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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Key value for chemical safety assessment

Additional information

Read-across discussion:

In order to address toxicological endpoints as part of the REACH registration of Sodium d-glycero-d-gulo-heptonate (target substance) it is proposed to read across data from Sodium glucoheptonate (source substance). The use of read across is within the spirit of REACH, in order to reduce animal testing where possible.

The source and target substances are structurally similar consisting of the alpha/ beta and alpha only form of the same isomer (respectively) and have the same molecular weight, the substances also have comparable physical chemical properties. Due to the similar properties shown between the two materials it is believed that the results obtained in the testing of sodium glucoheptonate (source substance) will be a reliable representation of the properties for sodium d-glycero-d-gulo-heptonate (target substance) to allow classification and labelling and for risk assessment purposes. Therefore read across is justified. The substance sodium d-glycero-d-gulo-heptonate is considered to have similar properties to sodium glucoheptonate and therefore is considered to be relatively harmless and would not be classified in accordance with Regulation (EC) No 1272/2008 (CLP).

OECD Guideline 471: Bacterial Reverse Mutation Test (Ames):

Methods

Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA were treated with the test item using both the Ames plate incorporation and pre-incubation methods at up to eight dose levels, in triplicate, both with and without the addition of a rat liver homogenate metabolizing system (10% liver S9 in standard co-factors). The dose range for Experiment 1 was pre-determined and was 1.5 to 5000 µg/plate. The experiment was repeated on a separate day (pre-incubation method) using fresh cultures of the bacterial strains and fresh test item formulations. The dose range was amended slightly to allow for the change in test methodology and was 15 to 5000 μg/plate.

Results

The vehicle (sterile distilled water) control plates gave counts of revertant colonies within the normal range. All of the positive control chemicals used in the test induced marked increases in the frequency of revertant colonies, both with or without metabolic activation. Thus, the sensitivity of the assay and the efficacy of the S9-mix were validated.

The test item caused no visible reduction in the growth of the bacterial background lawn at any dose level and was, therefore, tested up to the maximum recommended dose level of 5000 µg/plate. No test item precipitate was observed on the plates at any of the doses tested in either the presence or absence of S9-mix.

No significant increases in the frequency of revertant colonies were recorded for any of the bacterial strains, with any dose of the test item, either with or without metabolic activation or exposure method.

Conclusion

Sodium D-glycero-D-gulo-heptonate was considered to be non-mutagenic under the conditions of this test.

OECD 473: In vitro Chromosome Aberration Test (Read-across on Sodium glucoheptonate)

Methods.

Duplicate cultures of human lymphocytes, treated with the test item, were evaluated for chromosome aberrations at three dose levels, together with vehicle and positive controls. Four treatment conditions were used for the study; i.e. In Experiment 1, 4 hours in the presence of an induced rat liver homogenate metabolising system (S9), at a 2% final concentration with cell harvest after a 20-hour expression period and a 4 hours exposure in the absence of metabolic activation (S9) with a 20-hour expression period. In Experiment 2, the 4 hours exposure with addition of S9 was repeated (using a 1% final S9 concentration); whilst in the absence of metabolic activation the exposure time was increased to 24 hours.

The dose levels used in the main experiments were selected using data from the preliminary toxicity test and were as follows:

Group

Final Concentration of test item (µg/ml)

4(20)-hour without S9

88.75, 177.5, 355, 710, 1420, 2840

4(20)-hour with S9 (2%)

88.75, 177.5, 355, 710, 1420, 2840

24-hour without S9

88.75, 177.5, 355, 710, 1420, 2840

4(20)-hour with S9 (1%)

88.75, 177.5, 355, 710, 1420, 2840

Results.

All vehicle (MEM) controls had frequencies of cells with aberrations within the range expected for normal human lymphocytes. All the positive control items induced statistically significant increases in the frequency of cells with aberrations indicating the satisfactory performance of the test and of the activity of the metabolising system.

The test item was only moderately toxic and did not induce any statistically significant increases in the frequency of cells with aberrations, in either of two separate experiments, using a dose range which exceeded the maximum recommended dose level. The maximum dose level tested was based on the molecular weight of the hydrated form of Sodium Glucoheptonate. It was subsequently discovered that when Sodium Glucoheptonate is in solution, as in the sample tested, the water of crystallisation is lost and the molecular weight is therefore reduced. The test item was consequently over tested at 11.44 mM which was beyond the maximum recommended dose level (10 mM) using the molecular weight of the dihydrate form of Sodium Glucoheptonate. However, since there was no response from the test item at any dose level in any of the exposure groups this was considered to be acceptable and have no impact on the study integrity.

Conclusion.

The test item was considered to be non-clastogenic to human lymphocytes in vitro.

OECD Guideline 474: Mammalian Erythrocyte Micronucleus Test (mouse micronucleus): (Read-across on Sodium glucoheptonate)

Methods:

A range-finding test was performed to find suitable dose levels of the test item, route of administration, and to investigate if there was a marked difference in toxic response between the sexes. There was no marked difference in toxicity of the test item between the sexes; therefore the main test was performed using only male mice. Following discussions with the Sponsor, the micronucleus test was conducted using the intraperitoneal route in groups of seven mice (males) at the maximum recommended dose (MRD) of 2000 mg/kg and with 1000 and 500 mglkg as the two lower dose levels. Animals were killed 24 or 48 hours later, the bone marrow extracted, and smear preparations made and stained. Polychromatic (PCE) and normochromatic (NCE) erythrocytes were scored for the presence of micronuclei.

Additional groups of mice were given a single intraperitoneal dose of phosphate buffered saline (PBS) (7 male mice) or dosed orally with cyclophosphamide (5 male mice), to serve as vehicle and positive controls respectively. Vehicle and positive control animals were killed after 24 hours.

Results:

There were no premature deaths seen in any of the dose groups in the main test. Clinical signs were observed in animals dosed with the test item at and above 1000 mg/kg in both the 24 and 48-hour dose groups, where applicable, and included hunched posture and included hunched posture and ptosis.

Statistically significant decreases in the PCE/NCE ratio were not observed in any of the test item dose groups when compared to the vehicle control group. However, the observation of clinical signs was taken to indicate that systemic absorption had occurred and exposure to the target tissue had been achieved.

There was no evidence of any statistically significant increases in the incidence of micronucleated polychromatic erythrocytes in animals dosed with the test item when compared to the vehicle control group.

The positive control group showed a marked increase in the incidence of micronucleated polychromatic erythrocytes hence confirming the sensitivity of the system to the known mutagenic activity of cyclophosphamide under the conditions of the test.

The test item was found not to produce a toxicologically significant increase in the frequency of micronuclei in polychromatic erythrocytes of mice under the conditions of the test.

Conclusion:

The test item was considered to be non-mutagenic under the conditions of the test.


Justification for selection of genetic toxicity endpoint
Two in vitro genetic toxicity studies have been conducted (one of the test substance and one on a similar test material) and an in vivo study conducted on a similar test material as follows:
OECD 471 Bacterial Reverse Mutation Test (test substance)
OECD 473: In vitro Chromosome Aberration Test (read-across from similar substance)
OECD Guideline 474: Mammalian Erythrocyte Micronucleus Test (mouse micronucleus) (read-across from similar substance).

All studies have been conducted to OECD Guidelines and GLP and are adequately reported.

Short description of key information:
OECD 471 Bacterial Reverse Mutation Test:
Sodium D-glycero-D-gulo-heptonate was considered to be non-mutagenic under the conditions of this test.

OECD 473: In vitro Chromosome Aberration Test:
The test item (Sodium glucoheptonate) was considered to be non-clastogenic to human lymphocytes in vitro.

OECD Guideline 474: Mammalian Erythrocyte Micronucleus Test (mouse micronucleus):
The test item (Sodium glucoheptonate) was considered to be non-mutagenic under the conditions of the test.

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Based on negative results in two in vitro studies and one in vivo study the substance is not classified for mutagenicity:

OECD 471 Bacterial Reverse Mutation Test:

Sodium D-glycero-D-gulo-heptonate was considered to be non-mutagenic under the conditions of this test.

OECD 473: In vitro Chromosome Aberration Test:

The test item (Sodium glucoheptonate) was considered to be non-clastogenic to human lymphocytes in vitro.

OECD Guideline 474: Mammalian Erythrocyte Micronucleus Test (mouse micronucleus):

The test item (Sodium glucoheptonate) was considered to be non-mutagenic under the conditions of the test.

The study results read-across from Sodium glucoheptonate are considered valid in the assessment and classification of Sodium D-glycero-D-gulo-heptonate.