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

Endpoint summary

Description of key information

The oral rat LD50 value for the TS can be predicted to be ~3.07 g/kg bw.

 

The acute inhalation toxicity study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance.

The acute dermal LD50 of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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 six analogue source substance studies. The results of the read-across studies agree as to the acute oral toxicity and are sufficient to fulfil the information requirements as further explained in the provided acute toxicity 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 (TS): 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

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Sex:

not specified

Dose descriptor:

LD50

Effect level:

ca. 3 070 mg/kg bw

Conclusions:

The oral rat LD50 value for the TS can be predicted to be ~3.07 g/kg bw.

Executive summary:

Although the result of a definitive acute oral toxicity test on the TS is not available, information is available on the acute oral toxicity of structurally-related analogue source substances, which can be used to adequately predict this property of the TS. Acute mammalian toxicity tests have been performed on the analogue source substances, SS1, SS2, SS3, SS5, SS6 and SS7.

The acute oral toxicity values of SS1, SS6, and SS7 were determined in male Wistar rats (Smyth, et al., 1941). The study was conducted in a similar manner as OECD Test Guideline 401. Animals (n=10/compound) were orally administered (gavage) a maximum concentration of 50% diluted in water or dispersed in 1% aqueous sodium sulfate of heptadecanol (Tergitol) and were observed for 14 days for signs of toxicity and mortality. A gross necropsy was performed on any animals whose death was inconsistent with the indications from others receiving the same treatment. The oral LD50 values in rats were determined to be 27.50, 1.51, and 8.54 g/kg bw for SS1, SS6 and SS7, respectively.

SS6 is structurally analogous to the TS diformate constituents, but is based on the smaller diol, ethylene glycol, rather than the larger triol, glycerol. Like the TS, SS6 is expected to be hydrolysed by esterases, following a similar stepwise process releasing formic acid at each step, but producing free ethylene glycol rather than free glycerol. In this way, SS6 is considered to be a comparable source of formic acid to the TS, and information on SS6 will be used to predict the effects of equivalent molar doses of formic acid arising from exposure to the TS. SS7 is the free ethylene glycol hydrolysis product that will be generated alongside the formic acid following exposure to SS6, and information on SS7 will be used to help clarify whether any effects of exposure to SS6 should be attributed to its formic acid or ethylene glycol components.

Since SS6, a formate ester, exhibited significantly greater toxicity than SS1 and SS7, which are both un-esterified alcohols, it is reasonable to conclude that the presence of the formate (whether in esterified form or as formate ion hydrolysis product) was responsible for the effect. Given that SS6 contains 203% of the formate in the same dose of TS, the oral LD50 of the TS in rats can be predicted to be 3.07 g/kg bw.

The acute toxicity values of formic acid salts SS2, SS3 and SS5 were determined in 45 or 50 white mice (Malorny, 1969). The oral LD50 values were 11.2 g/kg bw for SS2 (equivalent to 7.58 g/kg bw as formate), 5.5 g/kg bw for SS3 (equivalent to 3.01 g/kg bw as formate), and 1.92 g/kg bw for SS5 (equivalent to 1.36 g/kg bw as formate). As discussed by the author, the greater toxicity of SS3 and SS5 over SS2 is due to the inherent toxicity of the cations, so each of the three results represents a worse case than formate alone, Allowing the acute oral toxicity of neutral formate in mice to be concluded to be ≥ 7.58 g/kg bw, which would be equivalent to ≥ 19.8 g/kg bw TS.

Source Substance	Source Substance (SS) LD50 mg/kg bw	Predicted LD50 of the Target Substance (TS) mg/kg bw
SS1: Glycerol	27,500	35,700
SS2: Sodium formate	11,200	19,800
SS3: Potassium formate	5,500	7,870
SS5: Calcium formate	1,920	3,550
SS6: Ethylene glycol diformate	1,510	3,070
SS7: Ethylene glycol	8,540	Data to clarify the source of the SS6 result only.

On the basis of the acute oral toxicity information presented above, it can be concluded that the acute oral toxicity of the TS is driven by its formate content, and that the oral rat LD50 value for the TS can be predicted to be ~3.07 g/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 070 mg/kg bw

Quality of whole database:

The available information meets the tonnage driven data requirements of REACH, and there is acceptable reliability and consistency across the different studies.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

The available information meets the tonnage driven data requirements of REACH, and there is acceptable reliability and consistency across the different studies.

Justification for classification or non-classification

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

 

Oral toxicity: The oral LD50 value is predicted to be >2000 mg/kg bw and therefore does not meet the classification criteria.

 

Dermal toxicity: The dermal LD50 value is predicted to be >2000 mg/kg bw and therefore does not meet the classification criteria.

 

Inhalation toxicity: As no inhalation toxicity data is available, route-to-route extrapolation (CLP Annex I, 3.1.3.6.2.1.(a)) of the oral to inhalation toxicity is permitted. Following the guidance from ECHA, the oral LD50 value of 3070 mg/kg bw is extrapolated to 15.96 mg/L/4h taking into account the vapour pressure of the substance that mists are the most likely form of exposure, the substance does not meet the classification criteria.

 

Specific target organ toxicity – single exposure: No systemic toxicity was reported following single exposure and therefore does not meet the classification criteria.