Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.304 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: To describe the ClO2 uptake in the respiratory tract, the gas categorization scheme of EPA (EPA/600/8-90/066F, October 1994) was used. This scheme separates gases into three categories based on physicochemical characteristics (see discussion below).
Overall assessment factor (AF):
37.5
Dose descriptor:
LOAEC
AF for dose response relationship:
3
Justification:
LOAEL/NAEL extrapolation
AF for differences in duration of exposure:
1
AF for interspecies differences (allometric scaling):
1
AF for other interspecies differences:
1
Justification:
Local effect in the respiratory tract
AF for intraspecies differences:
5
Justification:
Worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
2.5
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

1. Introduction

In this dossier, all the toxicological information on Chlorine dioxide (ClO2) are re-examined and analyzed in order to define a DNEL (s)/DMEL (s) for each human health endpoints if possible. The followed method is that proposed in the guidance for the implementation of Reach (Chapter R.8: Characterisation of dose (concentration)-response for human health, May 2008).

 

2. Classification according to the CLP Regulation (1272/2008)

The harmonized classification of ClO2 (as gas) is:

- Fatal if inhaled, Category 2 (H330); however, this is a minimum classification (* mark), and based on data, Category 1 is suitable.

- Corrosive, Skin corr. 1B (H314)

The harmonized classification of ClO2 (as aqueous solutions) is:

- Toxic if swallowed, Category 3 (H301)

- Corrosive, Skin corr. 1B (H314)

However, for the concentration range considered in this registration dossier (i.e. 0.6 to 2%), solutions are not considered as corrosive, but only Irritant to eyes, cat.2 (for 0.6 to 2%), and Skin irritant cat.2 above 1%.

An additional self-classification is proposed:

- Harmful if inhaled (Category 4, H332), applying to solutions containing at least 0.82% chlorine dioxide.

 

3. Worker-DNELs/DMELs derivation according to the toxicological profile of ClO2

Inhalation and dermal exposure were the most appropriate routes for assessing occupational risk in workers. Effects from exposure of animals to ClO2 are limited to the respiratory system: irritation of the nasal mucosa, bronchopneumonia, lymphocytic infiltration of the alveolar spaces, alveolar vascular congestion, haemorrhagic alveoli, epithelial erosions, and inflammatory infiltrations of the bronchi caused by important local irritation.

Neither indications of systemic toxicity nor evidence of a reprotoxic potential were observed. Tests assessing the mutagenic potential of ClO2 in vivo provided no evidence of any mutagenic or genotoxic activity. Therefore, DNELs were only derived for local effects.

 

3.1 Worker-DNEL acute – local effects:

 

3.1.1 Inhalation route:

A key study was identified for this endpoint, LC50inhalation = 89 mg/m3 air (Kr. 1, EU Method B.2, GLP, Schorsch et al., 1996) (see § 7.2.2).

Clinical signs observed in all dose groups included: respiratory distress and general weakness. Lungs from treated animals showed frequent mottling, redness and depressed area. The main lesion induced by ClO2 is the destruction of alveolar walls, which creates pulmonary emphysema lesions. This emphysema was found on all rats of the study (except control) whatever the tested concentration. The severity of the lesion is proportional to the dose. Animals died by respiratory deficiency showing that the mechanism of action is corrosivity.

This study classifies ClO2 as Fatal if inhaled (Category 1 H330). but Category 4 for the concentration range considered (0.6% to 2%). Therefore, a qualitative risk assessment shall be considered, since high toxicity is sufficient to warrant a strict control of potential exposure (see R.8, Box 8, p113). The RMMs/OCs should ensure that peak concentrations exceeding the long-term DNEL will not occur.

 

3.1.2 Dermal route:

No acute toxicity study by dermal route was available. Since ClO2 is classified as corrosive again not for the concentration range considered, maximum EDI2 +SCI2, and since no systemic effects were expected no test was proposed considering animal welfare. Hence only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

 

 

3.2 Worker-DNEL long-term – local effects:

 

3.2.1 Inhalation route:

 

Introduction

The threshold limit value TLV-TWA: 0.28 mg/m3 (0.1 ppm) is recommended by the Conference of Governmental Industrial Hygienists (ACGIH, 2001). This value was set based on:

- the repeated dose toxicity study by inhalation of Dahlamn (1957) identifying a NOEC of 0.28 mg/m3 in rats exposed 5h/day for 10 weeks to chlorine dioxide gas.

- the clinical investigation conducted on workers by Gloemme and Lundgren (1957) attributing effects to short periods of exposure at concentrations considerably in excess of 0.28 mg/m3 of ClO2 and chlorine gas.

 

The value of 0.28 mg/m3 is used without the application of any assessment factor for the derivation of the TLV-TWA.

However, the clinical investigation of Gloemme and Lundgren (1957) does not properly describe and justify the recruitment procedures of the study workers. The characterization of exposure is not adequate: atmospheric concentrations were not measured continuously. Consideration of bias and confounding factors is not done and statistics could not be done as the worker numbers is too low (only three cases are reported).

In conclusion bias are numerous in this study. Therefore, according to the draft guidance for DNEL derivation from human data (2010) this study considered as inadequate (low quality) is not taken for derivation.

Consequently, the studies conducted by Paulet and Debrousses (1970, 1971) which include more details than those of Dalhamn are used for the DNEL derivation.

 

DNEL derivation

The concentration descriptor is obtained from the sub-acute inhalation toxicity studies of Paulet and Debrousses (1970, 1971). Collectively these studies suggested that effects from repeated exposure in rats exposed to Chlorine dioxide gas by inhalation are limited to effects on the respiratory tract due to local irritation. A LOAEC of 2.76 mg/m3 was determined for these local effects based on peribronchiolar oedema and vascular congestion in the lungs observed in the two-month study (Paulet and Debrousses, 1971).

 

To describe the ClO2 uptake in the respiratory tract, the gas categorization scheme of EPA (EPA/600/8-90/066F, October 1994) was used. This scheme separates gases into three categories based on physicochemical characteristics:

- Category 1 gases are defined as highly water soluble and/or irreversibly reactive gases. These gases do not significantly accumulate in the blood.

- Category 2 gases are moderately water soluble and rapidly reversible reactive or moderately to slowly irreversibly metabolized in respiratory tract tissue.

- Category 3 gases are relatively water insoluble and unreactive in the extrathoracic and tracheobronchial regions.

ClO2is defined as a Category 1 gas as it is water soluble and rapidly reduced in contact with organic compounds. Based on this assumption a regional gas dose ratio (RGDR) of ClO2 can be calculated for extrathoracic (ET), tracheobronchial (TB) and pulmonary (PU) regions using empirical models (see attached document). A human equivalent concentration (HEC) for the LOAEL was thereafter calculated by multiplying the LOAEC and the RGDRs.

 

The following table indicates the inhalation DNEL-long term for local effect calculation.

 

Table 1.1: Calculation of long-term DNEL by inhalation for local effects of Chlorine dioxide:

 

Worker

Local long-term DNEL / inhalation

Step a: Determination of the critical dose

Key studies

Paulet and Debrousses (1970, 1971), K4, WoE

Relevant dose descriptor

LOAEC = 2.76 mg/m3 for local irritant effects

Step b: Correction for Human Equivalent Concentration

Regional Gas Dose Ratios (RGDR)

RGDRET= 0.178

RGDRTB= 1.815

RGDRPU= 2.167

Overall RGDR

RGDRs = 4.129

Adjusted dose descriptor = relevant dose descriptor x RGDRs

LOAECHEC= 11.40 mg/m3

Step c: Correction for uncertainty factors

Differences in metabolic rate per b.w. (allometric scaling)

-

(local effects)

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

-

(local effects)

Modification for exposure

(experiment and human)

-

(local irritant effects depending on concentration only)

Correct starting point = adjusted dose descriptor / overall factor for uncertainties

11.4 mg/m3

Step d: Correction for assessment factors

Interspecies differences

2.5

(effects on respiratory tract)

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

1

(similar respiratory irritant effects were observed after acute exposure in rats)

Issues related to dose-response

3

(LOAEL/NAEL extrapolation)

Quality of whole database

1

Overall assessment factor

37.5

DNEL calculation

0.304 mg/m3

0.11 ppm

DNELppm= DNELmg/m3* 24.05 / MW at 20°C = 0.304 * 24.45 / 67.45 at 25°C

 

Conclusion

The inhalation DNEL long-term for local effects is 0.304 mg/m3in the workers.

 

 

3.2.2 Dermal route:

No repeated toxicity study by dermal route was available. Since ClO2 (gas) is classified as corrosive to the skin

not for the concentration range considered (0.6% to 2%), maximum EDI2 +SCI2.

and since no systemic effects were expected at non-irritating doses no test was proposed considering animal welfare.

Hence only qualitative assessment can be performed following the approach described in the dossier to define the risk management measures (RMMs) and operational conditions (OCs).

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Indirect exposure of humans via the environment is very unlikely due to the high reactivity of ClO2 and consumers are not exposed to ClO2. Therefore, no hazard is identified for general population exposure to Chlorine dioxide.