Registration Dossier

The two year NOAEL for the TS in rats is predicted to be 370 mg/kg bw/day in drinking water and 92.5 mg/kg bw/day in feed

Toxic effect type:

dose-dependent

Reference

Endpoint:

chronic 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 four analogue source substance studies. The results of the read-across studies agree as to the repeated dose toxicity potential and are sufficient to fulfil the information requirements as further explained in the provided repeated dose 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: 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

Dose descriptor:

NOAEL

Remarks:

2-year

Effect level:

370 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

Remarks on result:

other: in drinking water

Dose descriptor:

NOAEL

Remarks:

2-year

Effect level:

92.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

Remarks on result:

other: in feed

Critical effects observed:

no

The lack of repeated dose toxicity of SS1 evidenced by a one year NOEL of 10,000 mg/kg bw/day in rats further supports the conclusion that any toxicity of the TS will be attributable to its formate content rather than its glycerol content. On this basis, the 80-week NOAEL in mice for SS4 of 400 mg/kg bw/day would be equivalent to 740 mg/kg bw/day for the TS. Similarly, the 104-week NOAEL in rats for SS4 and 2-year NOEL in rats for SS5 of 50 and 200 mg/kg bw/day, respectively, would be equivalent to 92.5 and 370 mg/kg bw/day, respectively, for the TS.

Conclusions:

The two year NOAEL for the TS in rats is predicted to be 370 mg/kg bw/day in drinking water and 92.5 mg/kg bw/day in feed

Executive summary:

No repeated dose toxicity data were available for the TS; however, data on the analogue source substances SS1, SS4, and SS5 were identified.

The effects of the analogue source substance SS1 were evaluated in a 2-year study (Hine, et al., 1953). Long-Evans rats (at least 22 animals per group) were fed diets containing SS1 at a dose of 0, 5, or 10% for 2 years (equivalent to 0, 2,500, 5,000 mg/kg bw/day, respectively) or 20% for 1 year (equivalent to 10,000 mg/kg bw/day). The study authors concluded that the administration of 10% (equivalent to 5,000 mg/kg bw/day) of SS1via the diet for two years did not induce any adverse effects in rats. Based on the results, a no observed effect level (NOEL) was determined to be 10,000 mg/kg bw/day (20% in diet) for 1 year.

In an unpublished oral feed study, the analogue source substance SS4 was administered at doses of 0, 50, 400, and 2,000 mg/kg bw/day to Crl:HanWist(Glx:BRL)BR rats (50/sex/group) for 104 weeks (OECD SIDS, 2008). The study design was comparable OECD Test Guideline 453. The NOAEL was determined to be 50 mg/kg bw/day.

Similarly, the analogue source substance SS4 was tested in the combined chronic toxicity and oncogenicity study (OECD SIDS, 2008). In this study, Crl:CD-1(ICR)BR mice (51/sex/group) were fed diets containing 0, 50, 400, and 2,000 mg/kg body weight/day of SS4 for 80 weeks. The NOAEL was 400 mg/kg bw/day, with a LOAEL of 2,000 mg/kg bw/day based on the microscopical findings in the stomachs of the high-dose males.

The chronic toxicity of the analogue source substance SS5 was investigated in a drinking water study (Malorny, 1969). Eight male and 24 female Wistar rats were administered drinking water containing the analogue source substance at 0.2% in drinking water and animals were kept for over two years. The study authors concluded that the administration of 200 mg/kg bw/day of SS5viathe drinking water for two years did not cause any substance-specific damage to the organ functions in rats.

The lack of repeated dose toxicity of SS1 evidenced by a one year NOEL of 10,000 mg/kg bw/day in rats further supports the conclusion that any toxicity of the TS will be attributable to its formate content rather than its glycerol content. On this basis, the 80-week NOAEL in mice for SS4 of 400 mg/kg bw/day would be equivalent to 740 mg/kg bw/day for the TS. Similarly, the 104-week NOAEL in rats for SS4 and 2-year NOEL in rats for SS5 of 50 and 200 mg/kg bw/day, respectively, would be equivalent to 92.5 and 370 mg/kg bw/day, respectively, for the TS.

On the basis of the information presented above, the two year NOAEL for the TS in rats is predicted to be 370 mg/kg bw/day in drinking water and 92.5 mg/kg bw/day in feed.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

370 mg/kg bw/day

Study duration:

chronic

Experimental exposure time per week (hours/week):

168

Species:

rat

System:

gastrointestinal tract

No repeated dose toxicity data were available for the TS; however, data on the analogue source substances SS1, SS4, and SS5 were identified.

The effects of the analogue source substance SS1 were evaluated in a 2-year study (Hine, et al., 1953). Long-Evans rats (at least 22 animals per group) were fed diets containing SS1 at a dose of 0, 5, or 10% for 2 years (equivalent to 0, 2,500, 5,000 mg/kg bw/day, respectively) or 20% for 1 year (equivalent to 10,000 mg/kg bw/day). The study authors concluded that the administration of 10% (equivalent to 5,000 mg/kg bw/day) of SS1viathe diet for two years did not induce any adverse effects in rats. Based on the results, a no observed effect level (NOEL) was determined to be 10,000 mg/kg bw/day (20% in diet) for 1 year.

In an unpublished oral feed study, the analogue source substance SS4 was administered at doses of 0, 50, 400, and 2,000 mg/kg bw/day to Crl:HanWist(Glx:BRL)BR rats (50/sex/group) for 104 weeks (OECD SIDS, 2008). The study design was comparable OECD Test Guideline 453. The NOAEL was determined to be 50 mg/kg bw/day.

Similarly, the analogue source substance SS4 was tested in the combined chronic toxicity and oncogenicity study (OECD SIDS, 2008). In this study, Crl:CD-1(ICR)BR mice (51/sex/group) were fed diets containing 0, 50, 400, and 2,000 mg/kg body weight/day of SS4 for 80 weeks. The NOAEL was 400 mg/kg bw/day, with a LOAEL of 2,000 mg/kg bw/day based on the microscopical findings in the stomachs of the high-dose males.

The chronic toxicity of the analogue source substance SS5 was investigated in a drinking water study (Malorny, 1969). Eight male and 24 female Wistar rats were administered drinking water containing the analogue source substance at 0.2% in drinking water and animals were kept for over two years. The study authors concluded that the administration of 200 mg/kg bw/day of SS5viathe drinking water for two years did not cause any substance-specific damage to the organ functions in rats.

The lack of repeated dose toxicity of SS1 evidenced by a one year NOEL of 10,000 mg/kg bw/day in rats further supports the conclusion that any toxicity of the TS will be attributable to its formate content rather than its glycerol content. On this basis, the 80-week NOAEL in mice for SS4 of 400 mg/kg bw/day would be equivalent to 740 mg/kg bw/day for the TS. Similarly, the 104-week NOAEL in rats for SS4 and 2-year NOEL in rats for SS5 of 50 and 200 mg/kg bw/day, respectively, would be equivalent to 92.5 and 370 mg/kg bw/day, respectively, for the TS.

On the basis of the information presented above, the two year NOAEL for the TS in rats is predicted to be 370 mg/kg bw/day in drinking water and 92.5 mg/kg bw/day in feed.

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

STOT RE: The oral (rat) 2-year effective concentration is greater than 100 mg/kg bw/day and therefore does not meet the classification criteria.