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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
59 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
13
Modified dose descriptor starting point:
NOAEC
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Acute DNELs:

Worker: Production of the gluconates is in excess of 10 t/y. According to the REACh "Guidance on information requirements and chemical safety assessment, Part B: Hazard Assessment", above 10 t/y, the establishment of acute toxicity DNEL is unnecessary in most cases, as the DNEL based on long-term exposure is normally sufficient to ensure that adverse effects do not occur. Thus, as long term DNELs are available for gluconates and these substances are not classified for acute toxicity via any route of exposure, separate acute DNELs were not derived.

Long-term DNELs:

DNELs are based on the oral rat study (key study selected) entitled "Teratologic evaluation of FDA 71-72 (Glucono-Delta-Lactone). With respect to the most sensitive endpoint, although the study was for teratogenicity, the chemical was not found to be a teratogen or developmental toxicant; thus the most sensitive endpoint was selected as repeated dose toxicity.

Starting Dose for DNEL calculation:

594 mg/kg/day (based on NOAEL)

Modified dose for DNEL Calculation

Worker – Inhalation = 594 mg/kg/day x 1/0.38 x 6.7/10 x 70.5%/100% (adjustment for differences in absorption) = 738 mg/m3

Worker – Dermal = 594 mg/kg/day (no adjustment for absorption)

Assessment Factors (AF) –

Worker – Inhalation = 2.5 (for non-metabolic species differences) x 5 for (intraspecies difference); no scaling factor required (as per REACh guidance); no duration factor applied since exposure was for sensitive lifestage (in utero)

Worker – Dermal = 4 x 2.5 (species differences) x 5 for (intraspecies difference); no scaling factor required (as per REACh guidance); no duration factor applied since exposure was for sensitive lifestage (in utero)

Absorption assumed to be 70.5% for oral absorption (toxicokinetic statement). In the absence quantifiable data, inhalation absorption was assumed to be 100%. While the high molecular weight (178.14 g/mol) and high water solubility of D-glucono-δ-lactone do not favour its absorption via the dermal route of exposure, in the absence of quantifiable data, absorption via the dermal route was assumed to be the same as for oral absorption.

Final DNELs

Worker – Inhalation = 59 mg/m3

Worker – Dermal = 11.9 mg/kg/d

Read-Across Justification:

D-glucono-δ-lactone is a cyclic ester of gluconic acid which, in aqueous solution, forms an equilibrium mixture of the lactone and gluconic acid. Gluconic acid is a somewhat weak carboxylic acid with a dissociation constant of pKa = 3.6. The dissociation of an acid into a proton and an anion is an equilibrium, the reverse of which is the re-association of that same anion with a proton to reform the original acid. The pKa of 3.6 means that, when the ambient pH = 3.6, half the gluconic acid molecules will exist in the form of the uncharged acid, and half as the anion. At pH < 3.6, the undissociated form will predominate, and pH > 3.6 the anion will predominate. Sodium gluconate and potassium gluconate are both 1:1 salts of gluconic acid, which will each dissolve in water to generate separate sodium or potassium cations and gluconate anions. Sodium and potassium are both strong bases, and are therefore expected to remain ionized at essentially any pH, but the gluconate anions deriving from the salts will be subject to the same equilibrium as those deriving from the free acid. To be in equilibrium, both the forward and the backward reaction must possess the same pKa value, so the gluconate anion is predicted to posses the same pKa of 3.6 as the free acid. In this way, gluconic acid in aqueous solution is in equilibrium with its cyclic esters and its anion, according to the pH of the system, and in any system with sufficient buffering capacity, the effects of introducing equimolar amounts of gluconic acid, D-glucono-δ-lactone, sodium gluconate or potassium gluconate would be indistinguishable. Hence these four substances are considered to be appropriate surrogates for each other in sufficiently buffered aqueous systems, such as environmental waters, flora and fauna.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
25
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Acute DNELs - General Population: Similar to above for worker, assessment of acute systemic effects should default to the long term systemic DNELs. Also, gluconates are not classified as irritant or other endpoints; default to systemic DNEL for inhalation local effects.

Long-term DNELs:

DNELs are based on the oral rat study (key study selected) entitled "Teratologic evaluation of FDA 71-72 (Glucono-Delta-Lactone). With respect to most sensitive endpoint, although the study was for teratogenicity, the chemical was not found to be a teratogen or developmental toxicant; thus the most sensitive endpoint was selected as repeated dose toxicity.

Starting Dose for DNEL calculation:

594 mg/kg/day (based on NOAEL)

Modified dose for DNEL Calculation

General Population – Inhalation = 594 mg/kg/day x 1/1.15 x 70.5%/100% (adjustment for differences in absorption) = 364 mg/m3

General Population – Oral/Dermal = 594 mg/kg/day (no adjustment for absorption)

Assessment Factors (AF) –

General – Inhalation = 2.5 (for non-metabolic species differences) x 10 for (intraspecies difference); no scaling factor required (as per REACh guidance); no duration factor applied since exposure was for sensitive lifestage (in utero)

General Population – Oral/Dermal = 4 x 2.5 (species differences) x 10 for (intraspecies difference); no scaling factor required (as per REACh guidance); no duration factor applied since exposure was for sensitive lifestage (in utero)

Absorption

Same as for worker.

Final DNELs General Population – Inhalation = 14.6 mg/m3

General Population – Oral& Dermal = 5.9 mg/kg/d

Read-across justification:

Same as for worker.