Docosanoic acid, monoester with glycerol

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

other: weight of evidence analysis based on expert evaluated data on structural analogues

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Based on expert group reviews

Justification for type of information:

Because of the structural and functional similarities, data from other glyceryl monoesters, and other similar compounds, are also included in thie weight of evidence assessment as supporting data.
The following expert opinions (attached in sections 13) will be used in the weight of evidence approach:
CIR 2016: Cosmetic Ingredient Review. Safety assessment of monoglyceryl monoesters as used in cosmetics. Final amended report, January 15, 2016
CIR 2019: Safety Assessment of Fatty Acids & Fatty Acid Salts as Used in Cosmetics. Final release, January 4, 2019.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2022

Report date:

2022

Materials and methods

Principles of method if other than guideline:

The results are based on a weight of evidence analysis from collection of data extracted from the literature and from expert opinions. For more details please refer to the attached weight of evidence documents as well as documents attached in section 13 identified as key references.

In relation to the data requirements of REACH Annex VIII (10-100 t/y), data on reproductive toxicity must be provided. No data on this endpoint is available for docosanoic acid, monoester with glycerol (glycerol monobehenate). Glycerol monobehenate is a mono-constituent substance. The main component is docosanoic acid, monoester with glycerol which is present in the product at a concentration of 80 – 90%, the remaining compounds are mainly fatty acids and monoesters of fatty acid and glycerol. Glycerol can also be present in a low concentration. Glyceryl monoesters (monoglycerides) are metabolized to free fatty acids and glycerol, both of which are available for the resynthesize of triglycerides.

The possible genetic toxicity of this substance is therefore assessed in the present weight of evidence analysis based on expert group assessments of the substances, which is considered the most valid data for the assessment, an overall weight of evidence approach based on these expert evaluations. The assessment is also supported by Q(SAR) predictions using different QSAR models (VEGA QSAR Tool and The Danish EPA QSAR database).
Expert group assessments of the substances are considered the most valid data

GLP compliance:

not specified

Remarks:

Data extracted from expert opinions

Test material

Test material information

Constituent 1

Reference substance name:

Docosanoic acid, monoester with glycerol

EC Number:

250-097-0

EC Name:

Docosanoic acid, monoester with glycerol

Cas Number:

30233-64-8

Molecular formula:

C25H50O4

IUPAC Name:

2-hydroxy-1-(hydroxymethyl)ethyl docosanoate

Test material form:

solid

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Remarks on result:

other: Based on collection of relevant data, see attached file

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

Any other information on results incl. tables

From the literature search, specific data on reproductive toxicity of mono-glyceryl monoesters and other substances with similar structure was found in two assessment performed by the Cosmetic Ingredient Review (CIR) expert panel (CIR 2016, 2019). These are described in the following:

- A reproduction/developmental toxicity screening test was conducted in male and female
Sprague-Dawley rats for glyceryl oleate. Both males and females were dosed by gavage with 0,
100, 300, or 1000 mg/kg bw/day glyceryl oleate in corn oil once daily for 14 days prior to
mating; the males were dosed for an additional 28 days, and dosing of the females continued
until day 4 of lactation. There were 12 females in the control and 3 test groups, 7 males in the
control and high dose groups, and 12 males in the low- and mid-dose groups. A satellite group
of 5 males and 5 females were dosed for 42 days, with a 14-day post-dosing observation
period. The NOAELs for systemic toxicity (males and females), fertility (males and females),
and development (F1 generation) were 1000 mg/kg bw/day. No effects related to the
administration of the test-article were observed in parental animals or offspring.

- A gavage study in accordance with OECD 414 was performed on 7 female Sprague-Dawley
rats (per dose group). Dams received undecylenic acid: 0, 150, 450, or 1000 mg/kg bw/day in
corn oil from day 6 to day 20 of gestation. The maternal NOEL was set at 450 mg/kg bw/day
and the maternal LOAEL was set at 1000 mg/kg bw/day. Hypersalivation was observed from
gestation day 12 in all dose groups in a dose- dependent manner; 3 dams in the high dose
group died on gestation day 7 without clinical signs of toxicity or adverse effects at necropsy; no
treatment-related adverse effects observed in offspring.

- A gavage study in accordance with OECD 415 was performed on 24 female Sprague Dawley
rats (per dose group). The rats received undecylenic acid: 0, 150, 450 or 750 mg/kg bw/day in
corn oil. The high dose group treatment was terminated due to high mortality; dams in mid-dose
group were observed with hypersalivation and signification reduced body weight gain compared
to controls; no treatment-related adverse effects observed in offspring. The maternal NOAEL
was set at 150 mg/kg bw/day and maternal LOAEL was set at 450 mg/kg bw/day. The foetal
NOAEL was set at 450 mg/kg bw/day.

Further, data from expert opinions on docosanoic acid (behenic acid) were identified and data from
reproductive and developmental toxicity studies are described in the following:
- Two gavage studies in accordance with OECD 422 was performed with docosanoic acid using
male/female Sprague Dawley rats. In one study, the NOAEL = 1000 mg/kg bw/day for
reproduction and development. For this study, no adverse effects fertility indexes, no changes
in gestation length, delivery and lactation and no adverse effects on the sex ratio, body weight
or viability of pups. Further, No morphological abnormalities in external and visceral observation
in pups. In another study, NOAEL > 1000 mg/kg bw/day based on no treatment-related adverse
effects observed in parental animals or offspring.
Overall, CIR (2019) concluded that Lithium Stearate caused no treatment-related adverse reproductive
or developmental effects at doses up to 1000 mg/kg bw/day in dermal studies. While non-reproductive
effects were noted in parental animals in a few oral studies, no treatment-related adverse effects were
observed on the reproductive cycles or development of offspring in rats exposed to Behenic Acid,
Calcium Stearate, Capric Acid, Caprylic Acid, or Undecylenic Acid.

EFSA (2017), in their evaluation of glycerol concluded that reproductive and prenatal developmental
studies were limited to conclude on reproductive toxicity, but no dose-related adverse effects were
reported. None of the animal studies identified an adverse effect for glycerol.

Applicant's summary and conclusion

Conclusions:

Data on reproductive and developmental toxicity of glycerol monobehenate
was not available. However, data from other glyceryl monoesters with
structural and functional similarities are available and were included in this
weight of evidence assessment. Data on Docosanoic acid (behenic acid) was
also used as well as data on glycerol. The available data has been extracted
from expert opinions (CIR 2016; CIR 2019; EFSA 2017; OECD 2001).
No signs of reproductive or developmental toxicity were observed in studies
performed with similar mono-glyceryl monoesters. For docosanoic acid
(behenic acid), NOAEL was > 1000 mg/kg bw/day in OECD 422 studies. For
glycerol, no signs of reproductive or developmental toxicity were identified.

Therefore, it can with a high degree of confidence it can be concluded that no
adverse effects on fertility and developmental endpoints would be expected
and that an assumed NOAEL for glycerol monobehenate will be >1000 mg/kg
bw/day which is normally considered as the highest relevant dose level when
testing for reproduction and prenatal developmental toxicity. Thus, glycerol
monobehenate is not to be classified for reproductive or developmental toxicity.

Executive summary:

Data on reproductive and developmental toxicity of glycerol monobehenate was not available. However, data from other glyceryl monoesters with structural and functional similarities are available and were included in this weight of evidence assessment. Data on Docosanoic acid (behenic acid) was also used as well as data on glycerol. The available data has been extracted from expert opinions (CIR 2016; CIR 2019; EFSA 2017; OECD 2001).
No signs of reproductive or developmental toxicity were observed in studies performed with similar mono-glyceryl monoesters. For docosanoic acid (behenic acid), NOAEL was > 1000 mg/kg bw/day in OECD 422 studies. For
glycerol, no signs of reproductive or developmental toxicity were identified.
Further, CIR (2019) concluded that Lithium Stearate caused no treatment related adverse reproductive or developmental effects at doses up to 1000 mg/kg bw/day in dermal studies. While non-reproductive effects were noted in parental animals in a few oral studies, no treatment-related adverse effects were observed on the reproductive cycles or development of offspring in rats exposed to Behenic Acid, Calcium Stearate, Capric Acid, Caprylic Acid, or Undecylenic Acid.
EFSA (2017), in their evaluation of glycerol concluded that reproductive and
prenatal developmental studies were limited to conclude on reproductive
toxicity, but no dose-related adverse effects were reported. None of the animal
studies identified an adverse effect for glycerol.
In support, based on Q(SAR) predictions using the Danish EPA QSAR
database and the VEGA Q(SAR) prediction model, it can be concluded that
glycerol monobehenate does not show possible mechanisms of reproductive
toxicity.
Therefore, it can with a high degree of confidence it can be concluded that no
adverse effects on fertility and developmental endpoints would be expected
and that an assumed NOAEL for glycerol monobehenate will be >1000 mg/kg
bw/day which is normally considered as the highest relevant dose level when
testing for reproduction and prenatal developmental toxicity. Thus, glycerol
monobehenate is not to be classified for reproductive or developmental toxicity.
The available information comprises adequate, reliable studies from reference
substances with similar structure and intrinsic properties. The weight-ofevidence approach is justified based on common functional group and common
precursors/breakdown products. The information from these independent
sources is consistent and provides sufficient weight of evidence leading to an
endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No
1907/2006