Reaction mass of glycerol, glycerol 1-formate, glycerol 2-formate, glycerol 1,2-diformate, glycerol 1,3-diformate and glycerol triformate

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effects on developmental toxicity

Description of key information

The developmental NOAEL for the target substance in rats is predicted to be 370 mg/kg bw/day

Link to relevant study records

Reference

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:

This endpoint study record is part of a Weight of Evidence approach comprising of read-across from two analogue source substance studies. The results of the read-across studies agree as to the toxicity to reproduction potential and are sufficient to fulfil the information requirements as further explained in the provided toxicity to reproduction endpoint summary.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Data for propane-1,2,3-triol (glycerol; CAS No. 56-81-5), formic acid, sodium salt (1:1) (sodium formate; CAS No. 141-53-7), formic acid, potassium salt (1:1) (potassium formate; CAS No. 590-29-4), formic acid, potassium salt (2:1) (potassium diformate; CAS No. 20642-05-1), formic acid, calcium salt (2:1) (calcium formate; CAS No. 544-17-2), 1,2-ethanediol, 1,2-diformate (ethylene diformate; CAS No. 629-15-2), 1,2-ethanediol (ethylene glycol; CAS No. 107-21-1) and formic acid (CAS No. 64-18-6) is used to address the toxicological data requirements for propane-1,2,3-triol and its esterification products with formic acid (EC No. 701-316-8) in an analogue read-across approach. The basis for this read-across approach is that, upon oral administration, the target substance is expected to undergo stepwise transformation by esterases in which the triformate constituent is converted into diformate constituents, diformate constituents are converted to monoformate constituents, and monoformate constituents to free glycerol, with formic acid being released at each step, as illustrated in Figure 1. The toxicity of the glycerol constituent/metabolite will be assessed using information on glycerol, and the toxicity of the formic acid metabolite will be assessed using information on sodium formate, potassium formate, potassium diformate, calcium formate, ethylene diformate, ethylene glycol and formic acid.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Target Substance: Propane-1,2,3-triol and its esterification products with formic acid; 701-316-8
Source Substance 1: Propane-1,2,3-triol ; 200-289-5 ; 56-81-5
Source Substance 2: Formic acid, sodium salt (1:1) ; 205-48-0 ; 141-53-7
Source Substance 3: Formic acid, potassium salt (1:1) ; 209-677-9 ; 590-29-4
Source Substance 4: Formic acid, potassium salt (2:1) ; 243-934-6 ; 20642-05-1
Source Substance 5: Formic acid, calcium salt (2:1) ; 208-863-7 ; 544-17-2
Source Substance 6: 1,2-Ethanediol, 1,2-diformate ; 211-077-7 ; 629-15-2
Source Substance 7: 1,2-Ethanediol ; 203-473-3 ; 107-21-1
Source Substance 8: Formic acid ; 200-579-1 ; 64-18-6
[See attached JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION for further details.]

The TS is a UVCB substance of 100% purity. On this basis, the source substances collectively represent 100% w/w of the target substance. The purities of the samples of source substances that were tested are not specifically known, but it is assumed that they would not have been sufficiently impure as to substantially affect the study results. On this basis, the applicability of the data on the source substances to the TS is not expected to be compromised by the presence of impurities in any of the substances.

3. ANALOGUE APPROACH JUSTIFICATION
The basis for this read-across approach is that, upon oral administration, the TS is expected to undergo stepwise hydrolysis by esterases in which the triformate constituent is converted into diformate constituents, diformate constituents are converted to monoformate constituents, and monoformate constituents to the free glycerol constituent, with formic acid being released at each step.
The TS is manufactured from a 1:1 molar ratio of glycerol and formic acid reactants and will therefore metabolize back to those same proportions of those same reactants. An exposure of an organism to the TS is therefore considered to be essentially equivalent to an exposure to a 1:1 molar mixture of glycerol and formic acid.

Refer to the attached JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION for further details as to how the source substances relate to the target substance.

For the following toxicity endpoints:
8.2 serious eye damage / eye irritation
8.3 skin sensitisation
8.5.1 acute toxicity by oral route
8.4.1 in vitro gene mutation study in bacteria;
8.4.2 mutagenicity: in vitro cytogenicity study in mammalian cells;
8.4 mutagenicity: in vivo genotoxicity;
8.6.3 long-term repeated dose toxicity: ≥ 12 months; and
8.7.2 developmental toxicity
information on the glycerol constituent/metabolite and the formic acid metabolite of the target substance will be used to predict the properties of the target substance.

4. DATA MATRIX
Refer to the attached JUSTIFICATION FOR READ-ACROSS OF TOXICOLOGICAL INFORMATION for data matrix details.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

370 mg/kg bw/day (nominal)

Basis for effect level:

other: lack of developmental toxicity

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

370 mg/kg bw/day (nominal)

Basis for effect level:

other: lack of developmental toxicity

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

The developmental NOAEL for the target substance in rats is predicted to be 370 mg/kg bw/day

Executive summary:

The analogue source substance propane-1,2,3-triol was reported to produce no clearly discernible effect on implantation or maternal or fetal survival in a study which followed the intent of OECD Test Guideline 414 (FDRL, 1974). The application of up to 1,310 mg/kg bw/day of propane-1,2,3-triol to pregnant rats from gestation Days 6 through 15 had no clearly discernible effect on nidation or on maternal or fetal survival.

Additionally the maternal toxicity, and toxicity to reproduction and development of the analogue source substance formic acid, calcium salt (2:1) was investigated in a pre-guideline study (Malorny, 1969). The analogue formic acid, calcium salt (2:1) was repeatedly administered to male and female Wistar rats in drinking water (0.2 and 0.4% in water; 7 days/week) in multigenerational experiments that lasted for 36 and 24 months (F0 to F4 and F2 generation, respectively). The authors reported that there were no signs of maternal toxicity, developmental toxicity or teratogenicity in rats exposed to 200 mg/kg bw/day of formic acid, calcium salt (2:1). Fertility, gestation, litter size, fetal development and the development of the progeny were unaffected in 3 generations. The NOAEL for developmental toxicity was therefore 200 mg/kg bw/day under the conditions of the study.

The lack of developmental toxicity of propane-1,2,3-triol was demonstrated in female rats with a NOAEL of 1,310 mg/kg bw/day and further supports the conclusion that any toxicity of the target substance will be attributable to its formate content rather than its glycerol content. On this basis, the developmental and reproductive NOAEL in rats for formic acid, calcium salt (2:1) of 200 mg/kg bw/day would be equivalent to 370 mg/kg bw/day for the target substance.

On the basis of the information presented above, the developmental NOAEL for the target substance in rats is predicted to be 370 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

370 mg/kg bw/day

Study duration:

chronic

Experimental exposure time per week (hours/week):

7

Species:

rat

Justification for classification or non-classification

As per Regulation (EC) 1272/2008 as amended, the target substance does not meet the criteria for classification.

The lack of developmental toxicity for the target substance indicates that the substance does not meet the classification criteria.