Butyl (S)-2-hydroxypropionate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No data is available for the target substance butyl-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 butyl-S-lactate. Moreover, in repeated dose toxicity and reproductive/developmental toxicity studies conducted with the target substance itself, n-butanol or its surrogate n-butyl acetate or ethylhexyl-lactate, no adverse effects on reproductive tissues or organs were observed. 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 butyl-S-lactate. Nevertheless, available data from suitable source substances is used to assess the potential of the target substance to induce reproductive toxicity.

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

Link to relevant study records

Reference

Reference 1

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

Reference 2

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

Reference 3

Endpoint:

fertility, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

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:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry 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

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

not specified

Overall there was no evidence of male reproductive toxicity at any exposure concentration based on lack of significant differences between treatments and controls for testicular spermatid head counts and epididymidal spermatozoa counts as endpoints of toxicity. Overall weight gains for 3000 ppm exposure groups were 64% and 59% of controls for males and females, respectively. Overall weight gains for 1500 ppm exposure groups were 82% and 74% of controls for males and females, respectively. No significant differences in weight gain at 500 ppm vs. control.

Dose descriptor:

NOAEL

Remarks:

male reproductive toxicity

Effect level:

3 000 ppm (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

reproductive function (sperm measures)

Critical effects observed:

no

Conclusions:

There was no evidence of testicular toxicity in male rats exposed via inhalation to 0, 500, 1500, or 3000 ppm of n-butyl acetate (6 hrs/day) for at least 65 exposures over 14 weeks. Therefore, the NOAEL for male reproductive toxicity following repeated inhalation exposure was determined to be 3000 ppm.

Executive summary:

In a repeated dose toxicity study, male rats were exposed via inhalation to 0, 500, 1500, or 3,000 ppm (6 hrs/day) for at least 65 exposures over 14 weeks. At necropsy, right testes (n=40) were prepared for histological examination and left testes and left epididymis (n=40) from the same animal were frozen and processed for determination of sperm concentrations.

Overall weight gains for 3000 ppm exposure groups were 64% and 59% of controls for males and females, respectively. Overall weight gains for 1500 ppm exposure groups were 82% and 74% of controls for males and females, respectively. No significant differences in weight gain at 500 ppm vs. control.

Furthermore, there was no evidence of male reproductive toxicity at any exposure concentration based on lack of significant differences between treatments and controls for testicular spermatid head counts and epididymal spermatozoa counts as endpoints of toxicity. Therefore, a NOAEL for male reproductive toxicity following repeated exposure was 3000 ppm.

It should also be mentioned that the rapid in vivo hydrolysis of n-butyl acetate to n-butanol makes this study directly applicable to n-butanol exposures.

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.

Reference 4

Endpoint:

reproductive toxicity, other

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For 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:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights of the rabbits were similar in both n-butyl-acetate-exposed groups, but the filtered-air-exposed rabbits tended to have the lowest body weights throughout the experimental period, particularly from GD 15 through 30.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The lowest values for food consumption were consistently observed in animals from the group inhaling filtered air. When the two groups of n-butyl-acetate-exposed rabbits were compared, there were significant differences in food consumption after the onset of exposure. From 1 to 5 dg, values for Group 2 (exposed to filtered air at this time) were higher than those of Group 3. Once the n-butyl-acetate exposure was initiated in Group 2, food consumption was lower than that of Group 3 until the exposure was terminated on GD 19.

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathologic studies performed on the rabbits necropsied on GD 30 did not relate any observed lesions to the n-butyl acetate exposures. A variety of lung lesions were seen, some of which are probably within the range of normal; others may be related to Pasteurella infections. Small foci of mononuclear inflammatory cells were common around alveoli, small airways and small blood vessels. A few bronchi and bronchioles contained small accumulations of heterophils and minimal to mild increases in bronchus-associated lymphoid tissue (BALT). Epithelial hyperplasia of bronchi was mild in theGroup 1 rabbits and minimal in the two n-butyl-acetate-exposed groups. The
changes were evenly distributed in all groups. Renal changes, consisting of minimal to mild tubular mineralization and sub-acute to chronic interstitial nephritis, were evenly distributed throughout all exposure groups. Incidental findings of extramedullary hematopoiesis in the spleen appeared minimally to mildly excessive in only four animals, one of which had peritonitis.

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to pregnancy rates, numbers of corpora lutea, implantation sites, resorptions, and live fetuses per litter were unremarkable. In addition, the sex ratios between the treatment groups were similar.

Key result

Dose descriptor:

NOAEC

Effect level:

1 500 ppm (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects observed

Key result

Critical effects observed:

no

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

No differences seen for live fetuses per litter between the treatment groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No differences seen body weight changes between the treatment groups.

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

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

no effects observed

Description (incidence and severity):

No major malformations were observed in fetuses from any exposure group. In terms of minor anomalities, there was a significantly higher incidence of misaligned sternebrae and of retinal folds among fetuses from rabbits inhaling n-butyl acetate from GD 1 to 19 than in those exposed to filtered air (Group 1). Group was not affected. The presence of a clear liquid in the gallbladder, rather than bile, was a more frequent variation in Group 3 fetuses than in those of Group 1.

Other effects:

no effects observed

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

1 500 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

In a reproductive/developmental toxicity study, pregnant New Zealand White rabbits were treated between gestation day 1 to 19, 7 hours per day via whole body inhalation. The nominal concentration of n-butyl acetate applied was 1500 ppm (equals 7230 mg/m³). Based on the results obtained from this study, the NOAEC for maternal and reproductive/developmental toxicity can be considered to be 1500 ppm.

Executive summary:

In a reproductive/developmental toxicity study n-butyl acetate (purity 99.1%) pregnant New Zealand White rabbits (30 animals/group) were exposed for 7 hours per day whole body inhalation to 1500 ppm (equivalent to 7230 mg/m³). The control group received filtered air through gestation days 1-19. Group 2 animals received through GD 1-6 filtered air, followed by exposure to the test chemical until GD 19. Group 3 animals were exposed to the test material vapor through GD 1-19. This exposure was followed with a period of no exposure. On GD 30 all animals were sacrificed, and necropsies were performed. Pregnant animals were examined for toxic changes, including altered food consumption, body weight, tissue weights and histopathology. Reproductive measures included the determination of numbers of corpora lutea, implantation sites, resorptions, dead fetuses and live fetuses. Live fetuses were weighed, measured, and subjected to external, visceral and skeletal examinations to detect morphologic anomalies.

No effects were seen for food consumption and body weight development in comparison to the control. Organ weight and histopathology were not affected by the exposure to n-butyl-acetate. 

The reproductive performance was unaltered by n-butyl acetate exposure. Fetal growth measures, such as body weight and crown-rump length, were similar for n-butyl-acetate and filtered-air-exposed rabbit. Placental weights and sex ratios were also similar. Furthermore, no major malformations were observed in fetuses from any exposure group. There was a significantly higher incidence of misaligned sternebrae and of retinal folds among fetuses from rabbits inhaling n-butyl acetate from GD 1 to 19 than in those exposed to filtered air (Group 1). The presence of a clear liquid in the gallbladder, rather than bile, was a more frequent variation in Group 3 fetuses than in those of Group 1. However, the authors concluded that rabbit foetuses, were unaffected by n-butyl acetate exposure based upon a lack of uniform response between the two n-butyl acetate exposure groups.

Therefore, based on the results and in conclusion with the OECD SIDS assessment for n-butanol, the NOAEC for maternal and reproductive/developmental toxicity is considered to be 1500 ppm (equals 7230 mg/m³).

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).

Reference 5

Endpoint:

fertility, other

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 read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

The general appearance and behaviour of the animals exposed to n-butyl alcohol given in drinking water during the 8 weeks, were similar to that of the control animals.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

There were no cases of mortality in either group.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight gain of the animals exposed to n-butyl alcohol given in drinking water during the 8 weeks, were similar to that of the control animals.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption of the animals exposed to n-butyl alcohol given in drinking water during the 8 weeks, were similar to that of the control animals.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

Hemoglobin concentration and hematocrit values did not differ between the exposed and control groups.

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The duration of the cycle in the control rats and the exposed female rats was similar, 4 days on average. The duration of the individual stages, of the oestrous cycle was not dependent on exposure to n-butanol and was similar to that observed in the control animals.

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

No differences were observed between control and treated animals.

PRE-and POST-NATAL DATA
There were no test item treatment related effects on the number of corpora lutea, number of implantation sites, number of live pups, percentage of pre- and post-implantation loss and litters with early and late resorptions in the dose groups when compared to the control group.

Key result

Dose descriptor:

NOAEL

Remarks:

maternal toxicity and fertility

Effect level:

5 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Foetal body weights were unaffected

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

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

effects observed, treatment-related

Description (incidence and severity):

Skeletal examinations were conducted. Please refer to box "Details on results".

Other effects:

effects observed, treatment-related

Description (incidence and severity):

In the high dose group the crown-rump length was decreased (mean of 4.0 to 3.8 cm for the control and treated group, respectively)

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

At 4% (about 5000 mg/kg bw/day) the crown-rump length was decreased (from a control mean of 4.0 cm to 3.8 cm. Developmental effects were reported in all 3 dose groups. Skeletal effects were limited to an extra 14th rib in one foetus in the low dose group and two foetuses in the high dose group and way ribs in one foetus in the low dose group. CNS defects included dilation of either the subarachnoid space or lateral and/or third ventricles of the brain or external or internal hydrocephalus. Dilated renal pelvis was only observed. Of the 65 control foetuses examined for skeletal effects, none had an extra 14th or wavy rib(s) or any other skeletal malformation or variation. Two of the 61 control foetuses examined for visceral anomalies had dilatation of the lateral and/or third ventricles of the brain, while none had dilatation of the subarachnoid space or external or internal hydrocephalus. Although the authors considered all three dose levels to have increased levels of defects when compared to controls, there was no clear dose-dependent increase. The authors considered the recorded developmental effects (dilatation of the brain ventricles/spaces or renal pelvis, hydrocephalus, wavy or extra ribs) as being related to n-butanol and assessed these findings as variations or delayed development commonly seen in large historical control databases. Of significance, the incidence of all but one of the reported developmental effects in the actual control population was 0%. In the MARTA-MTA 1995 database, using Crl:CD BR rat, the incidence of renal pelvis, dilated is 0.95%/foetus or 5.2%/litter. The malformations reported that were assessed as variations in other databases should be classified based on the incidence within the rat strain. Since the strain of rat and type and quality of diet can have a profound effect on rates or variations and malformations and since there is no historical database for these animals, the term “variation” has to be assigned with reservation. However, since these variations are common to several rat strains commonly used in the United States, the term “variation” appears appropriate. It should not be surprising that high oral doses of n-butanol that would be expected to alter normal maternal physiology would cause an increase in common variations in laboratory rodents. Thus, the developmental effects seen by the authors cannot be regarded as a selective fetotoxic effect. Overall, the NOAEL for maternal toxicity and reproductive toxicity is considered to be 5000 mg/kg bw/day. Moreover, it has to be considered that the limit dose for this study type in accordance to the current OECD test guidelines is 1000 mg/kg bw/day.
 

Dose descriptor:

NOEL

Generation:

F1

Effect level:

< 300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Visceral & skeletal effects

Key result

Reproductive effects observed:

no

Conclusions:

In a reproductive/developmental toxicity study, female rats were given drinking water containing 0, 300, 1000 and 5000 mg/kg bw/day n-butanol during 8 weeks before mating, during the mating until the animals were killed on day 20 of gestation, when foetuses were collected and examined for skeletal and visceral malformations. General appearance, food consumption, body weight, rate of weight gain, oestrus cycle length and number, absolute and relative organ weight, hemoglobin concentration, haematocrit values, foetal body weights, intra-uterine mortality, corpora lutea, total implants and placental weight were unaffected by n-butanol exposure. Developmental effects were reported in all 3 dose levels, but there was no dose-dependency. The NOAEL for maternal and reproductive toxicity can be considered to be 5000 mg/kg bw/day.

Executive summary:

In a reproductive/developmental toxicity study, female rats were given drinking water containing 0, 300, 1000 and 5000 mg/kg bw/day n-butanol during 8 weeks before mating, during the mating until the animals were killed on day 20 of gestation, when foetuses were collected and examined for skeletal and visceral malformations. General appearance, food consumption, body weight, rate of weight gain, oestrus cycle length and number, absolute and relative organ weight, hemoglobin concentration, haematocrit values, foetal body weights, intra-uterine mortality, corpora lutea, total implants and placental weight were unaffected by n-butanol exposure.

The JACC-41 assessment of n-butanol assessed the developmental results of this study as following:

At 4% (about 5000 mg/kg bw/day) the crown-rump length was decreased (from a control mean of 4.0 cm to 3.8 cm. Developmental effects were reported in all 3 dose groups. Skeletal effects were limited to an extra 14th rib in one foetus in the low dose group and two foetuses in the high dose group and way ribs in one foetus in the low dose group. CNS defects included dilation of either the subarachnoid space or lateral and/or third ventricles of the brain or external or internal hydrocephalus. Dilated renal pelvis was only observed. Of the 65 control foetuses examined for skeletal effects, none had an extra 14th or wavy rib(s) or any other skeletal malformation or variation. Two of the 61 control foetuses examined for visceral anomalies had dilatation of the lateral and/or third ventricles of the brain, while none had dilatation of the subarachnoid space or external or internal hydrocephalus. Although the authors considered all three dose levels to have increased levels of defects when compared to controls, there was no clear dose-dependent increase. The authors considered the recorded developmental effects (dilatation of the brain ventricles/spaces or renal pelvis, hydrocephalus, wavy or extra ribs) as being related to n-butanol and assessed these findings as variations or delayed development commonly seen in large historical control databases. Of significance, the incidence of all but one of the reported developmental effects in the actual control population was 0%. In the MARTA-MTA 1995 database, using Crl:CD BR rat, the incidence of renal pelvis, dilated is 0.95%/foetus or 5.2%/litter. The malformations reported that were assessed as variations in other databases should be classified based on the incidence within the rat strain. Since the strain of rat and type and quality of diet can have a profound effect on rates or variations and malformations and since there is no historical database for these animals, the term “variation” has to be assigned with reservation. However, since these variations are common to several rat strains commonly used in the United States, the term “variation” appears appropriate. It should not be surprising that high oral doses of n-butanol that would be expected to alter normal maternal physiology would cause an increase in common variations in laboratory rodents. Thus, the developmental effects seen by the authors cannot be regarded as a selective fetotoxic effect. Overall, the NOAEL for maternal toxicity and reproductive toxicity is considered to be 5000 mg/kg bw/day. Moreover, it has to be considered that the limit dose for this study type in accordance to the current OECD test guidelines is 1000 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 read-across report attached to IUCLID section 13.

 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

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 butyl-S-lactate itself. Thus, available data from the suitable read-across partner n-butanol and its surrogate n-butyl acetate and from 2-ethylhexyl lactate was used to assess the potential of butyl-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 butyl-S-lactate.

Link to relevant study records

Reference

Reference 1

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):

Narcosis was observed in one-half of the maternal animals at 8000 ppm. No effects were detected in rats exposed to 6000 and 3500 ppm.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

At 8000 ppm 2/18 rats died.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

At 8000 ppm weight gain was reduced, but it was not statistically significant.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was significantly reduced at 6000 and 8000 ppm. Overall means were 382 g for controls versus 320 and 332 g.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Water intake increased as pregnancy progressed and was generally higher, though not significantly compared to the control.

Ophthalmological findings:

not examined

Haematological findings:

not examined

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:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Details on results:

Some evidence for maternal toxicity was observed with exposures to 1-butanol at doses of 6000 ppm and higher. Mortality was observed in 2/18 animals at 8000 ppm. Doses of 6000 and 8000 ppm caused a statistically significant reduction in food consumption. Narcosis was observed in one-half of the maternal animals at 8000 ppm.

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:

not examined

Early or late resorptions:

no effects observed

Description (incidence and severity):

No statistically significant effect was observed between the contol and the treatment groups.

Dead fetuses:

no effects observed

Description (incidence and severity):

No adverse effects were observed in the treatment groups.

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

The number of pregant females was comparable between the treatment groups.

Other effects:

not specified

Details on maternal toxic effects:

No effect was observed on number pregnant/number bred; corpora/litte, live foetuses and resorptions/litter.

Key result

Dose descriptor:

NOAEC

Effect level:

3 500 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed at 3500 ppm

Key result

Dose descriptor:

LOAEC

Effect level:

6 000 ppm (nominal)

Based on:

test mat.

Basis for effect level:

food consumption and compound intake

Abnormalities:

not specified

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Foetal weights were slightly depressed at 8000 (approx. 9 %) and 6000 ppm (approx. 73 % for females; approx. 76 % for males), which was statistically significant compared to the control values.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

No differences were seen in the mean live foetuses/litter between the control and the treatment groups.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

No effects were observed on the sex ratio (measured as % female/litter)

Changes in litter size and weights:

not specified

Description (incidence and severity):

Foetal weight was significantly decreased at 6000 and 8000 ppm in comparison to the untreaated control.

Changes in postnatal survival:

not specified

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 concentration. At 3500 ppm no effects were seen. Variations seen were typical of foetotoxicity, particulary reduced ossification. Only for 1-butanol the percentage of normal foetuses was reduced from control levels was at 8000 ppm, where rudimental cervical ribs were observed.

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 ventricels, dilated remal pelvis), but the incidences were not significantly affected by treatment.

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Foetal male and female body weights were significantly decreased at 6000 and 8000 ppm. No external foetal malformations were observed. There were no differences in malformation rates (skeletal or visceral). However, there was a slight increase in the percent of foetuses with skeletal variation or malformation (mainly rudimentary cervical ribs) in the 8000 ppm group but not in the lower two exposure groups.

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

Key result

Dose descriptor:

LOAEC

Effect level:

6 000 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Abnormalities:

effects observed, treatment-related

Localisation:

skeletal: rib

Description (incidence and severity):

Rudimental cervical ribs were observed at 8000 ppm.

Developmental effects observed:

not specified

Analytical results:

Throughout the exposures the concentrations were easily generated and were uniform. The mean concentrations ± SD (number of exposure days) from the daily infrared readings of 1-butanol were 8000 ± 80 (25 days), 6000 ± 80 (21 days) and 3510 ± 20 ppm (40 days). Charcoal tube results were typically 10–15 % lower (mean values of 7700, 5960 and 3000 ppm). No contaminants were detected in the charcoal tubes collected from the control chambers.

Conclusions:

In this study, inhalation of 1-butanol from gestation day 1 to 19 resulted in a maternal and developmental NOAEC of 3500 ppm, which corresponds to 10589 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, 6000 and 8000 ppm of 1-butanol (≥ 99 % purity) via the inhalation route for 7 hours/day during gestation days 1 to 19.

Evidence for maternal toxicity was observed with exposures to 1-butanol at concentrations of 6000 ppm and higher. At 8000 ppm mortality (2/18 animals) and reduced weight gain was observed. Moreover, narcosis was observed in one-half of the maternal animals at 8000 ppm. Exposure to 6000 and 8000 ppm caused a statistically significant reduction in food consumption.

No effects were observed on mean corpora lutea/litter, mean resorptions/litter, mean number of live foetuses/litter and sex ratio. Moreover, no external foetal malformations were observed. Skeletal malformation (primarily rudimentary cervical ribs) was observed at 8000 ppm. Furthermore, at 6000 and 8000 ppm male and female fetuses showed a reduced body weight.

Based on the findings from this study, the maternal and developmental NOAEC is considered to be 3500 ppm, which corresponds to 10589 mg/m³.

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.

Reference 2

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 read-across report attached to IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

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.

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 subsequnetly suffocated. Daily clinical observations did not reveal any differences between dose and control group animals.

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):

not examined

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

Description (incidence and severity):

not specified

Changes in number of pregnant:

not examined

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 chnage 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.

Dose descriptor:

NOAEC

Remarks:

maternal toxicity

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.

Dose descriptor:

NOAEC

Remarks:

developmental toxicity

Effect level:

600 mg/m³ air (nominal)

Based on:

test mat.

Basis for effect level:

other: No differences between foetuses from treated and control dams, except slightly retarded ossification in treated foetuses. This effect was considered to be related to the stress conditions.

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:

not examined

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.

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:

Reproduction and litter data at Caesarian section:
From the 12 mated female rats per group, 11 of each group were pregnant. 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.

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.

Key result

Dose descriptor:

NOAEC

Remarks:

developmental toxicity

Effect level:

600 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: No differences between foetuses from treated and control dams, except slightly retarded ossification in treated foetuses. This effect was considered to be related to the stress conditions.

Key result

Abnormalities:

no effects observed

Developmental effects observed:

not specified

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:

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).

Reference 3

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 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:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weights of the rabbits were similar in both n-butyl-acetate-exposed groups, but the filtered-air-exposed rabbits tended to have the lowest body weights throughout the experimental period, particularly from GD 15 through 30.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The lowest values for food consumption were consistently observed in animals from the group inhaling filtered air. When the two groups of n-butyl-acetate-exposed rabbits were compared, there were significant differences in food consumption after the onset of exposure. From GD 1 to 5, values for Group 2 (exposed to filtered air at this time) were higher than those of Group 3. Once the n-butyl-acetate exposure was initiated in Group 2, food consumption was lower than that of Group 3 until the exposure was terminated on GD 19.

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

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Weights of the lungs, kidneys, and spleens of the pregnant, filtered-air-exposed rabbits were significantly lower than those of the n-butyl-acetate-exposed groups. When relative organ weights (which correct for differences in body weight) were considered, these differences were not significant, although spleen weights tended to be lower in the filtered-air-exposed animals (p< 0.06). No effects on the placental weight.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathologic studies performed on the rabbits necropsied on GD 30 did not relate any observed lesions to the n-butyl acetate exposures. A variety of lung lesions were seen, some of which are probably within the range of normal; others may be related to Pasteurella infections. Small foci of mononuclear inflammatory cells were common around alveoli, small airways and small blood vessels. A few bronchi and bronchioles contained small accumulations of heterophils and minimal to mild increases in bronchus-associated lymphoid tissue (BALT). Epithelial hyperplasia of bronchi was mild in theGroup 1 rabbits and minimal in the two n-butyl-acetate-exposed groups. The
changes were evenly distributed in all groups. Renal changes, consisting of minimal to mild tubular mineralization and sub-acute to chronic interstitial nephritis, were evenly distributed throughout all exposure groups. Incidental findings of extramedullary hematopoiesis in the spleen appeared minimally to mildly excessive in only four animals, one of which had peritonitis.

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to implantation sites were unremarkable.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to resorptions were unremarkable.

Early or late resorptions:

no effects observed

Description (incidence and severity):

No adverse effects observed.

Dead fetuses:

no effects observed

Description (incidence and severity):

No dead fetuses were observed.

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to pregnancy rates, were unremarkable.

Other effects:

not specified

Dose descriptor:

NOAEC

Remarks:

maternal toxicity

Effect level:

1 500 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse signs of toxicity observed

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to live fetuses per litter were unremarkable.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Thee sex ratios between the treatment groups were similar.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Differences among exposure groups with regard to live fetuses per litter and weights were unremarkable.

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

For futher details see section " details on embryotoxicity/teratogenicity" below.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

For futher details see section " details on embryotoxicity/teratogenicity" below.

Visceral malformations:

no effects observed

Description (incidence and severity):

For futher details see section " details on embryotoxicity/teratogenicity" below.

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

MORPHOLOGY:
There was no increase in the incidence of “Major Malformations” in any of the n-butyl acetate exposure groups. In terms of “Minor Anomalities,” there was an increase in the incidence of “misaligned sternabra” and “retinal folds” in Group 3; Group 2 was not affected. Only a single increased incidence of “Morphologic Variations” was found, an increase in “clear gallbladder”; and that only in Group 3. The authors concluded that rabbit fetuses were unaffected by n-butyl acetate exposure based upon a lack of uniform response between the two exposure groups.

Dose descriptor:

NOAEC

Effect level:

1 500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: rabbit fetuses were unaffected by n-butyl acetate exposure

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

In a reproductive/developmental toxicity study, pregnant New Zealand White rabbits were treated between gestation day 1 to 19, 7 hours per day via whole body inhalation. The nominal concentration of n-butyl acetate applied was 1500 ppm (equivalent to 7230 mg/m³). Based on the results obtained from this study, the NOAEC for maternal and reproductive/developmental toxicity can be considered to be 1500 ppm.

Executive summary:

In a reproductive/developmental toxicity study n-butyl acetate (purity 99.1%) pregnant New Zealand White rabbits (30 animals/group) were exposed for 7 hours per day whole body inhalation to 1500 ppm (equivalent to 7230 mg/m³). The control group received filtered air through gestation days 1-19. Group 2 animals received through GD 1-6 filtered air, followed by exposure to the test chemical until GD 19. Group 3 animals were exposed to the test material vapor through GD 1-19. This exposure was followed with a period of no exposure. On GD 30 all animals were sacrificed, and necropsies were performed. Pregnant animals were examined for toxic changes, including altered food consumption, body weight, tissue weights and histopathology. Reproductive measures included the determination of numbers of corpora lutea, implantation sites, resorptions, dead fetuses and live fetuses. Live fetuses were weighed, measured, and subjected to external, visceral and skeletal examinations to detect morphologic anomalies.

No effects were seen for food consumption and body weight development in comparison to the control. Organ weight and histopathology were not affected by the exposure to n-butyl-acetate. 

The reproductive performance was unaltered by n-butyl acetate exposure. Fetal growth measures, such as body weight and crown-rump length, were similar for n-butyl-acetate and filtered-air-exposed rabbit. Placental weights and sex ratios were also similar. Furthermore, no major malformations were observed in fetuses from any exposure group. There was a significantly higher incidence of misaligned sternebrae and of retinal folds among fetuses from rabbits inhaling n-butyl acetate from GD 1 to 19 than in those exposed to filtered air (Group 1). The presence of a clear liquid in the gallbladder, rather than bile, was a more frequent variation in Group 3 fetuses than in those of Group 1. However, the authors concluded that rabbit foetuses, were unaffected by n-butyl acetate exposure based upon a lack of uniform response between the two n-butyl acetate exposure groups.

Therefore, based on the results and in conclusion with the OECD SIDS assessment for n-butanol, the NOAEC for maternal and reproductive/developmental toxicity is considered to be 1500 ppm (equivalent to 7230 mg/m³).

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 study available

Additional information

Due to the rapid, enzymatically catalysed hydrolysis of Butyl-S-lactate into n-butanol and L-lactic acid, the toxicology of butyl-S-lactate can be understood in terms of the toxicology of n-butanol and L-lactic acid. Lactic acid is a ubiquitous and integral part of mammalian metabolism and therefore of minor toxicological relevance in comparison to n-butanol which is, as an alcohol, more important for the toxicological assessment. No study is available elucidating the reproductive/developmental toxicity potential of the target substance. Thus, available data from suitable read-across partner n-butanol and its surrogate n-butyl acetate and from 2-ethylhexyl lactate was used to assess the potential of Butyl-S-lactate to induce reproductive/developmental effects. For justification of the read-across approach please refer to IUCLID section 13.

No treatment-related effects in developmental or maternal parameters were detected in a developmental toxicity study (OECD 414) in rats after inhalation of 2-ethylhexyl lactate. 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. 

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, 6000 and 8000 ppm of n-butanol (≥ 99 % purity) via the inhalation route for 7 hours/day during gestation days 1 to 19. Based on the findings from this study, the maternal and developmental NOAEC is considered to be 3500 ppm, which corresponds to 10589 mg/m³. In this study fetotoxicity was observed in the offspring, but only in combination with maternal toxicity (Nelson, 1989).

The lack of specific developmental toxicity is further supported in a behavioural teratology study conducted with n-butanol. In this study, n-butanol (≥ 99 % purity) was administered to 15 pregnant Sprague-Dawley rats for 7 h/day throughout gestation (GD 1–20) at doses of 0, 3000 and 6000 ppm 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. 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, rotarod and running wheel performance, open-field and photoelectrically-monitored activity, avoidance conditioning and operand conditioning. In addition, the levels of the neurotransmitter acetylcholine, dopamine, norepinephrine, serotonin, met-encephalin, ß-endorphin and substance P were measured in 4 brain regions (cerebrum, cerebellum, brainstem and midbrain) taken from animals on day 21 after birth. No effects on pregnancy rate was found and no general toxicity to maternal and paternal animals were reported. A small number of effects were seen on both the behavioural and neurochemical measures following exposure to 6000 ppm n-butanol, but that no discernible pattern of effects was apparent. Therefore, the NOAEC for maternal, paternal and their offspring was 6000 ppm, which corresponds to 18152 mg/m³ (Nelson, 1989).

That n-butanol does not induce teratogenicity is further supported by the results presented in the publication by Sitarek et al., 1994. In this study the general appearance, food consumption, body weight, rate of weight gain, oestrus cycle length and number, absolute and relative organ weight, haemoglobin concentration, haematocrit values, foetal body weights, intra-uterine mortality, corpora lutea, total implants and placental weight were unaffected by n-butanol exposure. Developmental effects were reported in all 3 dose levels, but there was no dose-dependency. The ECETOC JACC No. 41 assessment report mentioned that the developmental effects seen by the authors cannot be regarded as a selective fetotoxic effect. Thus, the NOAEL for maternal and reproductive toxicity can be considered to be 5000 mg/kg bw/day.

For the source substance n-butyl acetate reproductive/developmental toxicity studies conducted in rats and rabbits are available (Hackett, 1982).

In the first study, pregnant Sprague Dawley rats were exposed to n-butyl acetate concentrations of either 0 or 1500 ppm (equivalent to 7230 mg/m³) for 7 hours per day via whole body inhalation. The rats were maintained in the exposure chambers throughout the study period, 3 weeks pregestational until gestation day 21. Group 1 was not exposed to test material throughout the study and served as the control. Group 2 was exposed to 1500 ppm n-butyl acetate from day 7 to 16 of gestation. Group 3 received n-butyl acetate from Day 1 to 16 of gestation and Group 4 was exposed from 3 weeks pregestational through day 16 of gestation. All test material exposures were discontinued from gestation day 17 through study termination on GD 21. Based on the results obtained from this study, the LOAEC for maternal toxicity is 1500 ppm and the NOAEC for reproductive/developmental toxicity can be considered to be 1500 ppm. In the second study, pregnant New Zealand White rabbits were treated between gestation day 1 to 19, 7 hours per day via whole body inhalation. The nominal concentration of n-butyl acetate applied was 1500 ppm (equivalent to 7230 mg/m³). Based on the results obtained from this study, the NOAEC for maternal and reproductive/developmental toxicity can be considered to be 1500 ppm.

Supporting information was derived from data presented in the OECD SIDS assessment for n-butanol (OECD, 2001). In a testicular toxicity study male rats were exposed via inhalation to 0, 500, 1500, or 3000 ppm of n-butyl acetate (6 hrs/day) for at least 65 exposures over 14 weeks. There was no evidence of testicular toxicity and therefore, the NOAEL for male reproductive toxicity following repeated inhalation exposure was determined to be 3000 ppm.

The presented studies are also highlighted in the OECD SIDS assessment for n-butanol, 2001. The OECD SIDS experts stated, that n-butanol is not a reproductive toxicant. In addition, the (eco-) toxicological review published by ECETOC (ECETOC JACC No. 41, 2003) also concluded that n-butanol "does not present a hazard for male or female reproductive function in experimental animals". Based on the available data, no classification for developmental/reproductive toxicity is warranted for the target substance Butyl-S-lactate.

In summary, based on the assessment of the available data in a weight-of-evidence approach, no classification for developmental/reproductive toxicity is warranted for the target substance butyl-S-lactate.

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 butyl-S-lactate.