Sodium hypochlorite

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.55 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Modified dose descriptor starting point:

NOAEC

Value:

0.5

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

Justification:

Human data

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: STEL derived by the SCOEL

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

other:

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.55 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: STEL derived by the SCOEL

Overall assessment factor (AF):

1

Dose descriptor starting point:

other:

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 % in mixture (weight basis)

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: Qualitative approach based on Human data

Overall assessment factor (AF):

1

Dose descriptor:

other: NOAEL

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

Acute /short-term DNELs (dermal)

A DNEL for acute/short-term, dermal exposure will not be derived for the following reasons:

- The acute toxicity of corrosive substances is more related to concentration then to dose,

extrapolation from data obtained with hypochlorite solutions to a fictive 100% sodium

hypochlorite is not possible.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if an acute toxicity hazard

(leading to C&L) has been identified. Sodium Hypochlorite is not classified regarding acute

dermal toxicity.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if there is a potential for high

peak exposures, for instance when sampling or connecting/disconnecting vessels. This is not

the case for sodium hypochlorite. High peak exposures do not occur during the

manufacturing or use.

- The risk for dermal corrosion/irritation will be evaluated qualitatively (see repeated dose

toxicity).

Acute /short-term DNELs (inhalation)

Being an anion, ClO- will not volatilize from aqueous solutions. Thusno sodium hypochlorite as such can be present in the atmosphere except in the case in which an aerosol is formed. This does not occur during the production however workers can be exposed to chlorine atmosphere during the production of sodium hypochlorite or during the sampling or connecting/disconnecting vessels.

In Appendix R.8-13 of the Guidance on information requirements and chemical safety assessment Chapter R.8:Characterisation of dose [concentration]-response for human health (May 2008, ECHA) it is noted that:

‘When an EU IOEL exists the registrant may, under conditions as described below, use the IOEL in place of developing a DNEL. A registrant is allowed to use an IOEL as a DNEL for the same exposure route andduration, unless new scientific information that he has obtained in fulfilling his obligations under REACH doesnot support the use of the IOEL for this purpose. This could be because the information obtained is more recentthan the information that was used to support setting the IOEL at EU level and because it leads to another valuebeing derived which requires different risk management measures (RMMs) and operational conditions (OCs) ’.

The SCOEL has derived a STEL(15 min)forchlorine(SEG/SUM/76final,December1998) based on the fact that a constant exposure to 0.5 ppm (1.5 mg/m3) has been shown to be without effect in two human studies and also in rhesus monkeys whereas there is a clear evidence of irritation at 1.0 ppm (2.95 mg/m3). On this basis, the SCOEL considers that occupational exposure levels should not exceed 0.5 ppm.

The STEL derived by the SCOEL will be used as DNEL for acute inhalation exposure: 0.5 ppm of chlorinefor an exposure duration of 15 minutes.This value is equal 3.1mg/m3hypochlorite taking molecular ratio and molecular weight into account.

DNELacute short , inhalation= 3.1 mg/m3(local and systemic effects)

Long-term DNEL (dermal)

 Active chlorine will not pass the skin and will not be transported via the blood to become systemically available, therefore no systemic toxicity is expected after dermal exposure to hypochlorite. A qualitative approach based on local effects of hypochlorite is appropriate

For local effects after repeated dose dermal exposure a qualitative risk assessment will be

performed. The study by Cotter et al. (see IUCLID5 section 7.12) provides indication that

continuous exposure towards 0.5% hypochlorite concentration is about the threshold for

effects on basal cell viability (Cotter, 1985). The NOAEL is 0.1 % and the LOAEL is 0.5 %, based on a 15 % decrease of basal cell viability. As this decrease is marginal, and as human case reports supports a NOAEL of 0.5 %, as specified in the EU RAR, a NOAEL for local effects after repeated dermal exposure of 0.5% is thus established. A concentration of 0.5% is equivalent to 6.8 g/L (with a density of 1.3 g/mL and a correction factor of 1.05 (74.5/71) convert the doses given in active chlorine to NaOCl).

Long-term DNEL (inhalation)

Because the effects appear to be related to concentration in the air and not to the duration of exposure, the SCOEL does not recommend an 8-hour TWA. However, by a conservative approach, a long termDNEL inhalation will be derivedbased on the data that is available from human volunteer studies, as follows:

- 0.5 ppm (NOEL)/1.0 ppm (LOEL) following 8-hour exposure of chlorine gas in normal subjects (Rotman et al 1983);

- 0.4 ppm (NOEL)/1.0 ppm (LOEL) following 1-hour exposure of chlorine gas in hyper-responsive subjects (D'Alessandro et al 1996 )

- 0.5 ppm (NOEL) following 3 x 6-hour exposure of chlorine gas in young health subjects (Emmen & Hoogendijk 1997 - "EuroChlor").

From this data, a NOEL of 0.5 ppm is selected and the following assessment factors will be applied as follows:

- 1 for the interspecies variation as the data are human data,

- 1 for the Intraspecies differences as a study in hyper-responsive subjects showed no significant difference in sensitivity),

- 2 for the exposure duration sincethe animal and human studies showed that there is no substantial difference in N(L)OAECs following acute, subacute and/or chronic exposure by inhalation. This is supported by the fact that the toxic effects of chlorine are considered concentration- rather dose-dependent,

- 1 for the dose-response reliability,

- 1 for the quality of whole database,

DNEL = 0.5 x 1/2 = 0.25 ppm(chlorine)

This value is equal 1.55 mg/m3 hypochlorite taking molecular ration and molecular weight into account.

DNEL long-term inhalation = 1.55 mg/m3 (local and systemic effects)

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.55 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Modified dose descriptor starting point:

NOAEC

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

1

Modified dose descriptor starting point:

NOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.55 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other: STEL derived by the SCOEL

Overall assessment factor (AF):

1

Dose descriptor starting point:

other:

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 % in mixture (weight basis)

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

other:

Overall assessment factor (AF):

1

Dose descriptor:

other: NOAEL

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

50

AF for dose response relationship:

1

AF for differences in duration of exposure:

2

AF for interspecies differences (allometric scaling):

4

AF for other interspecies differences:

2.5

AF for intraspecies differences:

10

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

Acute /short-term DNELs (dermal)

A DNEL for acute/short-term, dermal exposure will not be derived for the following reasons:

- The acute toxicity of corrosive substances is more related to concentration then to dose,

extrapolation from data obtained with hypochlorite solutions to a fictive 100% sodium

hypochlorite is not possible.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if an acute toxicity hazard

(leading to C&L) has been identified. Sodium Hypochlorite is not classified regarding acute

dermal toxicity.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if there is a potential for high

peak exposures, for instance when sampling or connecting/disconnecting vessels. This is not

the case for sodium hypochlorite. High peak exposures do not occur during the

manufacturing or use.

- The risk for dermal corrosion/irritation will be evaluated qualitatively (see repeated dose

toxicity).

Acute /short-term DNELs (inhalation)

Being an anion, ClO- will not volatilize from aqueous solutions. The minute fraction of HOCl present in commercial solutions has a very low volatility. Gaseous chlorine can be released from a sodium hypochlorite solution only in accidental case by mixing with strong acids. Therefore, exposure does not comprise inhalation exposure, except in the case in which an aerosol is formed as for the trigger sray bottles for household cleaners.

The SCOEL has derived a STEL(15 min) for chlorine(SEG/SUM/76final,December1998) based on the fact that a constant exposure to 0.5 ppm (1.5 mg/m3) has been shown to be without effect in two human studies and also in rhesus monkeys whereas there is a clear evidence of irritation at 1.0 ppm (2.95 mg/m3). On this basis, the SCOEL considers that occupational exposure levels should not exceed 0.5 ppm.

The STEL derived by the SCOEL will be used as DNEL for acute inhalation exposure: 0.5 ppm of chlorinefor an exposure duration of 15 minutes.This value is equal 3.1mg/m3hypochlorite taking molecular ratio and molecular weight into account.

DNELacute short , inhalation= 3.1 mg/m3(local and systemic effects)

Acute /short-term DNELs (oral)

A DNEL for acute/short-term, oral exposure will not be derived for the following reasons:

- Effects of accidental ingestion of domestic sodium hypochlorite bleaches (strongly diluted

hypochlorite solutions only) are not expected to lead to severe or permanent damage of the

gastrointestinal tract as recovery is rapid and without any permanent health consequences,

based on human data.

- The acute toxicity of corrosive substances is more related to concentration then to dose,

extrapolation from data obtained with hypochlorite solutions to a fictive 100% sodium

hypochlorite is not possible.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if an acute toxicity hazard

(leading to C&L) has been identified. Theoretical pure sodium hypochlorite should be

classified as “harmful for ingestion” (Xn, R22) on the basis of the oral LD50 data. However,

the effects noted can be considered of secondary nature and caused by local tissue damage

due the substance corrosive properties. This classification does not apply to solutions as

their concentration is always below 25%. The acute toxicity of corrosive substances is more

related to concentration then to dose, and extrapolation from data obtained from using a

hypochlorite solution to a fictive 100% sodium hypochlorite is not possible.

As the highest concentrations of hypochlorite solutions industrially produced and marketed

are about 15%, and solutions marketed for consumer use are typically 5% or less, it can be

concluded from the data presented that hypochlorite solutions are of low acute oral toxicity.

This is confirmed by the available data from human accidents, where the few deaths that

have occurred after hypochlorite ingestion are mostly attributable to aspiration pneumonia.

- According to chapter R8 of the ECHA “Guidance on information requirements and chemical

safety assessment” a DNEL for acute toxicity should be derived if there is a potential for high

peak exposures. This is not the case during the use of sodium hypochlorite.

Long-term DNEL (oral)

The study by Hasegawa (1986) was chosen as key study for the derivation of the DNEL,

although usually a value from a chronic study is preferred over a value from a sub-chronic

study. In the Hasegawa study the dosing levels include “no-effect” and “effect” levels. Thus, a

NO(A)EL and a LO(A)EL could be distinguished. In the NTP study (1992) as in all other

studies, dose levels were maximum levels, the highest dose level is a NO(A)EL and there

was no LOAEL. Basically, when selecting a NOAEL for risk assessment. One should base it

on the highest NOAEL which lower then the lowest LOAEL level (which incorporates in its

evaluation all relevant – i.e. most sensitive - parameters).

The NOELlong-term, oral, determined in the Hasegawa study (rat, 90 day drinking water study)

was 50 mg/kg bw/day (see section 5.6.1.1). An assessment factor of 4 for the interspecies

variation (allometric scaling from rat to human), an additional 2.5 factor for other interspecies

differences, a factor of 2 for extrapolation from subchronic to chronic exposure plus a factor

of 10 for intraspecies differences (general population) was applied resulting in a final

assessment factor of 200. In addition a correction factor of 1.05 (74.5/71) has to be applied

to convert the doses given in active chlorine to NaOCl.

DNELlong-term, oral= 0.26 mg/kg bw/day.

Long-term DNEL (dermal)

Active chlorine will not pass the skin and will not be transported via the blood to become systemically available, therefore no systemic toxicity is expected after dermal exposure to hypochlorite. A qualitative approach based on local effects of hypochlorite is appropriate

For local effects after repeated dose dermal exposure a qualitative risk assessment will be

performed. The study by Cotter et al. (see IUCLID5 section 7.12) provides indication that

continuous exposure towards 0.5% hypochlorite concentration is about the threshold for

effects on basal cell viability (Cotter, 1985). The NOAEL is 0.1 % and the LOAEL is 0.5 %, based on a 15 % decrease of basal cell viability. As this decrease is marginal, and as human case reports supports a NOAEL of 0.5 %, as specified in the EU RAR, a NOAEL for local effects after repeated dermal exposure of 0.5% is thus established. A concentration of 0.5% is equivalent to 6.8 g/L (with a density of 1.3 g/mL and a correction factor of 1.05 (74.5/71) convert the doses given in active chlorine to NaOCl).

Long-term DNEL (inhalation)

Because the effects appear to be related to concentration in the air and not to the duration of exposure, the SCOEL does not recommend an 8-hour TWA. However, by a conservative approach, a long termDNEL inhalation will be derivedbased on the data that is available from human volunteer studies, as follows:

- 0.5 ppm (NOEL)/1.0 ppm (LOEL) following 8-hour exposure of chlorine gas in normal subjects (Rotman et al 1983);

- 0.4 ppm (NOEL)/1.0 ppm (LOEL) following 1-hour exposure of chlorine gas in hyper-responsive subjects (D'Alessandro et al 1996 )

- 0.5 ppm (NOEL) following 3 x 6-hour exposure of chlorine gas in young health subjects (Emmen & Hoogendijk 1997 - "EuroChlor").

From this data, a NOEL of 0.5 ppm is selected and the following assessment factors will be applied as follows:

- 1 for the interspecies variation as the data are human data,

- 1 for the Intraspecies differences as a study in hyper-responsive subjects showed no significant difference in sensitivity,

- 2 for the exposure duration sincethe animal and human studies showed that there is no substantial difference in N(L)OAECs following acute, subacute and/or chronic exposure by inhalation. This is supported by the fact that the toxic effects of chlorine are considered concentration- rather dose-dependent,

- 1 for the dose-response reliability,

- 1 for the quality of whole database,

DNEL = 0.5 x 1/2 = 0.25 ppm (chlorine)

This value is equal 1.55 mg/m3 hypochlorite taking molecular ration and molecular weight into account.

DNEL long-term inhalation = 1.55 mg/m3 (local and systemic effects