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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.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 ammonium-S-lactate itself. The target substance completely dissociates into NH4+ ions and lactate under aqueous and/or physiological conditions. Therefore, the requirement for reproduction toxicity shall be addressed based on information for lactic acid and ammonium ions. For more details on the read-across justification, please refer to IUCLID section 13.

As lactic acid is a major and essential species in mammalian primary metabolism, and a ubiquitous ingredient in all kinds of food it is of minor toxicological relevance in comparison to the second dissociation product ammonium. In repeated dose toxicity and reproductive/developmental toxicity studies conducted with suitable source substances for both dissociation products, no adverse effects on reproductive tissues or organs were observed. E.g. in a repeated dose toxicity study combined with the reproduction/developmental toxicity screening test (OECD 422), no adverse effects were seen on any reproductive or developmental toxicity parameters in rats after exposure to the source substance diammonium phosphate. Thus, and 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 ammonium-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
Endpoint:
screening for reproductive / 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 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):
A dosage dependent increase in transient post-dosing salivation was apparent, which was considered to be due to the palatability of the test formulations rather than toxicity. A dosage-dependent increase in the number of animals with reddening of the extremities was also apparent mainly during the early stages of treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No treatment-related deaths were observed.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain and food consumption of males at 1500 mg/kg bw/day appeared to be suppressed when compared with the control group (78% of controls during weeks 0-5). The body body weight gain for reproductive subgroup females receiving 1500 mg/kg bw/day was reduced during the first week of gestation, after which the values returned to levels comparable with the control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Body weight gain and food consumption of males at 1500 mg/kg bw/day appeared to be suppressed when compared with the control group (78% of controls during weeks 0-5).
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In males, a dosage-dependent reduction in total protein at 750 and 1500 mg/kg bw/day with a slight elevated albumin/globulin ratio at the top dose was observed.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Some treatment-related effects on hematology were evident (reduction in activated partial thromboplastin time for males at 750 and 1500 mg/kg bw/day, a non-dosage-dependent elevation of alkaline phosphatase levels at 1500 mg/kg bw and 750 mg/kg bw/day, reduced glucose and phosphorous levels at 1500 mg/kg bw/day). Changes in females were limited to a decrease in phosphorous levels and a non-significant increase in alkaline phosphatase level at 1500 mg/kg bw/day.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were changes apparent at behavioural testing.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The only histological findings related to treatment were the inflammatory/degenerative stomach changes in all treated groups that were considered likely to have arisen due to an irritant effect of the test formulations.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Mating performance and fertility were unaffected by treatment. For details please refer to box "Details on results" (P0).
Summary of effects on reproduction parameters (control, low, mid, high dose):
Females achieving pregnancy: n= 9, 10, 10, 10
Dams with live young born: n= 9, 10, 10, 10
Implants/dam (mean): 15.7, 15.7, 14.1, 15.4
There were no effects on the time to achieve conception, and pregnancy length.
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse signs of toxicity were observed in the low dose
Dose descriptor:
LOAEL
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical biochemistry
Critical effects observed:
no
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects observed.
Histopathological findings:
not specified
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Parental treatment had no apparent effect on the offspring to day 4 of age.
Summary of effects (control, low, mid and high dose):
Live pups/dam at birth (mean): 14.8, 14.6, 12.7, 14.0
Live pups/dam at day 4 (mean): 14.6, 14.3, 12.7, 14.0
sex ratio (% m) at birth (mean): 54.2, 52.7, 50.0, 48.5
sex ratio (% m) at day 4 (mean): 54.2, 53.0, 50.0, 48.5
Male pup weight at birth (mean): 6.4, 6.3, 6.6, 6.3
Male pup weight at day 4 (mean): 8.7, 8.5, 9.2, 8.7
Female pup weight at birth: 5.9, 6.0, 6.1, 6.0
Female pup weight at day 4: 8.2, 7.9, 8.6, 8.4
Post-implantation survival index: 95.2, 93.5, 90.0, 94.8
Live birth index: 99.3, 99.4, 100.0, 95.9
Viability index: 98.6, 98.2, 100.0, 100.0

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed at the high dose
Critical effects observed:
no
Reproductive effects observed:
no
Conclusions:
In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), the test item diammonium phosphate was administered to male and female CD rats by gavage at dose levels of 0, 250, 750 and 1500 mg/kg bw/day. Based on the results, the NOAEL for parental toxicity was determined to be 250 mg/kg bw/day. No adverse effects were seen on any reproductive or developmental toxicity parameters. Thus, the NOAEL for reproductive/developmental toxicity can be considered to be 1500 mg/kg bw/day.
Executive summary:

In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422), the test item diammonium phosphate was administered to male and female CD rats (10 females and 5 males/dose group) by gavage at dose levels of 0, 250, 750 and 1500 mg/kg bw/day. Animals were paired 2 weeks after start of treatment. No mortality occurred. Some treatment-related effects on haematology parameters at 1500 and 750 mg/kg bw were evident, and body weight gain was temporarily reduced in the high dose group. Offspring was unaffected by parental exposure. Viability up to day 4 post-partum and macroscopic necropsy showed no effect on the pups. Based on the results, the maternal NOAEL is considered to be 250 mg/kg bw and the NOAEL for reproductive/developmental toxicity is considered to be 1500 mg/kg bw/day (equivalent to 1217 mg/kg bw/day ammonium-S-lactate).

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

No data is available for the target substance ammonium-S-lactate. The target substance fully dissociates into NH4+ ions and L(+)-lactic acid/lactate under aqueous and/or physiological conditions. Therefore, the requirement for reproduction toxicity shall be addressed based on information for lactic acid and ammonium ions. For more details on the read-across justification, please refer to IUCLID section 13.

Lactic acid is a ubiquitous and essential molecule of life, found in all higher animals and many micro-organisms. It is also found in many food items. This observation is common textbook knowledge hence can be considered as adequately and reliably documented, fulfilling the criteria of REACH Annex XI, section 1.1. Additional experimental evidence in support of the lack of potential of lactic acid (thus also ammonium-S-lactate) is scientifically not necessary.

The toxicity and toxicokinetics of lactic acid is specifically described in section 7.1 (Sterenborg, 2007). As lactic acid is a major and essential species in mammalian primary metabolism, and a ubiquitous ingredient in all kinds of food it is of minor toxicological relevance in comparison to the second dissociation product ammonium.

Publicly available data from the read-across substance diammonium phosphate was used to assess the toxicity of the ammonium ion. In a reproductive/developmental toxicity screening test (OECD 422), diammonium phosphate was administered to CD rats (10 females and 5 males/dose group) by oral gavage at dose levels of 250, 750 and 1500 mg/kg bw/day. The NOAEL for maternal toxicity is considered to be 250 mg/kg bw and the NOAEL for reproductive/developmental toxicity is considered to be 1500 mg/kg bw/day (equalling 1217 mg/kg bw ammonium-S-lactate).

Supporting information was derived from repeated dose toxicity studies conducted with suitable source substances for both dissociation products showing no adverse effects on reproductive tissues or organs. No histopathological changes of the testes were observed up 1792 mg/kg bw/day ammonium sulfate in a 13-week repeated dose toxicity study with rats (see IUCLID section 7.5.1; Takagi et al., 1999). In an oral combined chronic toxicity/carcinogenicity study all gonads of the males and females were examined. No substance-related histopathological changes were observed in the gonades up to 3 % in feed (1288.2 mg/kg bw/day in males and 1371.4 mg/kg bw/day in females) (see IUCLID chapter 7.7, Ota et al. 2006).

Thus, in accordance with REACH Annex IX, section 8.7.3, column 1, it is not necessary to perform an extended one-generation reproductive toxicity study with the target substance ammonium-S-lactate as there are no results that reveal concerns regarding reproductive toxicity.

Effects on developmental toxicity

Description of key information

No study is available elucidating the reproductive/developmental toxicity potential of the target substance. Thus, available data from the suitable read-across partner ammonium chloride and 2-ethylhexyl lactate was used to assess the potential of ammonium-S-lactate to induce reproductive/developmental effects.

In a developmental toxicity study conducted similar to OECD 414, ammonium chloride was administered to ten pregnant Sprague-Dawley rats at doses of 0 and 0.17 mol/L (corresponding to 9033 mg/L ammonium chloride) from gestation day 7 until gestation day 10. Neither maternal animals nor foetuses showed adverse effects after treatment with ammonium chloride.

In another developmental toxicity study (OECD 414), 2-ethylhexyl lactate was administered daily to female Wistar rats via inhalation at concentration levels up to 600 mg/m³ from day 6 through day 15 of gestation in sessions of six hours. Similarly, no treatment-related adverse effects were observed.

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:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality occurred
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
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:
not examined
Details on results:
No mortality occurred after treatment with the test item.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
not examined
Total litter losses by resorption:
not examined
Early or late resorptions:
no effects observed
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Dose descriptor:
NOAEL
Effect level:
9 033 mg/L drinking water
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Decreased foetal weights and crown-rump length were noted.
Reduction in number of live offspring:
not examined
Changes in sex ratio:
not examined
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No gross pathological abnomalities were noted.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No skeletal abnormalities were noted.
Visceral malformations:
not examined
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Ammonium chloride added to the oral fluids is not teratogenic, only producing an inhibition of fetal growth similar in degree to that caused by salicylate alone.
Dose descriptor:
NOAEL
Effect level:
9 033 mg/L drinking water
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed
Abnormalities:
no effects observed
Developmental effects observed:
no

Results of the study:

Control /NH4Cl /Na salicylate (500 mg/kg bw/day)
1) Maternal death (%):  0 /0 /0
2) Resorption-early( %): 6 /15 /15
3) Resorption-late (%) :  0 /1 /11
4) No.of conceptions: 136 /122 /288
5) Anomalous live young (%): 0 /0 /14 ±4
6) Growth weight (g): 3.2 /2.0 /2.1
7) Growth height (mm): 38 /27 /27

Conclusions:
In a developmental toxicity study in pregnant Sprague-Dawley rats, the maternal as well the fetal animals showed no adverse effects after treatment with ammonium chloride during gestation day 7-10.
Executive summary:

In a developmental toxicity study similar to guideline OECD 414, ammonium chloride was administered to ten pregnant Spraguw-Dawley rats at doses of 0 and 0.17 mol/L (corresponding to 9033 mg/L ammonium chloride) from gestation day 7 until gestation day 10.

The maternal as well the fetal animals showed no adverse effects after treatment with ammonium chloride. Pups were delivered by caesarean section on gestation day 20. No fetal skeletal or gross pathological signs of toxicity were noted, except a decreased fetal body weight and crown-rump-length. No maternal mortality was observed. The author concluded, that the test item is not teratogenic. Based on the results, the maternal and developmental NOAEL can considered to be 9033 mg/L (which equals 9.033 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.

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:
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).

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

No developmental toxicity data is available for the target substance ammonium-S-lactate. Due to complete dissociation of ammonium-S-lactate into NH4+ ions and L-lactic acid under aqueous and/or physiological conditions, the toxicology of ammonium-S-lactate can be understood in terms of effects of the dissociation products.

The lactate moiety of ammonium-S-lactate is considered to be devoid of any reproductive/developmental properties, based on the physiological role of lactic acid: lactic acid is a ubiquitous and essential molecule of life, found in all higher animals and many micro-organisms. It is also found in many food items. Reproductive/developmental toxicity is not a relevant endpoint for such a substance since there is no way of lowering exposure below minimum required levels or normal (or even abnormal) internal levels. The toxicity of lactic acid is specifically described in IUCLID section 7.1 (Sterenborg, 2007).

Nevertheless, available data from the suitable read-across partner 2-ethylhexyl lactate was used to assess the potential of the lactate moiety to induce reproductive/developmental effects. To assess the potential of the ammonium moiety available data from the read-across partner ammonium chloride was used. For justification of the read-across approach please refer to IUCLID section 13.

No treatment-related effects on 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, ammonium chloride was administered to ten pregnant Sprague-Dawley rats at doses of 0 and 0.17 mol/L (corresponding to 9033 mg/L ammonium chloride) from gestation day 7 until gestation day 10. Neither maternal animals nor foetuses showed adverse effects after treatment with ammonium chloride. Pups were delivered by caesarean section on gestation day 20. No foetal skeletal or gross pathological signs of toxicity were noted, except decreased foetal body weight and crown-rump-length. No maternal mortality was observed. The author concluded that the test item is not teratogenic.

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 ammonium-S-lactate.

Additional information