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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

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

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No data is available for the target substance propyl (S)-lactate itself. Thus, by way of read-across available data from source substances are used in weight-of-evidence approach.

Pre-natal developmental toxicity studies conducted with suitable read-across partners are available. Thus, in accordance with Annex VIII, column 2 of the REACH Regulation 1907/2006, information requirement 8.7.1, it is not necessary to perform a reproductive toxicity screening study on propyl (S)-lactate. Moreover, in repeated dose toxicity and reproductive/developmental toxicity studies conducted with 1-propanol, calcium lactate pentahydrate, butyl (S)-lactate, ethylhexyl-lactate or ethyl lactate, no adverse effects on reproductive tissues or organs were observed at doses corresponding to the limit doses of the respective OECD test guidelines. Thus, in accordance with REACH Annex IX, section 8.7.3, column 1, it is not necessary to conduct an extended one-generation reproductive toxicity study with the target substance propyl (S)-lactate.

In conclusion, based on the assessment of the available data, no classification for developmental/reproductive toxicity is warranted for propyl (S)-lactate.

Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
other:
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

No study is available elucidating the developmental toxicity potential of propyl (S)-lactate itself. The target substance fully hydrolyses into lactic acid/lactate and propanol under aqueous and/or physiological conditions. Therefore, the requirement for developmental toxicity shall/can be addressed based on information for lactic acid and propanol. Thus, available data from the suitable read-across partners ethyl lactate, ethylhexyl lactate and 1-propanol was used to assess the potential of propyl (S)-lactate to induce developmental effects. For justification of the read-across approach please refer to IUCLID section 13. Based on assessment of the available data in a weight-of-evidence approach, no classification for developmental toxicity is warranted for the target substance propyl (S)-lactate.

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
Justification for type of information:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Abnormalilics seen during exposure were confined to visually increased breathing rate in animals exposed lo 600 mg/m³ during Ihe entire treatment period and occasionally in rats exposed lo 200 mg/m3. One animal of the control group (A 101) lost part of its tail due to a mechanical trauma. Daily clinical observations did not reveal any noticeable differences in the animals' appearance, general condition or behaviour amongst the various groups.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal of the low dose group died on day 11 of gestation because it turned around in the inhalation tube and subsequently suffocated. All other females survived until scheduled Caesarian section.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no significant differences in body weight or body weight change between the control group and the groups exposed to the test substance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The food consumption of the high dose group was statistically significantly decreased when compared to the control group throughout the exposure period. The food consumption of the 200 mg/m³ was slightly decreased during the exposure period, but increased thereafter.
Food efficiency:
not specified
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
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Gross examination at autopsy did not reveal any significant differences of the maternal organs and tissues among the various groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Uterus and ovary weights:
Mean reproductive organ weights and net maternal body weight change during gestation were evaluated. No statistically significant differences in gravid and empty uterus weight, ovary weight, carcass weight and the net weight change (body weight gain from day 0 to 21 of gestation minus gravid uterine weight) were observed between the control group and he groups treated to 2-ethylhexyl lactate.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between the control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and post-implantation loss or in the sex ratio of the foetuses.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
From the 12 mated female rats per group, 11 of each group were pregnant.
Other effects:
not examined
Details on maternal toxic effects:
Details on maternal toxic effects:
Clinical signs and mortality:
One animal of the low dose group died on day 11 of gestation because it turned around in the inhalation tube and subsequnetly suffocated. Daily clinical observations did not reveal any differences between dose and control group animals.

Maternal body weight and body weight change:
There were no significant differences in body weight or body weight change between the control group and the groups exposed to the test substance.

Food consumption:
The food consumption of the high dose group was statistically significantly decreased when compared to the control group throughout the exposure period. The food consumption of the 200 mg/m³ was slightly decreased during the exposure period, but increased thereafter.

Parental necropsy observations:
Gross examination at autopsy did not reveal any significant differences of the maternal organs and tissues among the various groups.

Uterus and ovary weights:
Mean reproductive organ weights and net maternal body weight change during gestation were evaluated. No statistically significant differences in gravid and empty uterus weight, ovary weight, carcass weight and the net weight change (body weight gain from day 0 to 21 of gestation minus gravid uterine weight) were observed between the control group and the groups treated to 2-ethylhexyl lactate.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: No differences in clinical signs, maternal body weight or body weight change and necropsy seen in treated animals in comparison to control animals.
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
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):
See box “Details on embryotoxic / teratogenic effects” below.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Skeletal malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Visceral malformations:
no effects observed
Description (incidence and severity):
See box “Details on embryotoxic / teratogenic effects” below.
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Reproduction and litter data at Caesarian section:
From the 12 mated female rats per group, 11 of each group were pregnant.
Reproduction and litter data revealed no treatment-related changes either as evidenced by the absence of statistically significant differences between the
control group and the groups exposed to the test substance in the numbers of corpora lutea, implantations, live and dead foetuses and early and late resorptions nor in pre- and
post-implantation loss or in the sex ratio of the foetuses.

Foetal external observations:
No statistically significant differences were observed for the individual findings. When compared with the control group, the total number of fetal external
observations was slightly albeit statistically significantly increased in the high concentration group. This difference was mainly due to the low number of foetal
observations in the control group: Only one foetus with a small haemorrhage on the head in the control group versus 4 dysmature foetuses from 4 litters (i.e. foetus weight < 75 % of the mean foetal body weight in the control group) and three large foetuses (i.e. foetus weight > 125 % of the mean foetal body weight) plus one foetus with a flexed limb from one litter of the 600 mg/m³ group. Considering the nature of the findings and the low number in the control group, this difference is not considered treatment related.

Findings of the placenta:
Findings of the placenta were limited to two fused placenta in four fetuses of one female control group animal.

Foetal weight and placental weight:
No significant differences in mean foetal body weights were observed between the control group and the groups exposed to the test substance. Mean placental
weight of the 200 mg/m³ group was increased (statistically significantly for both sexes combined). Mean placental weights in of the 600 mg/m³ were comparable to these in the control group.

Visceral examination:
Examination of foetal soft tissues was limited to the control group and the high concentration group.
Visceral malformations:
No visceral malformations were seen in the control group and the high concentration group.
Visceral anomalies:
No visceral variations were observed in the control and the high-concentration group.

Skeletal examinations:
Skeletal examinations were conducted in all groups.
Skeletal malformations:
None of the fetuses showed skeletal malformations
Skeletal anomalies:
Skeletal anomalies were limited to wavy ribs in 3 foetuses out of 2 litters in the high-concentration groups. The incidence in the high-concentration group did not differ significantly from that in the control group.
Skeletal variations:
No statistically significant differences were observed for the individual findings.
Variations in the ossification of the skeletons
When compared with the control group, the 200 and 600 mg/m³ groups showed the following differences: Increase in the number of foetuses and litters with an incompletely ossified frontalis and unossified metatarsals, which was significant in the 200 mg/m³ group. Furthermore, a delay in the ossification of the hind limb phalanges was observed in the 200 and 600 mg/m³ group. The slightly retarded ossification as observed at 200 and 600 mg/m3, was considered to be a minor developmental effect, most attributable to the stress conditions. No teratogenic effects were observed in this study.
Key result
Dose descriptor:
NOAEC
Effect level:
600 mg/m³ air (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Key result
Abnormalities:
no effects observed
Developmental effects observed:
no

Gravimetric analysis:

The mean actual concentrations of 2-ethylhexyl lactate in the test atmospheres (and their standard deviations) were 230 (± 16) and 594 (± 48) mg/m³.

Nominal concentration:

The daily mean airflow through the exposure units were 26.5, 55.9, and 70.4 L/min for the control, low, and high concentration level, respectively. The nominal concentrations were 378 and 751 mg/m³, indicating generation efficiencies of 61 and 79 % for the low and high concentration level, respectively.

Particle size measurement:

Particle size measurement showed that almost all particles in the animals' breathing zone were respirable, viz. they were smaller than or equal to 4.2 µm. The mean mass median aerodynamic siameter (MMAD) was 2.7 and 1.7 µm for the low and high exposure level, respectively. The mean geometric standard deviation was 1.5 for the low concentration level and 1.6 for the high concentration level.

Temperature and relative humidity:

The daily mean temperature was 22.7 ± 0.6 °C, 22.6 ± 0.4 °C and 22.6 ± 0.4 °C for the control, low and high concentration level. respectively. The daily relalive humidity was 56 ± 6%, 52 ± 5% and 52 ± 6 %, respectively.

Conclusions:
In conclusion, no treatment-related effects in developmental parameters or maternal parameters were detected in a developmental toxicity study (OECD 414) after inhalation of 2-ethylhexyl lactate, except slightly retarded ossification. This is considered to be a minor developmental effect, most attributable to the stress conditions. Therefore, it can be stated that no teratogenic effects were observed in this study and the maternal and developmental NOAEC is considered to be 600 mg/m³.
Executive summary:

In a developmental toxicity study (OECD 414), 2-ethylhexyl lactate (98.2% purity) was administered to 12 female Wistar rats per dose level in clean air (nose-only exposure for 6 hours/day) at concentration levels of 0, 200 and 600 mg/m³ from day 6 through day 15 of gestation. On day 21 of gestation the animals were sacrificed. There were no treatment-related effects on mortality, clinical signs, body weight or Casarean parameters. Food consumption of the groups was statistically significantly decreased in comparison to the control group animals. As no differences were noticed in body weight change between control and treated animals this effect was classified as not biologically adverse. Based on the results, the maternal NOAEC is considered to be 600 mg/m³. Moreover, no treatment related effects were noted in developmental parameters, except slightly retarded ossification. This is considered to be a minor developmental effect, most attributable to the stress conditions. Thus, the developmental NOAEC is 600 mg/m³. This developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rat.

This information is used in a read-across approach in the assessment of the target substance.

For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

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:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
see box "Details on results"
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
see box "Details on results"
Mortality:
no mortality observed
Description (incidence):
see box "Details on results"
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see box "Details on results"
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
see box "Details on results"
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
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
see box "Details on results"
Gross pathological findings:
no effects observed
Description (incidence and severity):
see box "Details on results"
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
see box "Details on results"
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
see box "Details on results"
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
see box "Details on results"
Early or late resorptions:
no effects observed
Description (incidence and severity):
see box "Details on results"
Dead fetuses:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
see box "Details on results"
Other effects:
not examined
Details on maternal toxic effects:
No deaths occurred during this study. Of 25 animals assigned to each group, pregnancy occurred in 25, 24, 23 and 25 rats in the 0 (Sham), 517, 1551 and 3619 mg/kg bw/day dosage groups, respectively.
One low dosage group rat was inadvertently sacrificed on day 18 of gestation, reducing the number of low dosage group rats with day 20 of gestation litters from 24 to 23. The high dosage of Ethyl lactate resulted in a biologically important increase (not statistically significant) in the number of rats with slight (grade 1) erythema and slight (grade 1) desquamation, as compared with the sham control group number. These minimal signs of irritation or dehydration generally did not occur until the last one or two days of the dosage period and sometimes persisted until day 20 of gestation. Hyperactivity occurred on two days for one high dosage group rat; this clinical sign may have been interrelated with the minimal erythema and desquamation that also occurred for this rat.
No other skin reactions or clinical observations and no necropsy observations were considered effects of percutaneous administration of the test substance to the dams at dosages as high as 3619 mg/kg bw/day.
There were no dosage-dependent or statistically significant differences in average maternal body weight gains during the dosage period (calculated as days 6 to 16 of gestation). Similar average maternal body weight changes also occurred for the dams in the four dosage groups during the postdosage period.
Average maternal liver weights and liver weight/terminal body weight ratios (%) were unaffected by percutaneous administration of the test substance at dosages as high as 3619 mg/kg bw/day.
There were no biologically important or statistically significant differences in the absolute (g/day) or relative (g/kg/day) maternal feed consumption values during the dosage period (the entire dosage period is calculated as days 6 to 16 of gestation). Similarly, while slightly decreased for the high dosage group rats during the postdosage period (days 16 to 20 of gestation), there were no biologically important or statistically significant differences in absolute or relative maternal feed consumption average values for the four groups.
Key result
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
1 551 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: see Remarks
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Effect level:
3 619 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
see box "Details on results"
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in sex ratio:
no effects observed
Description (incidence and severity):
see box "Details on results"
Changes in litter size and weights:
not examined
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Skeletal malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Visceral malformations:
no effects observed
Description (incidence and severity):
see box "Details on results"
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
No observation made at Caesarean-sectioning of the dams was attributed to the test substance. Average values for corpora lutea, implantations, litter sizes, live and dead fetuses, and early and late resorptions were comparable in the four dosage groups. Similarly, the averages for fetal sex ratios, body weights and percentage of dead or resorbed conceptuses per litter were biologically comparable among the four groups. There were no statistically significant differences.
Gross external, soft tissue and skeletal examinations of the fetuses did not reveal any malformations or variations that were considered effects of the test substance.
Key result
Dose descriptor:
NOAEL
Effect level:
3 619 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Abnormalities:
not specified
Developmental effects observed:
no
Conclusions:
In a developmental toxicity study, ethyl lactate was administered to 25 female Crl:CD®(SD)BR presumed pregnant rats /dose applied percutaneously at dose levels of 0, 517, 1551 and 3619 mg/kg bw/day from days 6 through 15 of gestation. Based on the results, the maternal NOAEL is 1551 mg/kg bw/day and the NOAEL for developmental toxicity is 3619 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted according to EPA OTS 798.4000, ethyl lactate was administered for six hours/day to 25 female Crl:CD®(SD)BR presumed pregnant rats/dose group percutaneously under occlusive conditions at levels of 0, 517, 1551 and 3619 mg/kg bw/day from day 6 through 15 of gestation. On day 20 of gestation the animals were sacrificed.

Dermal application of ethyl lactate to pregnant rats at the highest dose that could be given (3619 mg/kg bw/day) caused slight erythema and/or desquamation more frequently in comparison to the control group. Hyperactivity occurred on two days for one rat from the high dose group, which is probably related to the slight erythema and desquamation that also occurred for this rat. No other skin reactions or clinical observations and no adverse necropsy findings were observed in the animals. There were no treatment-related effects on mortality, body weight, food consumption and caesarean parameters. Gross external, soft tissue and skeletal examinations of fetuses did not reveal any malformations or variations that were considered adverse.

It is concluded that percutaneous application of ethyl lactate to pregnant rats was minimally toxic to the dams at the highest dosage that could be tested (3619 mg/kg bw/day), and that this maximum dosage did not result in developmental toxicity. Based on the results, the maternal NOAEL is considered to be 1551 mg/kg bw/day, and the developmental NOAEL is considered to be 3619 mg/kg bw/day.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

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:
For details and justification of read-across please refer to the report attached in section 13 of IUCLID.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Description (incidence and severity):
At 10000 ppm, the dams (weighing 200-300 g) were not noticeably affected and at 7000 and 3500 ppm no effects were seen
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Maternal body weight gain was affected only at the end of gestation in the 10000 ppm group. At 7000 ppm body-weight gain was not significantly affected. At 3500 ppm no effects were observed.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 10000 ppm, the food intake was reduced throughout gestation. At 7000 ppm, food intake was reduced during the last two weeks of gestation. At an exposure of 3500 ppm, food intake was reduced by about 10% compared with controls, but this was not statistically significant.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No dose-related effects on water consumption were observed.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
The number of pregnant females in comparison to the number of females bred are comparable between control and treatment groups
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
Three out of fifteen litters exposed to 10000 ppm n-propanol were totally resorbed, and resorptions were statistically increased when compared with control levels in this group (p< 0.05).
Early or late resorptions:
not specified
Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
The implants alive/litter in % were: 94% (control), 96% (3500 ppm), 89% (7000 ppm) and 43% (10000 ppm).
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The number of pregnant females in comparison to the number of females bred are comparable between control and treatment groups
Other effects:
not examined
Details on maternal toxic effects:
Please refer to Table 2 im box "Any other information on results incl. tables" for detailed results of maternal developmental toxicity.
Key result
Dose descriptor:
NOAEC
Effect level:
3 500 ppm (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Remarks on result:
other: no maternal toxicity observed at 3500 ppm
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Foetal weights were reduced after maternal exposure to either 7000 or 10000 ppm n-propanol.
Reduction in number of live offspring:
effects observed, treatment-related
Description (incidence and severity):
The implants alive/litter in % were: 94% (control), 96% (3500 ppm), 89% (7000 ppm) and 43% (10000 ppm).
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, treatment-related
Description (incidence and severity):
After exposure to 10000 ppm n-propanol, the incidence of external malformations was significantly increased compared with control levels (approximately one-third of the foetuses having a short or missing tail or ectrodactyly).
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
The skeletal malformations (mostly rudimentary cervical ribs) were increased at exposure to 7000 ppm and 10000 ppm n-propanol.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Visceral malformations (principally cardiovascular or urinary defects) were increase at exposure to 10000ppm n-propanol
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
In order of increasing concentrations of n-propanol, the numbers of litters with skeletal or visceral malformations/number of litters examined were 5/15, 2/15, 9/15 and 12/12. Thus, no significant teratogenic effects were noted for n-propanol after maternal exposure to 3500 ppm. Some effects were seen at 7000 ppm, and severe effects were found at 10000 ppm.
Key result
Dose descriptor:
NOAEC
Effect level:
3 500 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Abnormalities:
effects observed, treatment-related
Localisation:
external: tail
skeletal: rib
visceral/soft tissue: urinary
visceral/soft tissue: cardiovascular
Developmental effects observed:
yes
Lowest effective dose / conc.:
7 000 ppm (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Table 1: Conditions of inhalation exposure of pregnant rats

Period of measurement**(days)

Mean alcohol concentration (ppm)

 

Target

IA (mean ± SD)

Charcoal tube

(mean ± SD)

21

10000

10103 ± 72

9743 ± 1284

22

7000

7015 ± 26

6054 ± 255

23

3500

3516± 63

3659 ± 226

Table 2: Reproductive observations
Parameter n-propanol (ppm)
0 3500 7000 10000
No pregnants/no. Bred 15/16 15/15 15/15 15/15
Mean of corpora lueta/dam 15.1 15.9 14.1 14.6
Mean of implants/dam 14.6 15.5 13.9 14.1
Implants resorbed/litter (%) 6 4 11 57*
Implants alive/litter (%) 94 96 89 43*
Mean fetal weights +/- SD (g)  
Female 3.16 +/- 0.26 3.14 +/- 0.33 2.60 +/- 0.32* 1.70 +/- 0.25
Male 3.33 +/- 0.26 3.30 +/- 0.34 2.77 +/- 0.30* 1.79 +/- 0.29

*= p< 0.05

Table 3: External, skeletal and visceral malformations in rats after exposure of the dams to n-propanol for 7 hr/day throughout gestation

Parameter

No of litters (foetuses) with specific malformations after exposure to n-propanol (ppm)

0

3500

7000

10000

External malformations

No. of litters (foetuses) examined

15(206)

15(225)

15(187)

 

12(94)

Micrognathia

0

0

1(1)

0

Crooked tail

0

0

0

1(1)

Short/missing tail

0

0

0

9(29)

Syndactyly

0

0

0

3(6)

Ectrodactyly

0

0

 

 

Forefoot

 

 

 

6(18)

Hindfoot

 

 

 

4(5)

Total external malformations

0

0

1(1)

9(34)*

Skeletal malformations

No. of litters (foetuses) examined

15(100)

15(109)

15(95)

 

12(48)

Cranial (exoccipital) malformation

0

0

0

1(1)

Vertebral malformations

0

0

 

 

Abnormal thoracic arches

 

 

1(1)

2(4)

Abnormal lumbar arch

 

 

0

1(1)

Rib malformations

0

0

 

 

Rudimentary cervical

1(1)

 

8(17)

9(15)

Extra cervical

0

 

0

0

Fused/wavy

0

 

1(1)

5(6)

Missing

1(1)

 

0

1(1)

Total skeletal malformations

1(1)

0

9(19)*

12(22)*

Total skeletal variants

15(41)

15(52)

15(64)

12(48)

Visceral malformations

No. of litters (foetuses) examined

15(106)

15(116)

15(92)

 

10(46)

Brain

 

Encephalocoel

0

0

0

0

Cardiovascular malformation

 

 

 

 

Dextrocardia

1 (1)

 

 

0

Right aortic arch

1 (1)

 

 

2 (2)

Double aortic arch

1 (1)

 

 

0

Right azygous vein

0

 

 

1 (1)

Right ductus arteriosis

0

 

 

3 (3)

Ventricular septal defect

0

 

 

6 (6)

Abnormal subclavian

0

 

 

3(3)

Urinary malformations

 

Hydronephrosis

3 (3)

2 (2)

1 (3)

2 (3)

Hydroureter

0

0

1 (1)

0

Renal hypoplasia

0

0

0

4 (11)

Renal agenesis

0

0

0

3 (4)

Ectopic kidney

0

0

0

1 (2)

Bladder hypoplasia

0

0

0

5 (10)

Bladder agenesis

0

0

0

5 (6)

Other malformations

 

Situs inversus

1 (1)

 

0

0

Rudimentary tongue

0

 

1 (1)

0

Ovary agenesis

0

 

0

1 (1)

Ovary hypoplasia

0

 

0

1 (1)

Adrenal agenesis

0

 

0

2 (2)

Total visceral malformations

4(4)

2 (2)

2 (4)

10 (26)*

Total visceral variants

9(12)

6(8)

10(13)

10(25)
Conclusions:
In this study, inhalation of n-propanol from gestation day 1 to 19 resulted in a maternal and developmental NOAEC of 3500 ppm, which corresponds to 8730 mg/m³.
Executive summary:

In a developmental toxicity study conducted similar to guideline OECD 414, 15 female Sprague-Dawley rats were whole-body exposed to concentrations levels of 0, 3500, 7000 and 10000 ppm of n-propanol via the inhalation route for 7 hours/day during gestation days 1 to 19.

Throughout gestation, food consumption was significantly reduced in the 7000 and 10000 ppm groups; maternal body weight was affected only at the end of gestation in the 10000 ppm group. Resorptions were increased in the 10000 ppm group and fetal body weights were significantly reduced in the 7000 and 10000 ppm groups. No effects were seen at 3500 ppm.

After exposure to 10000 ppm n-propanol, the incidence of external malformations was significantly increased compared with control levels (approximately one-third of the foetuses having a short or missing tail or ectrodactyly). The skeletal malformations (mostly rudimentary cervical ribs) were increased at exposure to 7000 ppm and 10000 ppm n-propanol. Visceral malformations (principally cardiovascular or urinary defects) were increase at exposure to 10000 ppm n-propanol. No effects were seen at 3500 ppm. Based on the results, a maternal and developmental NOAEC of 3500 ppm (8730 mg/m³) is established. The maternal and developmental LOAEC is established at 7000 ppm (17460 mg/m³). With the assumption for rats of a respiratory rate of 0.8 L/min/kg bw, the effective concentrations of 7000 ppm for 7 h/day can be converted to an oral uptake of ca. 5800 mg/kg bw/day, which is clearly above the limit concentrations of the respective OECD test guidelines.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the read-across report attached to IUCLID section 13.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Weight gain of exposed females (compared using multivariate analysis) was not affected by exposure to 1-propanol.
Weekly mean weights (±SD) for the six weeks in which the males were exposed to 7000 ppm propanol were 444 (± 40) g, 444 (± 38) g, 466 (± 36) g, 489 (± 38) g, 511 (± 38) g, and 528 (± 40) g. For those exposed to 3500 ppm propanol, the weights were 510 (± 24) g, 504 (± 26) g, 514 (± 29) g, 527 (± 30) g, 539 (± 32) g, and 554 (± 34) g.


Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Feed intake was reduced was reduced in the females (p< 0.05) exposed to 7000 ppm 1-propanol (weekly means ± SD for the exposed vs. control groups were 107 (± 13) vs. 134 (± 20) g, 122 (± 12) vs. 145 (± 18) g, and 137 (± 14) vs. 158 (± 18) g.
At 3500 ppm 1-propanol, there were no significant effects on maternal weight gain or feed intake.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Exposure of male rats to 7000 ppm 1-propanol for 6 weeks produced reversible infertility.
Number of abortions:
not examined
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
not examined
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No significant differences were found among any of the groups for the number of live pups per litter, the length of gestation, the birth weights, or neonatal survival.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The number pregnant/number bred were 17/17 for maternally-exposed rats, 2/16 for paternally-exposed rats, 18/18 for controls, and 38/40 for foster rats in the 7000 ppm 1-propanol group.
Other effects:
no effects observed
Description (incidence and severity):
No significant differences were found among any of the groups for the number of live pups per litter, the length of gestation, the birth weights, or neonatal survival.
Dose descriptor:
NOAEC
Effect level:
3 500 ppm (analytical)
Based on:
test mat.
Basis for effect level:
food consumption and compound intake
Remarks on result:
other: decreased food consumption at 7000 ppm
Abnormalities:
not examined
Fetal body weight changes:
not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No significant differences were found among any of the groups for the number of live pups per litter, the length of gestation, the birth weights, or neonatal survival.
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
no effects observed
External malformations:
effects observed, treatment-related
Description (incidence and severity):
Examination of the offspring revealed that 2 of 15 litters from the 7000 ppm l-propanol maternally exposed group had several pups (2-3/litter) with crooked tails (noted soon after birth), and these defects persisted.
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Behavior:
There were few differences from controls in this study.
At 7000 ppm 1-propanol, exposed animals were not significantly different from controls on any of the tests. At 3500 ppm 1-propanol, the only significant differences between exposed animals and controls were in the activity measures.
In the Open Field test, females from the paternally-exposed group were less active than the controls on days 44, 45, and 46. On the activity wheel, this same group was less active than the controls. In the optical activity monitor, males in the maternally-exposed group were less active than control males on days 44, 45, and 46. No other significant differences were observed.
Neurochemistry:
No treatment related effects were observed .
Dose descriptor:
NOAEC
Effect level:
3 500 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
external malformations
Abnormalities:
effects observed, treatment-related
Localisation:
external: tail
Description (incidence and severity):
Examination of the offspring revealed that 2 of 15 litters from the 7000 ppm 1-propanol maternally exposed group had several pups (2-3/litter) with crooked tails (noted soon after birth), and these defects persisted.
Developmental effects observed:
yes
Lowest effective dose / conc.:
7 000 ppm (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Analytical results:

Concentrations measured in the exposure chambers (hourly infrared analyzer readings) approximated the target concentrations of 3500 and 7000 ppm. Mean concentrations were 3510 ± 20 and 7300 ± 80 ppm. Results of periodic confirmatory charcoal tube samples were 3510 ± 20 and 3510 ± 10 ppm.

Conclusions:
No behavioural adverse effects were observed in a behavioural teratology study in rats after exposure to 1-propanol at concentrations of 3500 and 7000 ppm via inhalation.
Executive summary:

In a behavioral teratology study female Sprague-Dawley rats were exposed to 1-propanol (vapor), (≥ 99 % purity) at concentrations 0, 3500 and 7000 ppm for 7 hrs/day, on gestation days 1-19 in inhalation exposure chambers and were allowed to deliver. In addition, 18 male rats were exposed with the same concentrations for 7 h/day for 6 weeks and were then mated to non-exposed females.

Maternal weights, feed intake, and water intake were measured over weekly intervals The offspring of both cohorts were observed during postnatal days 10–90 for signs of developmental neurotoxic effects by measuring ascent on a wire mesh screen, rotorod, open field and optically monitored activity, running wheel, avoidance conditioning, and ID progressive fixed ratio schedule of reinforcement.

Additionally brains from 10 rats per group were dissected into cerebrum, cerebellum, brainstem, and midbrain, and were assayed for protein levels of acetylcholine, dopamine, norepinephrine, serotonin, beta-endorphin, Met-enkephalin, and substance P.

Weight gain of maternal animals was not affected by treatments. Feed intake was statistically significant (p< 0,05) reduced at 7000 ppm. At 3500 ppm, there were no significant effects on maternal weight gain or feed intake. No significant differences were found among any of the groups for the number of live pups per litter, the length of gestation, the birth weights, or neonatal survival.

Examination of the offspring revealed that 2 of 15 litters from the 7000 ppm of 1-propanol maternally exposed group had several pups (2-3/litter) with crooked tails (noted soon after birth), and these defects persisted. No statistically significant effects on behavior were observed at exposure to 7000 ppm of 1-propanol. No effects on neurochemistry measurements were noted upon the treatment.

Exposure of male rats to 7000 ppm 1-propanol for 6 weeks produced reversible infertility.

Under the conditions of this study, the NOEC maternal and developmental can be considered to be 3500 ppm (8730 mg/m³). With the assumption for rats of a respiratory rate of 0.8 mL/kg bw, the effective concentrations (reversible effects on male fertility) of 7000 ppm for 7 h/ day can be re-calculated to an oral exposure of ca. 5800 mg/kg bw/day. Thus, it is obvious that the effects observed at 7000 ppm occurred at very high inhalatory concentrations and clearly exceed the limit dose of the respective OECD test guidelines (1000 mg/kg bw/day) and are thus not appropriate to be used for classification and labelling.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

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

No study is available elucidating the developmental toxicity potential of propyl (S)-lactate itself. The target substance fully hydrolyses into lactic acid/lactate and propanol under aqueous and/or physiological conditions. Therefore, the requirement for developmental toxicity shall/can be addressed based on information for lactic acid and propanol. Thus, available data from the suitable read-across partners ethyl lactate, ethylhexyl lactate and 1-propanol was used to assess the potential of propyl (S)-lactate to induce developmental effects. For justification of the read-across approach please refer to IUCLID section 13.

 

In a developmental toxicity study conducted according to EPA OTS 798.4000, ethyl lactate was administered for six hours/day to 25 female Crl:CD®(SD)BR presumed pregnant rats/dose group percutaneously under occlusive conditions at levels of 0, 517, 1551 and 3619 mg/kg bw/day from day 6 through 15 of gestation. On day 20 of gestation the animals were sacrificed.

Dermal application of ethyl lactate to pregnant rats at the highest dose that could be given (3619 mg/kg bw/day) caused slight erythema and/or desquamation more frequently in comparison to the control group. Hyperactivity occurred on two days for one rat from the high dose group, which is probably related to the slight erythema and desquamation that also occurred for this rat. No other skin reactions or clinical observations and no adverse necropsy findings were observed in the animals. There were no treatment-related effects on mortality, body weight, food consumption and caesarean parameters. Gross external, soft tissue and skeletal examinations of fetuses did not reveal any malformations or variations that were considered adverse.

It is concluded that percutaneous application of ethyl lactate to pregnant rats was minimally toxic to the dams at the highest dosage that could be tested (3619 mg/kg bw/day), and that this maximum dosage did not result in developmental toxicity. Based on the results, the maternal NOAEL is considered to be 1551 mg/kg bw/day, and the developmental NOAEL is considered to be 3619 mg/kg bw/day.

 

In a developmental toxicity study (OECD 414), ethylhexyl lactate (98.2% purity) was administered to 12 female Wistar rats per dose level in clean air (nose-only exposure for 6 hours/day) at concentration levels of 0, 200 and 600 mg/m³ from day 6 through day 15 of gestation. On day 21 of gestation the animals were sacrificed. There were no treatment-related effects on mortality, clinical signs, body weight or Casarean parameters. Food consumption of the groups was statistically significantly decreased in comparison to the control group animals. As no differences were noticed in body weight change between control and treated animals this effect was classified as not biologically adverse. Based on the results, the maternal NOAEC is considered to be 600 mg/m³. Moreover, no treatment related effects were noted in developmental parameters, except slightly retarded ossification. This is considered to be a minor developmental effect, most attributable to the stress conditions. Thus, the developmental NOAEC is 600 mg/m³.

 

In a developmental toxicity study conducted similar to guideline OECD 414, 15 female Sprague-Dawley rats were whole-body exposed to concentrations levels of 0, 3500, 7000 and 10000 ppm of n-propanol via the inhalation route for 7 hours/day during gestation days 1 to 19.

Throughout gestation, food consumption was significantly reduced in the 7000 and 10000 ppm groups; maternal body weight was affected only at the end of gestation in the 10000 ppm group. Resorptions were increased in the 10000 ppm group and fetal body weights were significantly reduced in the 7000 and 10000 ppm groups. No effects were seen at 3500 ppm.

After exposure to 10000 ppm n-propanol, the incidence of external malformations was significantly increased compared with control levels (approximately one-third of the foetuses having a short or missing tail or ectrodactyly). The skeletal malformations (mostly rudimentary cervical ribs) were increased at exposure to 7000 ppm and 10000 ppm n-propanol. Visceral malformations (principally cardiovascular or urinary defects) were increase at exposure to 10000 ppm n-propanol. No effects were seen at 3500 ppm. Based on the results, a maternal and developmental NOAEC of 3500 ppm (8730 mg/m³) is established. The maternal and developmental LOAEC is established at 7000 ppm (17460 mg/m³). With the assumption for rats of a respiratory rate of 0.8 L/min/kg bw, the effective concentrations of 7000 ppm for 7 h/day can be converted to an oral uptake of ca. 5800 mg/kg bw/day, which is clearly above the limit concentrations of the respective OECD test guidelines.

 

In the behavioural teratology study conducted on Sprague-Dawley rats inhalation exposure to test substance 1-propanol at concentration-7000 ppm for 7 hr/day, on gestation days 1-19, produced minimal toxic effect to the maternal animals and low incidence of teratogenicity. Inhalation exposure to 3500 ppm of 1-propanol caused no maternal toxicity and no teratogenicity. Under condition of this study NOEC (maternal and teratogenicity) were established as 3500 ppm.

Justification for classification or non-classification

Based on the assessment of the available data in a weight-of-evidence approach and by way of read-across, no classification for developmental/reproductive toxicity is warranted for propyl (S)-lactate.

Additional information