data not collected for study performed at Huntingdon Life Sciences.

gNC – values not calculated in EMBSI studies.

hN – Mean number of females in 20,000 mg/m3 group through most of the study.

Conclusions:
Developmental effects seen in this study, exposing rats during gestation to gasoline, supplemented by ethers and alcohols, were unspecific and limited to reduced fetal body weights and even more pronounced to reduced body weights of parental animals; skeletal variations were seen in all studies incl. controls but slightly increased in G/TBA exposure at 20,000 mg/m³ only. Thus, the supplementation of DIPE or TBA to gasoline did not result in developmental toxicity and NOAEC maternal was set to 2'000 mg/m³ and the corresponding NOAEC for developmental toxicity was set to 10'000 mg/m³ in this study. BGVC as such had no effects on maternal or develpmental toxicity (NOAECs both set to high dose group of 20.000 mg/m³. There were no clear cut differences in developmental toxicity between vapours of gasoline and gasoline blended with the ether or alcohol oxygenates and no indication of teratogenicity in any of the studies.
Executive summary:

Gasoline-vapour condensate (BGVC) or condensed vapours from gasoline blended with methyl t-butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME) di-isopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for developmental toxicity in Sprague–Dawley rats exposed via inhalation on gestation days (GD) 5 – 20 for 6 h/day at levels of 0 (control filtered air), 2000, 10,000, and 20,000 mg/m³. These exposure durations and levels substantially exceed typical consumer exposure during refuelling (<1 – 7 mg/m³, 5 min). Dose responsive maternal effects were reduced maternal body weight and/or weight change, and/or reduced food consumption. No significant malformations were seen in any study. Developmental effects occurred at 20,000 mg/m ³ of G/TAME (reduced fetal body weight, increased incidence of stunted fetuses), G/TBA (reduced fetal body weight, increased skeletal variants) and G/DIPE (reduced fetal weight) resulting in developmental NOAEL of 10,000 mg/m³ for these materials. Developmental NOAELs for other materials were 20,000 mg/m³ as no developmental toxicity was induced in those studies. Developmental NOAELs were equal to or greater than the concurrent maternal NOAELs which ranged from 2000 to 20,000 mg/m³. There were no clear cut differences in developmental toxicity between vapours of gasoline and gasoline blended with the ether or alcohol oxygenates.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
hydrocarbons C6 and C8, aliphatic and olefinic are an important component in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of 12 - 15% (<35%) by weight. Thus, aliphatic and olefinic components cannot be ignored when assessing the developmental toxicity of “2-propanol and 2-butanol production, distn. residues”, also considering their volatility (inhalation study) and absorption rate, present in the distillation residue.
Thus, in combination with other data on reproductive toxicity of identified components in “2-propanol and 2-butanol production, distn. residues” such as ethers and alcohols, the reproductive toxicity can be assessed in a weight of evidence approach considering the gasoline vapour condensates developmental toxicity in combination with the developmental toxicity of ethers and alcohols present.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical gasoline vapour condensates (gasoline unleaded) was tested as such in three different doses applied by inhalation (vapour). It consists mainly of a aliphatic (~80%) but also olefinic components (~15%) with carbon numbers in the ranges C4 (~18.9%), C5 (46.4%), C6 (23.6%), C7 (~7.8%) and C8 (~3.1%) in the vapour phase and thus contains the same C6 and C8 components as the target substance “2-propanol and 2-butanol production, distn. residues” (C4, C5 and C7 components were not found therein and so the source gasoline may be seen as a worst-case surrogate of the aliphatic and olefinic components in the target compound) and thus results do contribute to the assessment of developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues. Additionally, as the final use of “2-propanol and 2-butanol production, distn. residues” is to become a component in fuels, the study performed by inhalation route of exposure provides a real-life scenario of the products final use.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
The hydrocarbons C4-C8 present in the tested gasoline used in the study, as shown above, are important components in sum typically in the range of 12% and thus using data from reproductive toxicity studies on these components in a weight of evidence approach together with data from other components (ethers and alcohols) provides a scientifically valid insight on reproductive toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
no effects observed
Description (incidence and severity):
Physical examinations performed pre- and post-exposure did not indicate any adverse effect from exposure to unleaded gasoline vapor condensate.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All mated females survived to scheduled sacrifice.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean maternal body weight and weight gain during gestation were not adversely affected by treatment. Mean weight gains over days 6 through 20 of gestation using the corrected day 20 gestation weights were comparable to controls: 31.2 g, 30.5 g, 31.6 g, and 28.1 g for controls, 1000, 3000, and 9000 ppm groups, respectively.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption during the pretreatment (days 0- 6) and treatment period (days 6 - 20) for unleaded gasoline vapor condensate treated groups was comparable to control data.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic abnormalities related to test material exposure were observed in postmortem examination of maternal animals.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Description (incidence and severity):
No aborted pregnancies or premature deliveries in any group.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, uterine implantation sites, live fetuses, resorptions per female, and mean pre- and post-implantation loss indices for all treated groups were comparable to control data.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Mean number of corpora lutea, uterine implantation sites, live fetuses, resorptions per female, and mean pre- and post-implantation loss indices for all treated groups were comparable to control data.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
No adverse effects of treatment were evident from uterine implantation data. There were no dead fetuses in any litter from the control or treated groups.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Pregnancy rates in treated groups were statistically indistinguishable from the sham treated control group.
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects: No effects
Details on maternal toxic effects:
All mated females survived to scheduled sacrifice. Physical examinations performed pre- and post-exposure did not indicate any adverse effect from exposure to unleaded gasoline vapor condensate. Mean maternal body weight and weight gain during gestation were not adversely affected by treatment.
Dose descriptor:
NOAEC
Effect level:
23 900 mg/m³ air (analytical)
Based on:
test mat. (total fraction)
Basis for effect level:
other: maternal toxicity
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean fetal weights, by sex or combined, were comparable to controls for all treatment groups.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Mean number of male and female fetuses per pregnant female and the ratio of total male to female fetuses were also comparable to controls for all treatment groups.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
No external malformations or variations were recorded among fetuses from control or treated groups.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Results from the fetal examinations for soft tissue and skeletal malformations and variations are summarized by litter incidence.
Skeletal malformations included the presence of a fourteenth rib or rib pair and 27 presacral vertebrae in one fetus each from the control (0.6%; 1/160 fetuses) and 3000 ppm (0.6%; 1/162 fetuses) groups and two fetuses from one litter in the 9000 ppm group (1.3%; 2/156 fetuses). These incidences, both on a per fetus and per litter basis for the treatment groups were considered similar to control data and not an adverse effect of treatment. The only other skeletal malformation was the presence of 5 lumbar venebrae in one control fetus.
The overall incidence of ossification variations on a per fetus and per litter basis in groups exposed to unleaded gasoline vapor condensate was comparable to controls.The only ossification variation noted with increased incidence in treated groups was rudimentary rib(s), a finding seen frequently in rat fetuses. The incidence of this variation was compared with historical data from this laboratory (litter average 21.2%; maximum 63.6%) and published control data on the Crl:CD rat from MARTA [Mid-Atlantic Reproduction and Teratology Association] and MTA [Mid-west Tcratology Association - litter average 4%; maximum 55%].
Although the frequency of rudimentary first lumbar rib(s) in the exposed groups is slightly elevated from the range of historical control values. the frequency in these groups did not increase significantly with substantial increases in dose. When reviewed in conjunction with all ossification data for this study, the slight increase in rudimentary ribs among the treated groups is not biologically or toxicologically significant.
Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Results from the fetal examinations for soft tissue and skeletal malformations and variations are summarized by litter incidence. The only soft tissue malfomation was rnicroopthalmia of the left eye observed in one fetus among 172 (0.6%) in the 1000 ppm treatment group. Given the low incidence of this finding and the absence of similar malformations in the 3000 and 9000 ppm groups, this occurrence of microopthalmia is not considered a treatment related response.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: No effects
Details on embryotoxic / teratogenic effects:
Pregnancy rates in treated groups were statistically indistinguishable from the sham treated control group. No adverse effects of treatment were evident from uterine implantation data. There were no aborted pregnancies or premature deliveries in any group. No macroscopic abnormalities related to test material exposre were observed in postmortem examination of maternal animals. No external malformations or variations were recorded among fetuses from control or treated groups.
Dose descriptor:
NOAEC
Effect level:
23 900 mg/m³ air (analytical)
Based on:
test mat. (total fraction)
Sex:
male/female
Basis for effect level:
other: fetal toxicity
Abnormalities:
no effects observed
Developmental effects observed:
no
Conclusions:
The maternal NOAEL and developmental NOAEL for unleaded gasoline vapour condensate were 23900 mg/m³ , both. Under the conditions of this study, unleaded gasoline vapours did not produce evidence of developmental toxicity and thus there is no concern that hydrocarbon constituents (C6 and C8, aliphatic and olefinic), present in "2-propanol and 2-butanol production, distn. residues" will contribute to developental toxicity of the target substance.
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Well conducted and reported study in the peer-reviewed literature
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Secondary butyl alcohol (SBA, butan-2-ol) is one of the main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <15% by weight. Thus, this substance is one of those expected to have a significant impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, being considered higher for ethers and alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical secondary butyl alcohol (SBA) is one of the main components (beside di sec-butyl ether, di-isopropyl ether and isopropanol and tert. butanol) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Secondary butyl alcohol (SBA), as shown above, is one of the three alcohol components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Weight gain was reduced at all dose concentrations, but only achieved statistical significance at the mid- and high-doses.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight gain was reduced at all dose concentrations, but only achieved statistical significance at the mid- and high-doses.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decrease in food consumption noted starting at the lowest dose.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
not specified
Other effects:
not specified
Dose descriptor:
LOAEC
Effect level:
3 500 ppm
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
A decrease in fetal weight was seen at 5000 ppm.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
A decrease in live fetuses/litter was seen at the highest concentration (7000 ppm)
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
A decrease in fetal weight was seen at 5000 ppm.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: No effects

Details on embryotoxic / teratogenic effects:
There was no increase in the incidence of fetal malformations at any concentration. An increase in resorptions and decrease in live fetuses/litter was seen at the highest concentration (7000 ppm), and a decrease in fetal weight was seen at 5000 ppm.
Dose descriptor:
NOAEC
Effect level:
3 500 ppm (analytical)
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1. Fetal observations after exposure to SBA

 Parameter  0 ppm  3500 ppm  5000 ppm  7000 ppm
 No. Pregnant/No. bred  15/16  16/16  14/15  11/15
 Corpora lutea/litter  16  17  16  16
 Resorptions/litter 1.5   1.6  1.5  3.8*
 Live fetuses/litter  14  15  14  10*
 Fetal weight (g) - male  3.1 2.9 2.6* 1.4*
 Fetal weight (g) - female 3.3 3.1 2.7* 1.5*
 Skeletal
 No. examined (fetuses) 15 (102)  14 (104) 14 (93) 11 (53) 
 No. malformations  1 (1)  1 (1)  4 (4)  2 (2)
 No. variations  13 (33)  13 (40)  12 (32)  11 (53)*
 % normal fetuses  99  99  95  97
 Visceral        
No. examined  15 (106) 14 (105) 14 (98)  11 (57)
  No. malformations  1 (2) 1 (1)  2 (4) 1 (1)
 No. variations 3 (3)   7 (14)   6 (14)  11 (52)
 % normal fetuses   98  99  96  98

* p < 0.05

Conclusions:
Secondary butanol (SBA) was not teratogenic to rats exposed up to 7000 ppm, but caused embryo and fetotoxicity at concentrations which significantly reduced maternal body weight gain and food consumption. As SBA is a component in “2-propanol and 2-butanol production, distn. residues”, this result supports the assessment of the distillation residue via a weight of evience approach based on main components.
Executive summary:

Groups of 15 to 20 sperm-positive rats were exposed to secondary butanol at concentrations of 0, 3500, 5000, or 7000 ppm, 7 hours/day, throughout gestation. No treatment-related malformations were observed at any dose. Maternal food consumption was reduced in all treatment groups. Maternal body weights were significantly reduced at the mid- and high-doses only. Fetal body weights were reduced at the mid- and high-dose level. Resorptions were increased at the highest concentration and the number of live fetuses/litter was reduced also at the highest concentration. The NOAEC for developmental toxicity in this study was 3500 ppm, and the LOAEL for maternal toxicity was 3500 ppm.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1987
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
Well conducted and reported study in the peer-reviewed literature
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Tertiary butyl alcohol (TBA, 2-methylpropan-2-ol) is one of the main components in “2-propanol and 2-butanol production, distn. residues”, typically present in concentrations of <20% by weight. Thus, this substance is one of those expected to have a significant impact on systemic toxicity based on its amount in the distillation residues but also based on its volatility (inhalation study) and absorption rate, being considered higher for ethers and alcohols than for alkanes and alkenes being present in the distillation residue.
Thus, in combination with other data on teratogenicity of identified components in “2-propanol and 2-butanol production, distn. residues” the developmental toxicity can be assessed in a weight of evidence approach.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source chemical tertiary butyl alcohol (TBA) is one of the main components (beside di sec-butyl ether, di-isopropyl ether, isopropanol and sec. butanol) in the target compound “2-propanol and 2-butanol production, distn. residues” and thus results do provide an insight into developmental toxicity of the target substance following a weight of evidence approach based on components of the distillation residues.

3. ANALOGUE APPROACH JUSTIFICATION
The toxicity of a UVCB substance can be assessed based on the effects caused by the components of such a substance and here in a weight of evidence approach individual components are assessed individually to draw up a picture of the toxicity of the target substance “2-propanol and 2-butanol production, distn. residues”.

4. DATA MATRIX
The composition of “2-propanol and 2-butanol production, distn. residues” can be grouped as follows:
5 – 50% (~30% typically) DSBE
0 – 20% (~15% typically) TBA
0 – 15% (~10% typically) SBA
< 5% (~2% typically) C8 alkanes and alkenes
5 – 60% (~30% typically) DIPE
0 – 20% (~8% typically) IPA
<20% (~10% typically) C6 alkanes and alkenes
Tertiary butyl alcohol (TBA), as shown above, is one of the three alcohol components and thus using data from developmental toxicity studies on the individual components in a weight of evidence approach together with data from other components provides a scientifically valid insight on developmental toxicity of the “2-propanol and 2-butanol production, distn. residues”.
Reason / purpose:
read-across source
Vehicle:
other: see source study
Duration of treatment / exposure:
see source study
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
In the pilot study exposure of six nonpregnant rats to 10,000 ppm t-butanol for one day produced severe narcosis in all animals, and death in five of the six. 5000 ppm produced narcosis in all animals, and was seelected as high dose group for the main study. However, both 5000 and 3500 ppm t-butanol produced an unsteady gait at the end of the 7-hr exposure; all animals responded to a tap on the cage, but locomotor activity was impaired. In fact, after exposure to 2000 ppm t-butanol, the animals were also unsteady.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality was observed in the main study on pregnant rats.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight gain was reduced in all three doses applied. Only the 5000 ppm t-butanol group was significantly lighter than controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Regarding food consumption, only the 5000 ppm t-butanol group consumed significantly less than their respective controls, and the significance was only in the first 2 weeks (overall, the means were 361 g for controls versus 278 g at 5000 ppm t-butanol).
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Water intake increased as pregnancy progressed and was generally higher, though not significantly, in treatment groups than in controls.
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Both at 5000 and 3500 ppm t-butanol produced an unsteady gait at the end of the 7-hr exposure; all animals responded to a tap on the cage, but locomotor activity was impaired. In fact, after exposure to 2000 ppm t-butanol, the animals were also unsteady. Similar effects were seen in main study.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Slight effects at high dose group (7000 ppm)
Early or late resorptions:
not specified
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
The number of live fetuses was significantly reduced and resorptions were increased only at the highest concentration of 2-butanol.
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects: Yes
Details on maternal toxic effects:
Weight gain was reduced at all dose concentrations, but only achieved statistical significance at the mid- and high-doses. Statistically significant decrease in food consumption noted starting at the lowest dose. Animals in all dose groups showed narcosis effects or at least unsteady behaviour.
Dose descriptor:
LOAEC
Effect level:
2 000 ppm
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal weights were slightly depressed at all concentrations.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Fetal weight was slightly reduced in low and mid dose group and significantly in high dose group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No external malformations were observed.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
The majority of skeletal malformations were rudimentary cervical ribs. Skeletal variants generally increased with increasing concentrations but was not considered statistically significant.
Visceral malformations:
no effects observed
Description (incidence and severity):
Occasional visceral malformations (e.g., ventricular septal defect, hydronephrosis) were seen, as were variations (e.g., enlarged brain ventricles, dilated renal pelvis), but the incidences were not significantly affected by treatment with any ofthe butanol isomers.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: No effects
There was no increase in the incidence of fetal malformations at any concentration. An increase in resorptions and decrease in live fetuses/litter was seen at the highest concentration (5000 ppm), and a decrease in fetal weight was seen in all dose groups compared to control.
Dose descriptor:
NOAEC
Effect level:
2 000 ppm (analytical)
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1. Fetal observations after exposure to TBA

 Parameter  0 ppm  2500 ppm  3500 ppm  5000 ppm
 No. Pregnant/No. bred  15/16  18/20  15/15  13/15
 Corpora lutea/litter  16  16  16  16
 Resorptions/litter 1.1   1.2  0.9  1.1
 Live fetuses/litter  13  13  15  14
 Fetal weight (g) - male  3.2 2.9 2.8* 2.2*
 Fetal weight (g) - female 3.4 3.1 3.0* 2.3*
 Skeletal
 No. examined (fetuses) 15 (96)  17 (104) 14 (103) 12 (83) 
 No. malformations  0  0  2 (2)  2 (4)
 No. variations  10 (18)  14 (35)  14 (53*)  12 (76)*
 % normal fetuses  100  100  98  95
 Visceral        
No. examined  15 (100) 17 (116) 14 (102)  12 (83)
  No. malformations  1 (1) 1 (1)  2 (4) 1 (1)
 No. variations 6 (6)   4 (4)   6 (6)  12 (27)
 % normal fetuses   99  99  96  99

* p < 0.05

Conclusions:
Tertiary butanol was not teratogenic to rats exposed up to 5000 ppm, but caused embryo and fetotoxicity at concentrations which significantly reduced maternal body weight gain and food consumption as well as affecting behaviour of parent animals in all dose groups.
Executive summary:

Groups of 15 to 20 sperm-positive rats were exposed to tertiary butanol at concentrations of 0, 2000, 3500, and 5000 ppm, 7 hours/day, throughout gestation. No treatment-related malformations were observed at any dose. Maternal food consumption was reduced in all treatment groups. Maternal body weights were significantly reduced at the mid- and high-doses only. Fetal body weights were reduced at the mid- and high-dose level, and also slightly in the low dose group. Resorptions were increased at the highest concentration and the number of live fetuses/litter was reduced also at the highest concentration. The NOAEC for developmental toxicity in this study was 2000 ppm, and the LOAEC for maternal toxicity was 2000 ppm.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Species:
other: rats and rabbits
Quality of whole database:
Only two oral study on developmental toxicity of isopropyl alcohol (minor component in “2-propanol and 2-butanol production, distillation residues”) available with but this study is used with a weight of evidence approach together with studies following inhalation exposure on main components.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Di-isopropyl ether (DIPE), secondary butyl alcohol (SBA), tertiary butyl alcohol (TBA), isopropanol (IPA) and gasoline streams (containing hydrocarbons such as paraffins and olefins, branched and linear as present in the distillation residue) have been assessed for teratogenicity (developmental toxicity) in OECD 414 studies with rats but also some with mice and with rabbits.

No teratogenicity was observed in any of these studies and only tertiary butanol (TBA) showed some embryo toxicity and fetotoxicity at concentrations (5000 and less pronounced 3500 ppm) that also had effects on maternal body weight gain and food consumption of parental animals. In comparative studies performed by Gray et. al (2014) following a OECD 414 protocol with baseline gasoline vapour condensate (BGVC) and BGVC supplemented by alcohols and ethers such as DIPE and TBA, similar observations were made and in this study TBA appeared to have developmental effects at concentrations that also affected parental animals. However, as for TBA this study was not only performed in rats but also in mice, it was observed that effects were more pronounced in mice than in rats.

It is mentioned here (although no separate robust study summaries were recorded for these oxygenates) that also other ethers such as methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), as well as ethanol (G/EtOH) have been assessed accordingly and none of them did impact developmental toxicity, supporting the validity of the weight of evidence approach.

In assessing one reproductive toxicity screen on C4-C8 hydrocarbons, one two generation study, two one-generation studies and in total eleven developmental toxicity studies using the main components but also minor components found in “2-propanol and 2-butanol production, distillation residues” only tertiary butanol appeared to show some slight unspecific effects on body weight and weight gain on developmental toxicity but not on fertility, and these effects occurred at concentrations impacting also parental animals.

Thus, in a weight of evidence approach, based on data from a reproductive toxicity screen, a two generation reproductive toxicity study, two one-generation reproductive toxicity studies and eleven developmental toxicity studies on rats, mice and rabbit, all performed by inhalation exposure, assessing the different components (ethers, alcohols and hydrocarbons present in “2-propanol and 2-butanol production, distillation residues”) it can be concluded that this UVCB substance will not show reproductive toxicity by impacting fertility or teratogenicity.

Equivalently, when analysing available assessments performed within other programs before, none of the main components of the distillation residue (DSBE, DIPE, SBA, TBA and IPA) was found to be toxic for reproduction based on literature data, except for TBA, which showed some unspecific skeletal anomalies in a 19-day reproduction toxicity study (see table below).

Table: Reproduction toxicity data for the main components of the reaction mass from literature

 

Oral

Inhalation

Conclusion

DSBE (1)

From analogue, SBA: Rat, 8-week, 2-generation study: NOAEL (maternal and developmental toxicity): 1771 mg/kg/day

From analogue, SBA: Rat, 20-day, prenatal developmental toxicity study: NOAEL: 3500 ppm (maternal toxicity) NOAEL: >7000 ppm (developmental toxicity)

Overall the weight of evidence indicates that analogue SBA does not produce teratogenic (developmental) toxic effects in the developing embryo/fetus of laboratory animals. In a 2-generation study on rats, no effects of SBA on fertility were noted.

DIPE (2)

 

Rat, 20-day, prenatal developmental toxicity study: NOAEL: 430 ppm (maternal and developmental toxicity) Rat, 13-week, subchronic toxicity study: NOAEL: 480 ppm (reproductive effects)

DIPE is not a teratogen. No changes in reproductive organ weights and structure or sperm and spermatid number were noted in a subchronic toxicity study.

SBA (3)

Rat, 8-week, 2-generation study: NOAEL (maternal and developmental toxicity): 1771 mg/kg/day

Rat, 20-day, prenatal developmental toxicity study: NOAEL: 3500 ppm (maternal toxicity) NOAEL: >7000 ppm (developmental toxicity)

SBA is not a developmental toxicant. There was no evidence of teratogenic events nor was there evidence of selective developmental toxicity. In a 2-generation study on rats, no effects on fertility were noted.

TBA (4)

Rat, 4-weeks, 1-generation study: NOAEL (maternal toxicity) = 1000 mg/kg-bw/day NOAEL (reproductive/developmental toxicity) = 400 mg/kg-bw/day
Mouse, 22-days, prenatal developmental toxicity study: NOAEL (maternal toxicity) = 1500 mg/kg-bw/day LOAEL (developmental toxicity) =1125 mg/kg-bw/day
Mouse, 18-days, prenatal developmental toxicity study: LOAEL (developmental toxicity) = 1550 mg/kg-bw/day

Rat, 19-day, prenatal developmental toxicity study: NOAEL (maternal toxicity) = 15.2 mg/L LOAEL (developmental toxicity) = 6.06 mg/L

A prenatal developmental toxicity study revealed significant increases in the incidence of skeletal anomalies (primarily delayed skeletal ossification) in treated offspring. In a one-generation study, no effects on reproductive organs, mating success, fertility, or sperm quality were observed; however, a slight increase in the length of gestation (significance not specified) was observed at the two highest doses. Furthermore, an increase in estrous cycle length was observed in female mice in a 13-week repeated-dose study.

 

(1) HIGH PRODUCTION VOLUME (HPV) CHEMICAL CHALLENGE PROGRAM TEST PLAN For sec-Butyl Ether CAS NO. 6863-58-7, Prepared by: ExxonMobil Chemical Company, November 28,2006

(2) ExxonMobil Chemical Company Shell Chemical LP For: American Chemistry Council, lsopropanol Panel, Diisopropyl Ether HPV Task Group December 12,2005

(3) OECD SIDS Dossier for Butan-2-ol, CAS No.78 -92 -2, ExxonMobil Biomedical Sciences Inc.,09.01.2002

(4) Robust Summaries for t-Butanol, CAS Number 75 -65 -O USEPA HPV Challenge Program Submission April 10, 2002

Toxicity to reproduction: other studies

Description of key information

No further information available

Justification for classification or non-classification

Based on the available data on the constituents, the reaction mass is not classified as toxic to reproduction according to CLP, Regulation EC No 1272/2008 and no further studies are proposed.