Glyoxylic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

9.4 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

37.5

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

150

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Acute/short term exposure – systemic effects

According to ECHA Guidance on information requirements and CSR, chapter R8, a DNEL for acute systemic toxicity should be derived only if an acute systemic toxicity hazard leading to C & L has been identified.

Glyoxylic Acid 50% has a low acute toxicity as indicated by the LD50 values of 2528 mg/kg bw and > 2000 mg/kg bw determined in rats for oral and dermal exposure, respectively. Therefore, Glyoxylic Acid 50% is not subject to classification and labelling and consequently the establishment of DNELs for acute/short-term exposure - systemic effects is not required.

Acute/short term and long term exposure – local effects

Glyoxylic Acid 50% caused only minimal skin irritation reactions in the rabbit without any relevance for classification and labelling, but was severely eye irritating in the rabbit. Data on respiratory irritation are not available. In the LLNA Glyoxylic Acid 50% was sensitising. Below, local effects following acute/short term or long term exposure were assessed qualitatively. A quantitative assessment was not performed because of the following:

• The available data on irritation allow only a qualitative assessment of irritation/corrosion following acute exposure. No experimental data are available addressing local effects in the repsiratory tract.
• There have been several proposals made during the last years how to perform a quantitative assessment for sensitisation based on the LLNA’s EC3 value. However, at present there is no common agreement on the assessment factors to be used for a quantitative assessment. Thus, the regulatory acceptance of a proposed DNEL would be highly questionable.

Glyoxylic Acid 50% is classified and labelled with R41 (Risk of serious damage to eyes) and R43 (may cause sensitisation by skin contact) or Cat 1 / H 318 (causes serious eye damage) and Cat 1 / H317 (may cause an allergic skin reaction) according to Directive 67/548/EEC or Regulation 1272/2008/EC, respectively. The calculated EC3 value of 5.05 % indicates a moderate skin sensitisation potential.

Based on these data, Glyoxylic Acid 50% is allocated to the moderate hazard category. The operation conditions and risk management measures indicated in the respective IUCLID 5 and CSR chapters are appropriate and sufficient for controlling the risks.

Long term exposure - systemic effects

In a combined repeated dose toxicity study with the reproduction / developmental toxicity screening according to OECD TG 422 Glyoxylic acid 50% was given to male and female rats at dietary concentrations of 0, 2000, 6000 or 18000 ppm for a period of 5 weeks. The reduced male body weight gain at 18000 ppm reaching periodically statistical significance in comparison to control males was the only adverse effect seen. Based on this result a NOAEL of 6000 ppm corresponding to 200 mg/kg bw/d in males was derived.

Subchronic to chronic dose toxicity or specific reproduction dose toxicity studies (i.e. one or two generation reproduction toxicity and teratogenicity study) of Glyoxylic Acid 50% are not available. However, there is extensive information on ethylene glycol and glyoxal available, which can be used for the assessment of the long term and reproduction toxicity potential of Glyoxylic Acid 50% because Glyoxylic Acid plays a central role in the metabolism of both substances. Data on glyoxal have been given preference over data on ethylene glycol because much less metabolic transformation steps are needed for its conversion into Glyoxylic Acid than for the conversion of ethylene glycol. The available information shows that Glyoxylic Acid 50% does not adversely influence fertility and has no developmental/teratogenic toxicity potential. It also demonstrates that reduced body weight is the most sensitive or among the most sensitive effects following long term administration and that there is no specific target organ toxicity at dose levels relevant for classification, confirming the results obtained in the OECD 422 study with Glyoxylic Acid 50%. Futhermore, it became obvious, that the long term NOAEL does not decrease with increasing exposure time.

From studies on oral exposure of glyoxal, the NOAEL seems to be about 100 mg/kg body weight per day (adjusted to 100% glyoxal). The short- and medium-term studies seem to have similar outcomes, with no evidence of systemic effects, suggesting that exogenous glyoxal is efficiently detoxified and does not accumulate in the body.

As the DNELs obtained with the subacute NOAEL with glyoxylic acid are equivalent but a bit more conservative than with the subchronic NOAEL obtained with glyoxal, it is taken as starting point for the DNEL derivations:

Critical subacute NOAEL = 200 mg pure glyoxylic acid/kg bw/d.

No adequate experimental data are available on dermal or inhalation exposure with regard to systemic effects, thus route-to-route extrapolation based on the oral NOAEL of 200 mg/kg bw/d is the only alternative finding a dose descriptor as starting point for the derivation of the respective DNEL.

Glyoxylic Acid 50% has a low molecular weight (74.04 g/mol) and log Pow (-0.7). It is highly water soluble without a significant dermal irritation potential and is more than 99 % ionised at pH values above 5 (pKa = 3.1). These substance properties show, that absorption after inhalation exposure is lower than or comparable to oral absorption. In contrast, penetration through the lipid rich environment of the stratum corneum is very restricted, so that dermal absorption is significantly lower than oral absorption. This is also supported by the available acute toxicity data, where clinical signs and mortality were seen in rats after oral administration but not after dermal administration of 2000 mg/kg bw. For extrapolation from the oral to dermal exposure route it is conservatively assumed that dermal absorption is three times less than oral absorption, whereas for extrapolation from the oral to inhalation route comparable absorption is assumed.

The resulting corrected dermal NOAEL is then 600 mg/kg bw/d (oral DNEL of 200 mg/kg bw/d x 3).

For the calculation of the corrected inhalation NOAEC the standard breathing volume for the rat of 0.38 m³/kg (8 hours) and the correction factor for the difference between basal caloric demand and caloric demand under light activity have to be taken into account. The latter correction factor derives from the inhalation volume in 8 hours under the respective conditions (6.7 m³ for base level, 10 m³ for light activity). Accordingly, the corrected inhalation NOAEC is 200 mg/kg bw/d / 0.38 m³/kg bw x 6.7 m³ / 10 m³ = 352.6 mg/m³.

- Derivation of dermal DNEL for long-term exposure - systemic effects

The following assessment factors are used for the derivation of the long-term DNEL for dermal exposure:

inter-species factor: 4 (allometric scaling) and 2.5 (additional factor)

intra-species factor (worker): 5

exposure duration factor (subacute to chronic): 3.

The reduced duration assessment factor is justified by the finding, that the oral NOAEL does not decrease with increasing exposure time. Moreover, a recent evaluation of a data base consisting of more than 6000 repeated dose endpoints showed that the subacute to subchronic factor was rather 1.5 than 3 (Bitsch et al., 2006), additionally justifying the reduction of the default assessment factor from 6 to 3.

Based on the corrected dermal NOAEL of 200 mg/kg bw/d the dermal DNEL for long-term exposure - systemic effects is calculated as follows:

600 mg/ kg bw/d / (4 x 2.5 x 5 x 3) = 4 mg/kg bw/day

- Derivation of inhalation DNEL for long-term exposure - systemic effects

The following assessment factors are used for the derivation of the long-term DNEL for inhalation exposure:

inter-species factor: 2.5 (additional factor)

intra-species factor (worker): 5

exposure duration factor (subacute to chronic): 3 (justification as given above)

Based on the corrected inhalation NOAEC of 352.6 mg/m³ the inhalation DNEL for long-term exposure - systemic effects is calculated as follows:

352.6 mg/m³ / (2.5 x 5 x 3) = 9.4 mg/m³

Reference

Bitsch A et al. (2006). REPDOSE: a database on repeated dose toxcity studies of commmercial chemicals - amultifunctional tool. Reg. Tox. Pharmacol. 46, 202 -210.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

There is no intended use of Glyoxylic acid 50% in consumer products. Thus, DNELs for the general population do not need to be established according to the REACH legislation.