Bis(hydroxylammonium) sulphate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.008 mg/m³

Most sensitive endpoint:

carcinogenicity

DNEL related information

Overall assessment factor (AF):

62.5

Modified dose descriptor starting point:

LOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.032 mg/m³

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)

DNEL related information

Workers - Hazard via dermal route

Systemic 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

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:

low hazard (no threshold derived)

Additional information - workers

DNEL derivation - WORKER

Short Term Exposure - Systemic Effects - Dermal:

Dermal exposure estimations were assessed using a qualitative approach because for skin sensitisation no quantitative data was available. The moderate hazard category (see ECHA Guidance on information requirements and chemical safety assessment, Part E (2008)) was chosen as the substance is classified (among others) R36, R37, R40, 43 (moderate sensitizer according to ECHA guidance document R8).

 

Short Term Exposure - Systemic Effects - Inhalation:

The acute toxicological effect (systemic) of hydroxylammonium sulfate is the formation of methemoglobin and related effects on the blood. If acute studies in rats were used as basis for calculation, the acute DNEL is at least two magnitudes higher than the corresponding long term DNEL. Because the presentation of such a DNEL would lead to a severe underestimation of the toxic effects of hydroxylammonium sulfate, the DNEL short term inhalation exposure is calculated by multiplying the corresponding long term DNEL by a factor of 4 (see ECHA Guidance document R8, page 112).

DNEL - Short Term - Systemic Effects - Inhalation: 0.032 mg/m³

 

Short Term Exposure - Local Effects - Dermal:

There is no dose-response information available (irritation / sensitisation). Thus, a qualitative approach was chosen and DNELs were not derived. The sensitizing potency of hydroxylammonium sulfate was classified according to ECHA guidance R8: Concentrations used in the key study (GPMT) for intradermal induction was >1% and the incidence was ≥ 60 (Gad, 1986). Thus, the substance was classified as a moderate sensitizer.

 

Short Term Exposure - Local Effects - Inhalation:

There is no valid data available. However, as the long term systemic inhalation DNEL is very low, this DNEL is considered to protect also from short term local effects.

 

 

 

DNEL, long term, systemic

 

Point of departure for DNEL calculation:

OECD 451: Carcinogenicity study; rat; oral via drinking water (BASF, 2001)

LOAEL: 0.2 mg/kg bw/day

 

 

Reasoning for DNEL derivation:

 

The studies investigating the genotoxic effects of hydroxylammonium sulfate suggest that the substance has no or a low genotoxic potential in bacterial and mammalian cells. In addition, genotoxic effects in mammals could not be found in two ‘in vivo’ - micronucleus tests (MNTs) and one dominant lethal assay. The mechanism of cancer induction in rats is related to methemoglobin formation and erythotoxicity and the available data suggest the existence of a threshold-related mode of action.

 

This interpretation is in line with the evaluation of other expert groups:

 

OECD SIDS draft (SIAP, 2008):

Genetic toxicity: “Overall, hydroxylammonium sulfate has no genotoxic potential.”

Cancer: “It was considered that hydroxylammonium sulfate has no genotoxic potential, and the carcinogenicity observed in experimental animals is mediated via a non-genotoxic mechanism involving especially erythrotoxicity.”

 

EU risk assessment 2008:

Genetic toxicity: “Overall it may be concluded that hydroxylammonium sulfate has no or low genotoxic potential. In any case, it is unlikely that a mutagenic potential is expressed in mammals in vivo. Hydroxylammonium sulfate is not classified as a mutagen.”

Cancer: “There is no indication to assume that the tumours induced in the spleen of rats may be related to primary genotoxic effects (ashydroxylammonium sulfatehas no or a low genotoxic potential). The existence of other/alternative (non-genotoxic) mechanisms is assumed. It might be supposed that the carcinogenicity is mediated via accelerated destruction of erythrocytes and tumour growthwas released in hydroxylammonium sulfate -treated rats by chronic cell injury and persistent cell proliferation. At present, no other mode of action has been identified. The exact mechanisms remain unclear. A species-specific mechanism of tumour formation irrelevant for humans was not identified.”

 

A further study in rats indicates that the induction of oxidative stress in the spleen might also contribute to hydroxylammonium sulfate carcinogenicity in rats (BASF, 2003). This induction of oxidative stress is possibly related to iron release from decayed erythrocytes.

 

Because a thresholded effect is assumed, DNELs (and not DMELs) were derived for long term effects based on cancer data. Keeping in mind the severity of the effect, the DNELs were derived applying the following assessment factors (AF):

 

AF 2.5 for remaining differences: Because of the severity of the effect (cancer), this AF is considered to be appropriate

 

AF 5: for intraspecies differences: This standard factor is also considered appropriate as the susceptibility to oxidative stress is known to vary strongly among individuals.

 

AF 5 for having a LOAEL rather than a NOAEL: An AF of 5 is used for calculation. In the EU risk assessment, a NOAEL for nonneoplastic findings was established at 0.2 mg/kg bw/day, and a factor of 5 was used to address the “severity of a tumorigenic response”. The authors of the EU risk assessment chose this approach because they question the biological relevance of the increase of tumour incidence at 0.2 mg/kg bw/day (as the dose-response relationship is quite flat).

 

 

DNEL, long term, systemic, dermal:

Dermal exposure estimations were assessed using a qualitative approach because for skin sensitisation no quantitative data was available. Themoderate hazard category(see ECHA Guidance on information requirements and chemical safety assessment, Part E (2008))was chosen as the substance is classified (among others) R36, R37, R40, 43 (moderate sensitizer according to ECHA guidance document R8).

 

DNEL, long term, systemic, inhalation:

A DNEL was derived for systemic effects after long term inhalation exposure for the worker according to the procedure recommended in the current guidance document (R8, ECHA 2008). The LOAEL for systemic effects obtained from the chronic oral cancer study was set at 0.2 mg/kg bw/d hydroxylammonium sulfate for males and was taken as the point of departure for DNEL derivation.

 

LOAEL (oral) = 0.2 mg/kg bw/day

 

Correction for exposure duration: In the study, the animals were exposed 7 day/week. Worker exposure is 5 days/week

 

=> LOAEL (oral) = 0.28 mg/kg bw/day

 

Corrected starting point:

 

LOAC = LOAEL * 1 / 0.38 x 6.7 / 10

 

LOAC = 0.5 mg/m³(8h)

 

Assessment factors (AF):

remaining differences	2.5
intraspecies	5
LOAEL => NOAEL	5

           

Overall AF: 62.5

 

=> DNEL - long term - systemic - inhalation: 0.008 mg/m³

 

 

DNEL, long term, local effects, inhalation:

Because the DNEL for long term systemic effects is very low, it is also considered to be protective against local effects.

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:

DNEL (Derived No Effect Level)

Value:

0 mg/kg bw/day

Most sensitive endpoint:

carcinogenicity

DNEL related information

Overall assessment factor (AF):

500

Modified dose descriptor starting point:

LOAEL

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

Derivation of DNELs for the general population:

The general population is not exposed to hydroxylammonium sulfate via products or articles.

 

For the assessment of the exposure of humans via the environment, the long-term systemic oral DNEL was derived:

 

DNEL, long term, systemic, oral:

A DNEL was derived for systemic effects after long term oral exposure for the general population according to the procedure recommended in the current guidance document (R8, ECHA 2008). The LOAEL for systemic effects obtained from the chronic oral cancer study was set at 0.2 mg/kg bw/d hydroxylammonium sulfate for males and was taken as the point of departure for DNEL derivation.

LOAEL (oral) = 0.2 mg/kg bw/day

 

Assessment factors (AF):

interspecies	4
remaining differences	2.5
intraspecies	10
LOAEL => NOAEL	5

 

 

Overall AF: 500;

 

=> DNEL - long term - systemic - oral: 0.0004 mg/kg bw/day