Lauric acid, monoester with propane-1,2-diol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

a screening study for reproductive/developmental toxicity does not need to be conducted because there is evidence from available information on structurally related substances, from (Q)SAR estimates or from in vitro methods that the substance may be a developmental toxicant

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

250 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

A 90 day sub-chronic oral study in the rat on the read-across analogue substance (RD 15143) has been performed. The results of this study demonstrated that there were no adverse effects on reproductive organs or tissues, although adverse effects were
noted on other organs, therefore it is considered that a 2 generation study is not required.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
A read-across approach has been suggested based on the metabolism of the common structure of propylene glycol fatty acid esters. Read-across is implemented from already existing data from testing on Dapro FX511, on metabolism products (fatty acid and propylene glycol) and on propylene glycol monolaurate.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source chemical:

Dapro FX 511
EC Number: 285-503-5
CAS Number: 85114-00-7

Target chemical:

RM1004755:
Einecs No. 248-315-4
CAS No. 27194-74-7

See read-across justification report in section 13

3. ANALOGUE APPROACH JUSTIFICATION
A matrix of data has been created using the Dapro FX511 REACH dossier, read-across document for aquatic tox from Dapro FX510 (source) to Dapro FX511 (target), a HPV test plan for the glycol esters of the aliphatic esters chemicals (including Propylene glycol, monostearate (CAS 1323-39-3)) and a Petition to include propylene glycol monolaurate into 7 CFR 205 (constituent of RM1004755).
See read-across justification report in section 13

4. DATA MATRIX
Data matrix is given in read-across justification report in section 13

Reason / purpose for cross-reference:

read-across source

Species:

rat

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

See Tables 2 and 3 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the
rat Tables 2-10", attached in the background data section below, for data

Number of abortions:

no effects observed

Description (incidence and severity):

See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data. Rats do not abort foetuses but
resorb them

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Early and late implantation losses were not statistically significant compared to control animal group
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Table
s 2-10", attached in the background data section below, for data

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Early and late resorption values not statistically significant compared to control animal group
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tab
les 2-10", attached in the background data section below, for data

Early or late resorptions:

no effects observed

Description (incidence and severity):

See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data

Dead fetuses:

no effects observed

Description (incidence and severity):

No dead foetuses were noted on termination at day 20 of gestation in either the control group or any
of the treatment groups.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

No rat gave birth prior to termination at day 20.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tab
les 2-10", attached in the background data section below, for data
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): It is stated in the results section 3.3.1 (Reproductive assessment) of the report that -
"All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females
with live young at termination on Day 20 of gestation in the Control group, and at 100, 300 and 1000
mg/kg/day, respectively. "
From this information it is also apparant that there were no early deliveries or still births.
This shown in Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the
rat Tables 2-10", attached in the background data section below, for data

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

It is stated in the results section 3.3.1 (Reproductive assessment) of the report that -
"All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females
with live young at termination on Day 20 of gestation in the Control group, and at 100, 300 and 1000
mg/kg/day, respectively. "
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: No effects

Remarks on result:

not determinable due to absence of adverse toxic effects

Remarks:

There were no signs at routine examination that could be associated to treatment and no signs were observed in association with dose administration. Bodyweight, gravid uterine weight, food consumption and macroscopic evaluation were not adversely affected by treatment with RD 15134 up to 1000 mg/kg/day when compared with Control animals. At 1000 mg/kg/day, slight mean body weight loss was recorded during Days 6-7 of gestation and mean food consumption was slightly low during Days 6-9.

Abnormalities:

no effects observed

Description (incidence and severity):

There were no signs at routine examination that could be associated to treatment and no signs were observed in association with dose administration. Bodyweight, gravid uterine weight, food consumption and macroscopic evaluation were not adversely affected by treatment with RD 15134 up to 1000 mg/kg/day when compared with Control animals. At 1000 mg/kg/day, slight mean body weight loss was recorded during Days 6-7 of gestation and mean food consumption was slightly low during Days 6-9.

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Male, female and overall fetal weights were statistically significantly lower for females receiving 1000
mg/kg/day, when compared with Controls.
At 1000 mg/kg/day, mean fetal weight was lower than in Controls (11% lower) reflecting the fact that
the mean fetal weight in the majority of litters in this group was less than 3.40 grams whereas in the
Control group most litters had a mean fetal weight above 3.70 grams. This difference was considered
to reflect an effect of treatment on fetal growth and not to be due to the slightly higher mean litter size
in the 1000 mg/kg/day group.
See Table 7 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

Among females allocated to the 100, 300 or 1000 mg/kg/day groups, the mean numbers of corpora lutea were slightly higher than in Controls; as the number of corpora lutea reflect the number of
eggs shed and treatment did not start until Day 6 after mating these differences were due to chance as they were established before the start of treatment. Principally as a result of these differences
which were due to chance, the mean numbers of implantations and live fetuses in all treated groups were slightly higher than in Controls and the difference for live fetuses in the 1000 mg/kg/day group a
ttained statistical significance.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data

Changes in sex ratio:

effects observed, non-treatment-related

Description (incidence and severity):

The sex ratio was 45.6% males for the 300 mg/kg/day group compared to 57.1% for the control group
and 52.7% and 52.8% for the 100 mg/kg/day and 1000 mg/kg/day, respectively.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Gravid uterine weights, embryo-fetal survival and litter and placental weights were unaffected by treatment up to 1000 mg/kg/day. Intergroup differences in gravid uterine weight reflected intergroup
differences in litter size which were due to chance.
See Table 7 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data

External malformations:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg/day there were two fetuses in two litters with the major abnormality short/threadlike tail.
See Table 8 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterized by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent lobe of thyroid; partial
ly undescended lobe of thymus; small/absent renal papilla and dilated ureter when compared to concurrent control and the incidences were outside of the Historical Control Data with the exception of
delayed/incomplete ossification/unossified cervical vertebrae.
Although not adverse in isolation, many of these findings would usually be associated with a significant decrease in body weight signifying a delay in fetal development. However, this was not the case on this study with some abnormalities present in fetuses with weights at the upper end of the Control range. There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the
HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudalvertebrae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse.
Sixteen fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. In isolation, this finding was not considered to represent an adverse effect on fetal development.
See Tables 8-10 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Placental and litter weights were similar to Controls, and were not affected by the administration of RD 15134.
Male, female and overall fetal weights were statistically significantly lower for females receiving 1000mg/kg/day, when compared with Controls. This difference was considered to reflect an effect of treatment on fetal growth and not to be due to the sli
ghtly higher mean litter size in the 1000 mg/kg/day group.
There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterize d by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent lobe of thyroid;
partially undescended lobe of thymus; small/absent renal papilla and dilated ureter when compared to concurrent control and the incidences were outside of the Historical Control Data with the exception of delayed/incomplete ossification/unossified cervical vertebrae.
There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudal vertebrae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse.
Sixteen fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. In isolation, this finding was not considered to represent an adverse effect on fetal development.
See Tables 8-10 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: embryotoxicity - overall effects

Remarks on result:

other:

Remarks:

Male, female and overall fetal weights were statistically significantly lower for dams receiving 1000 mg/kg/day, when compared with Controls this reflected an effect of treatment on fetal growth, not due to the slightly higher mean litter size in the 1000 mg/kg/day group. There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterized by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent or partially undescended lobe of thyroid; small/absent renal papilla and dilated ureter compared to concurrent control, these incidences were outside of the Historical Control Data except the delayed/incomplete ossification/unossified cervical vertebrae. There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudal verte brae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse. 16 fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/ kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. This finding did not represent an adverse effect on fetal development.

Abnormalities:

not specified

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no-observed-adverse-effect-level (NOAEL) and 300 mg/kg/day was the no-observed-adverse-effect-level (NOAEL) for embryo-fetal survival, growth and development.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

An OECD 414 embryo-fetal development toxicity test on the read-across analogue structure in rats has been performed and the results are
included in this assessment.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

For the embryo-fetal assessment phase of the study three groups of 20 females received RD 15134 (the read-across analogue substance) at doses of 100, 300 or 1000 mg/kg/day by oral gavage administration, from Day 6 to 19 after mating. A similarly constituted Control group received the vehicle, corn oil at the same volume dose as treated groups. Animals were killed on Day 20 after mating for reproductive assessment and fetal examination.

Clinical observations, body weight, gravid uterine weight and food consumption were recorded. Adult females were examined macroscopically at necropsy on Day 20 after mating and all fetuses were

examined macroscopically at necropsy and subsequently by detailed internal visceral examination or skeletal examination.

It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no-observedadverse-effect-level (NOAEL) and 300 mg/kg/day was the no-observed-adverse- effect-level (NOAEL)

for embryo-fetal survival, growth and development.

Justification for classification or non

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008 no classification for maternal toxicity or developmental toxicity is required.