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

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

other: Weight of evidence analysis based on expert reviews on hydrolysis products and 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:

Stearic acid, monoester with propane-1,2-diol (PGMS) is manufactured by a reaction between stearic acid and propylene glycol. The UVCB substance belongs to the group of fatty acid esters.
Within this group is the group of polyglycerol fatty acid esters, which are commonly used in cosmetics and as food ingredients representing substances composed of chemical units of similar structure as the fatty acid esters with propylene glycol. The polyglycerol fatty acids are esters of fatty acids and units of glycerol. The glycerol units represent the propylene glycol in “Stearic acid, monoester with propane-1,2-diol”.

To assess the repeated dose toxicity of the UVCB substance, the toxicity of polyglyceryl fatty acid esters in general is therefore considered.

Further, Stearic acid, monoester with propane-1,2-diol (PGMS) is a UVCB substance. The two main constituents of the UVCB substance are the monoester of propane-diol with octadecanoic acid (45-98%) and the monoester of propane-diol with palmitic acid (2-50%).

Detailed study reports on this endpoint is not available for “Stearic acid, monoester with propane-1,2-diol (PGMS)”, however data on PGMS in expert reviews are available. Further, existing data on propylene glycol stearate (PGS) and glycerol stearate (CIR 2015; 2016) is used as support.

In general, data from the following expert assessments are used in a weight of evidence approach:
 
CIR (2015). Safety Assessment of Propylene Glycol Esters as Used in Cosmetics, Final Amended report, January 15, 2015
CIR (2016). Safety Assessment of Monoglyceryl Monoesters as Used in Cosmetics, Final Amended report, January 15, 2016
EFSA (2018a). Re-evaluation of propane-1,2-diol esters of fatty acids (E 477) as a food additive EFSA Panel on Food Additives and Flavourings (FAF). EFSA Journal 2018;16(12):5497.
EFSA (2018b). Re-evaluation of propane-1,2-diol (E 1520) as a food additive EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS). EFSA Journal 2018;16(4):5235

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:

In relation to the data requirements of REACH VIII (10-100 t/y), data on repeated dose toxicity must be provided. Detailed study reports on this endpoint is not available for Stearic acid, monoester with propane-1,2-diol (PGMS), however data on PGMS in expert reviews are available.

Metabolism studies of propane-1,2-diol esters of stearate show that the substances are partially hydrolysed by pancreatic lipase; approx. 70% in 15 h. As the passage through the small intestine has a duration of 6–8 h, unhydrolyzed propane-1,2-diol esters of stearate will be present in the gastrointestinal tract for absorption (EFSA 2018a).

The possible repeated dose toxicity of this substance is therefore assessed in the present weight of evidence analysis based on existing data on propane-1,2-diol esters of fatty acids including PGMS (EFSA 2018a) and the relevant hydrolysis products propane-1,2-diol (EFSA 2018b) and fatty propylene glycol stearate (PGS) and glycerol stearate (CIR 2015; 2016).

As the substance is an UVCB-substance and as the EFSA expert group assessments of the substance is considered the most valid data for the assessment, an overall weight of evidence approach is used for the assessment.

Test material

Test material information

1

Reference substance name:

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

EC Number:

215-354-3

EC Name:

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

Cas Number:

1323-39-3

Molecular formula:

C21H42O3

IUPAC Name:

2-hydroxypropyl stearate

Test material form:

solid: pellets

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (nominal)

Basis for effect level:

other: Collection of relevant data. Please see attached document

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Propane-1,2-diol esters of fatty acids are listed as a food additive (E 477) and has been re-evaluated by EFSA in 2018 (EFSA 2018). The Scientific Committee on Food (SCF) endorsed the acceptable daily intake (ADI) of 25 mg/kg bw/day established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 1974 (EFSA 2018)

Three studies on PGMS are reported for repeated dose toxicity. In a 13-week study, rats were exposed to PGMS via the diet containing 0%, 1.5%, 3.36% or 7.52% of PGMS (equivalent to 0, 1350, 3024 or 6768 mg/kg bw per day (Brandner, 1973 in EFSA 2018). At termination of the study, measurements of relative organ weights, histopathology, clinical chemistry and urinary analyses showed no treatment related difference between the groups.

The NOAEL identified in this study was therefore the highest dose tested; 6768 mg/kg bw/day (EFSA 2018a).

In a 90-day study in Sprague–Dawley rats received a diet containing 2.5%, 5% or 10% succistearin 14 (equivalent to 0, 390, 780 or 1,560 mg PGMS/kg bw/day); the control group was fed with soybean oil (King et al., 1971 in EFSA 2108a). The total fat content in each diet was 21%. No clinical symptoms were observed and no effects on body weight gain. Haematology, urinalysis and comparison of organ weight data revealed no treatment related effects as well as gross and microscopic pathology (EFSA 2018a).

Finally, a study in Beagle dogs is reported. The dogs were exposed for 6 months via the diet containing 0%, 5% or 10% succistearin (17.3% of PGMS) (equivalent to 0, 216 or 432 mg PGMS/kg bw/day); the control group was fed with soybean oil (King et al., 1971 in EFSA 2018). No treatment-related effects were detected in the Beagle dogs (EFSA 2018a).

Further, The safety of propylene glycol esters was reviewed by Cosmetic Ingredient Review (CIR) Expert Panel for the use in cosmetic products (CIR 2015). Propylene Glycol Stearate (PGS) is a mixture of the mono- and diesters of triple-pressed stearic acid and propylene glycol and data on repeated dose toxicity is included in the review. No detailed information is available, but it is stated that no evidence of oral or dermal toxicity was found in subchronic animal studies. A chronic six-month feeding study showed no signs of toxicity when a mixture containing 17% propylene glycol monostearate was incorporated at 10% into the diets of rats and dogs (CIR 2015).

The safety of monoglyceryl monoesters was also reviewed by CIR (CIR 2016) with a similar conclusion. No toxicity was reported in subchronic and chronic dermal toxicity tests, 4-5% Glyceryl Stearate (GS) in rabbits, other than local effects of moderate irritation (CIR 2016).

Further, it is noted that PGS and GS is considered Generally Recognized as Safe (GRAS) for food use (CIR 2015; 2016).

In support, Data on the repeated dose toxicity of propane 1,2-diol is available from a recent EFSA evaluation (2018b). Based on a large data package on short-term and subchronic toxicity, EFSA concluded that no treatment-related effects were observed in subchronic toxicity in rat, mice, rabbit. Further, no adverse effects
were reported in a 2-year chronic study in rats with propane-1,2-diol (up to 2500 mg/kg bw per day). Also, data from gavage studies using mice, rats and monkeys and dogs, did not show any repeated dose toxicity using 1000 mg/kg bw/day. Overall, EFSA (2018b) concluded no adverse effects of propane 1,2-
diol and that an ADI of 25 mg/kg bw/day could be established.

 

Based on the available studies on PGMS and the propylene glycol esters described above as well as propane 1,2-diol, it can from an overall weight of evidence approach be concluded that the UVCB substance Stearic acid, monoester with propane-1,2-diol (PGMS) is of very low concern for repeated dose toxicity. It can with a high degree of confidence be concluded that an assumed NOAEL for PGMS is far above 1000 mg/kg bw/day, which is normally considered as the highest relevant dose level when testing for repeated dose toxicity. Thus, no STOT RE classification should apply for the substance (PGMS).

Applicant's summary and conclusion

Conclusions:

Based on the available studies on Stearic acid, monoester with propane-1,2-diol (PGMS) and supportive data on propylene glycol stearate (PGS) and glycerol stearate (GS), it can from an overall weight of evidence approach be concluded that the UVCB substance PGMS is of very low concern for repeated dose toxicity. It can with a high degree of confidence be concluded that an assumed NOAEL is far above 1000 mg/kg bw/day, which is normally considered as the highest relevant dose level when testing for repeated dose toxicity. Thus, no STOT RE classification should apply for PGMS.

Overall, available information comprises adequate, reliable studies from
reference substances with similar structure and intrinsic properties. Using data
from comparable substances is justified based on common functional group,
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.

Executive summary:

Stearic acid, monoester with propane-1,2-diol (PGMS) is a UVCB substance. The two main constituents of the UVCB substance are the monoester of propane-diol with octadecanoic acid (45-98%) and the monoester of propane-diol with palmitic acid (2-50%). Detailed study reports on this endpoint is not available for PGMS, however data on PGMS in expert reviews are available. Further, existing data on propylene glycol stearate (PGS) and glycerol stearate (GS) (CIR 2015; 2016) are used as support.

 

Three studies on PGMS are reported for repeated dose toxicity. Two 90-day studies in rats exposed to PGMS via the diet at concentrations up to 6768 mg PGMS /kg bw per day was conducted. Animals were examined for differences in organ weights, gross and microscopic pathology, haematology and urinalysis. No clinical symptoms or treatment related effects were found. The NOAEL based on these studies is therefore the highest dose tested; ≥ 6768 mg/kg bw/day (EFSA 2018).

 

No treatment-related effects were detected in the Beagle dog exposed for 6 months via the diet containing up to 432 mg PGMS/kg bw/day (King et al., 1971 in EFSA 2018).

Supportive of this, no evidence of oral or dermal toxicity was found in subchronic studies of animals exposed to propylene glycol monostearate in rats and dogs (CIR 2015). No toxicity was reported in subchronic and chronic dermal toxicity tests, 4-5% GS in rabbits, other than local effects of moderate irritation (CIR 2016).

 

Further, it is noted that PGS and GS is considered Generally Recognized as Safe (GRAS) for food use (CIR 2015; 2016).

 

Also, data on propane 1,2-diol did not show any adverse effects of propane 1,2-diol, for which an ADI of 25 mg/kg bw/day could be established by EFSA (2018b).

 

Based on the available studies on PGMS and the propylene glycol esters described above, it can from an overall weight of evidence approach be concluded that the UVCB substance PGMS is of very low concern for repeated dose toxicity. It can with a high degree of confidence be concluded that an assumed NOAEL for PGMS is far above 1000 mg/kg bw/day, which is normally considered as the highest relevant dose level when testing for repeated dose toxicity. Thus, no STOT RE classification should apply for the substance.

 

Overall, available information comprises adequate, reliable studies from reference substances with similar structure and intrinsic properties. Using data from comparable substances is justified based on common functional group, 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.