Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
other: BMCL (extrapolated from a BMDL; the calculated BMR would imply a two-fold increase in the background mean concentration of methaemoglobin [EFSA, 2017])
Value:
16.25 mg/m³
Explanation for the modification of the dose descriptor starting point:

[See discussion section (Hazard via inhalation route: systemic effects following long-term exposure).]

AF for dose response relationship:
1
Justification:
Default ECHA AF for use of a BMDL05 is 1; no additional dose-response AF was considered necessary by EFSA in calculating an ADI using the BMDL (from the subchronic rat study) as the key POD.
AF for differences in duration of exposure:
1
Justification:
Although the default ECHA AF for subchronic (90-day) to chronic extrapolation is 2, no such factor was considered necessary by EFSA in calculating an ADI using the BMDL (from the subchronic rat study) as the key POD, because methaemoglobinaemia at similar levels was also the only observed effect in the chronic rat study.
AF for interspecies differences (allometric scaling):
1
Justification:
Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling) is not required
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. Read-across from the structural analogue sodium nitrite was used to fill the repeated dose toxicity (oral) endpoints. No AF is considered necessary for the use of read-across since the DNEL is based on the relative proportion of nitrite, the toxicologically active species.
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.84 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
other: BMDL (extrapolated from a BMDL; the calculated BMR would imply a two-fold increase in the background mean concentration of methaemoglobin [EFSA, 2017])
Value:
92.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

[See discussion section (Hazard via dermal route: systemic effects following long-term exposure).]

AF for dose response relationship:
1
Justification:
Default ECHA AF for use of a BMDL05 is 1; no additional dose-response AF was considered necessary by EFSA in calculating an ADI using the BMDL (from the subchronic rat study) as the key POD.
AF for differences in duration of exposure:
1
Justification:
Although the default ECHA AF for subchronic (90-day) to chronic extrapolation is 2, no such factor was considered necessary by EFSA in calculating an ADI using the BMDL (from the subchronic rat study) as the key POD, because methaemoglobinaemia at similar levels was also the only observed effect in the chronic rat study.
AF for interspecies differences (allometric scaling):
4
Justification:
Default ECHA AF for rat for toxicokinetic differences in metabolic rate (allometric scaling)
AF for other interspecies differences:
2.5
Justification:
Default ECHA AF for remaining toxicokinetic differences (not related to metabolic rate) and toxicodynamic differences
AF for intraspecies differences:
5
Justification:
Default ECHA AF for (healthy) worker
AF for the quality of the whole database:
1
Justification:
Default ECHA AF; the human health effects data are reliable and consistent, and confidence in the database is high. Read-across from the structural analogue sodium nitrite was used to fill the repeated dose toxicity (oral) endpoints. No AF is considered necessary for the use of read-across since the DNEL is based on the relative proportion of nitrite, the toxicologically active species.
AF for remaining uncertainties:
1
Justification:
Not required
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Hazard via inhalation route: systemic effects following long-term exposure

As no relevant data on effects of repeated inhalation exposure of humans or laboratory animals to calcium nitrite are available, route-to-route extrapolation to calculate an inhalation DNEL from reliable data (subchronic and chronic toxicity NTP studies in rodents by the oral route) on a structural analogue, sodium nitrite, was considered a suitable alternative method (particularly as nitrite does not undergo first pass metabolism following oral exposure; EFSA, 2017).

 

In the subchronic (14-week) oral toxicity studies, sodium nitrite was provided to rats and mice (10/species/sex/group) in the drinking water at 375, 750, 1500, 3000 or 5000 ppm (NTP, 2001). EFSA considered the critical effect in rats to be a dose-dependent increase in methaemoglobin concentration (with concomitant effects on blood parameters at the two highest dose levels). On this basis, EFSA established respective NOAELs of 115 and 130 mg/kg bw/day for males and females. Based on an increased incidence of extramedullary haematopoiesis in the spleen of both sexes of mice, EFSA established NOAELs of 345 and 240 mg/kg bw/day for males and females, respectively (EFSA, 2017).

 

In the analogous chronic (2-year) oral toxicity studies in rats and mice (50/species/sex/group), the relevant sodium nitrite concentrations in drinking water were 750, 1500 or 3000 ppm (NTP, 2001). The critical effect in rats was a dose-dependent increase in methaemoglobin concentration (considered by EFSA to be statistically significant at the highest tested dose level). On this basis, EFSA established respective NOAELs of 70 and 80 mg/kg bw/day for males and females. No significant treatment-related adverse effects were observed in mice. As such, the EFSA Panel have identified NOAELs of 220 and 165 mg/kg bw/day for males and females, respectively (EFSA, 2017).

 

The Panel selected the subchronic rat study as critical since methaemoglobin increases were observed in all treated groups. Following benchmark dose (BMD) modelling of the methaemoglobin data, the Panel calculated lower bound BMD (BMDL) values of 9.63 and 14.62 mg/kg bw/day for males and females, respectively. The Panel noted that the NOAELs identified in reproduction and developmental toxicity studies were higher than the calculated BMDLs. The lower such value was selected as the key point of departure (POD) in the derivation of an acceptable daily intake (ADI) for nitrite. Applying the default factor of 100 to the BDML resulted in an ADI of 0.1 mg/kg bw for sodium nitrite (0.07 mg/kg bw as nitrite). The Panel considered that there was no need to add a factor of 2 for extrapolation from the subchronic to chronic study, because methaemoglobinaemia at similar levels was also the only observed effect in the chronic rat study (EFSA, 2017). The BMDL of 9.63 mg/kg bw/day is therefore considered to be the critical (and health-precautionary) POD for (inhalation) DNEL calculation.

 

The available data suggest that oral absorption of nitrite is essentially complete, while calcium is also appreciably absorbed. Moreover, calcium nitrite’s high water solubility is also indicative of a high bioavailability, as ions, by the oral route. As such, predicted oral absorption of calcium nitrite is set at 100%. Based on limited available data, it is assumed that absorption following inhalation exposure could also be extensive; in line with ECHA (2012) guidance, a conservative default assumption of 100% inhalation absorption is proposed. [See toxicokinetic assessment in IUCLID section 7.1 for details.]

 

Modification of an oral starting point to assess human (worker) inhalatory exposure may be achieved using the following formula: corrected inhalatory NOAEC (worker, 8 h exposure/day) = oral NOAEL*(1/sRv[rat])*(ABS[oral-rat]/ABS[inh-human]) *(sRV[human]/wRV)

 

By extension, this formula is also applicable when a BMDL is used (in place of a NOAEL) as the starting point. Expressed as the source substance, sodium nitrite, the corrected inhalatory BMCL (worker, 8 h exposure/day) = 9.63 mg/kg bw/day*(1/0.38 m3/kg bw/day)*(100/100)*(6.7 m3 [8h]/10 m3 [8h]) = 16.98 mg/m3. This equates to a calcium nitrite exposure of 16.25 mg/m3 (based on relative nitrite proportions[1]).

 

Application of the assessment factors (overall AF 12.5) described above to this corrected inhaled BMCL gives a systemic long-term inhalation DNEL for calcium nitrite of 1.30 mg/m3.

 

Hazard via inhalation or dermal route: systemic effects following acute exposure

DNELs for acute toxicity should be calculated if an acute toxicity hazard, leading to classification and labelling (i.e. under EU CLP regulations) has been identified and there is a potential for high peak exposures (this is only usually relevant for inhalation exposures).

 

There are no data in relation to acute inhalation or dermal exposure to calcium nitrite. In a guideline (US EPA TSCA test rules) acute oral toxicity study in rats (5/sex/group), the LD50was determined to be 283 mg/kg bw (Olson, 1985). A supporting study, involving administration of the test material as a 34% aqueous solution, indicated the LD50 to exceed 50 mg/kg bw (discriminating dose) (McRae, 1996). On balance, the compound is classified for acute oral toxicity in Category 3 according to EU CLP criteria (EC 1272/2008).

 

“A qualitative risk characterisation for this endpoint could be performed for substances of very high or high acute toxicity classified in Category 1, 2 and 3 according to CLP … when the data are not sufficiently robust to allow the derivation of a DNEL” (ECHA, 2016). It is, therefore, considered suitably health precautionary to adopt the “moderate” hazard banding, and to consider the recommended Risk Management Measures/Operational Conditions (RMMs/OCs) in Table E.3-1 of ECHA (2016).

 

Hazard via inhalation route: local effects following long-term or acute exposure

There are no data in relation to respiratory tract irritation or sensitisation of calcium nitrite in humans or laboratory animals. The compound is not considered a significant skin irritant or sensitiser based on studies in rabbits and guinea pigs, respectively (Allan, 1997; Parcell, 1997) [see ‘Hazard via dermal route: local effects following long-term or acute exposure’ for more detailed discussion of this study]. Consequently, no worker-DNELs for long-term or acute local effects in the respiratory tract have been calculated.

 

Hazard via dermal route: systemic effects following long-term exposure

As no relevant data on effects of repeated dermal exposure of humans or laboratory animals to calcium nitrite are available, route-to-route extrapolation to calculate a dermal DNEL from reliable data (subchronic and chronic toxicity NTP studies in rodents by the oral route) on a structural analogue, sodium nitrite, was considered a suitable alternative method (particularly as nitrite does not undergo first pass metabolism following oral exposure; EFSA, 2017). These studies have been described above [“Hazard via inhalation route: systemic effects following long-term exposure”] (NTP, 2001).

 

The BMDL of 9.63 mg/kg bw/day calculated by EFSA following BMD modelling of the methaemoglobin data in the subchronic rat study is considered to be the critical POD for (dermal) DNEL calculation.

 

As described above [“Hazard via inhalation route: systemic effects following long-term exposure”], predicted oral absorption of calcium nitrite is set at 100%. A low dermal bioavailability is anticipated based on calcium nitrite’s highly water-soluble nature; a default value of 10% dermal absorption is proposed. [See toxicokinetic assessment in IUCLID section 7.1 for details.]

 

Modification of an oral starting point to assess human (worker) dermal exposure may be achieved using the following formula: corrected dermal NOAEL = oral NOAEL*(ABS[oral-rat]/ABS[der-human])

 

By extension, this formula is also applicable when a BMDL is used (in place of a NOAEL) as the starting point. Dose descriptor starting point, in terms of the source substance sodium nitrite (after route to route extrapolation) = 9.63 mg/kg bw/day*(100%/10%) = 96.3 mg/kg bw/day. This equates to a calcium nitrite exposure of 92.2 mg/kg bw/day.

 

Application of the assessment factors (overall AF 50) described above to this corrected dermal BMDL gives a systemic long-term dermal DNEL for calcium nitrite of 1.84 mg/kg bw/day.

 

Hazard via dermal route: local effects following long-term or acute exposure

In a guideline (EU Method B.4) skin irritation study using three rabbits, calcium nitrite (34% aqueous solution) induced slight, transient irritation in a single animal, reversible within 24 hours. There was no evidence of irritation up to 72 hours later and the overall irritation score was 0/8 (Parcell, 1997).

 

In another guideline (EU Method B.6) study, calcium nitrite (34% aqueous solution) produced evidence of skin sensitisation in only a single animal (with an inconclusive result in another) out of a group of 10 guinea pigs in a maximisation test (GPMT) involving a two-stage induction procedure (1% by intradermal injection and 10% by topical application) followed by dermal challenge at up to a concentration of 5% (Allan, 1997).

 

The evidence from studies on calcium nitrite (34% aqueous solution) indicates that classification of calcium nitrite as a skin irritant or skin sensitiser, according to the EU CLP Regulation (EC 1272/2008), is not required.

 

Hazard for the eyes

In a guideline (EU Method B.5) eye irritation study, calcium nitrite (34% aqueous solution) produced severe irritation and corrosive effects in the eyes of two rabbits; the effects tended to worsen with time, leading to the premature sacrifice of the animals (no further animals were tested) (Parcell, 1996). The test material is classified for serious eye damage (Category 1), based on the general worsening of the observed effects (i.e. not expected to be reversible).

 

No dose-response data were available from which to derive a DNEL, therefore a qualitative assessment was considered appropriate. Substances classified for serious eye damage (Category 1 in CLP) should be allocated to the “moderate hazard band on the basis that exposure to such corrosives, eye damaging or irritant substances should be well-controlled”. Therefore, consider recommended RMMs/OCs in Table E.3-1 of ECHA (2016).


[1]Calcium and sodium nitrite are 69.7 and 66.7% NO2-(w/w), respectively.

References(for which a ESR has not been created in IUCLID)

ECHA (2009). European Chemicals Agency. Guidance in a Nutshell: Chemical Safety Assessment. Reference: ECHA-09-B-15-EN. September 2009.http://echa.europa.eu/documents/10162/13632/nutshell_guidance_csa_en.pdf

 

ECHA (2011). European Chemicals Agency. Guidance on information requirements and chemical safety assessment Part B: Hazard assessment. Reference: ECHA-11-G-16-EN. Version 2.1. December 2011.https://echa.europa.eu/documents/10162/13643/information_requirements_part_b_en.pdf

 

ECHA (2012). European Chemicals Agency. Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Reference: ECHA-2010-G-19-EN. Version 2.1. November 2012.http://echa.europa.eu/documents/10162/13632/information_requirements_r8_en.pdf

 

ECHA (2016).European Chemicals Agency.Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation. ECHA-2016-G-04-EN.Version 3.0. May 2016.http://echa.europa.eu/documents/10162/13632/information_requirements_part_e_en.pdf

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