Calcium chloride

Toxicological Summary

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:

5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

1

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

1

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:

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

Derivation of DNELs for local and systemic effects by acute and prolonged exposure for calcium chloride for general population

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

After assessment of the toxicological properties of CaCl₂, it is concluded that systemic toxicity of CaCl₂ is low, but the substance is capable of inducing local effects, caused most probably due to its strong hygroscopic properties. Based on the results of reliable skin and eye irritation studies with rabbits, calcium chloride is not irritating to skin, but causes serious eye irritation. In the acute inhalation toxicity study of limited reliability, signs of irritation of the respiratory tract were described at both exposure levels (40 and 160 mg/m³), suggesting that inhalation of calcium chloride can cause an irritation of the respiratory tract.

Only limited data addressing repeated exposure to calcium chloride are available for assessment. Calcium and chloride are both essential nutrients for humans and a daily intake of more than 1000 mg for each of the ions is recommended. As for healthy humans, the tolerable upper intake level for calcium is set at 2500 mg per day (equivalent to 6.9 g CaCl₂ per day) [1]. For chloride, the reference nutrient intake is set at 2500 mg/day (equivalent to 3.9 g CaCl₂ per day) [2]. The estimated intake of calcium chloride in a form of food additives (160-345 mg/day) is considerably smaller than these values. Consistent with this, the establishment of an ADI for calcium chloride has not been deemed necessary by JECFA [3]. A recent re-evaluation of the use of calcium chloride as a food additive by the EFSA Panel on Food Additives and Flavourings [4] furthermore reconfirmed that calcium chloride does not raise a safety concern at the reported use and use levels.

Taking into account the physico-chemical properties, toxicokinetics and normal physiological role of calcium chloride systemic effects are not anticipated after repeated exposure.

Systemic effects: DNEL_acute and DNEL_{long term} 

Despite the limitations of the available 12-month repeated dosing oral study with rats, it can be concluded that administration of calcium chloride did not induce any adverse systemic effects. Also no evidence of systemic effects was obtained in the available acute toxicity studies and developmental toxicity studies with rats, mice and rabbits.

Furthermore, no systemic effects are expected due to the normal physiological role of calcium and chloride as essential nutrients, and the self-regulatory systems of the body for both ions. This is confirmed by the available human data which report local irritating effects only. Therefore, a DNEL for systemic effects (both acute and long term) is not required, also taking into account the recommended daily intake of > 1000 mg/day.

 

Local effects: DNEL_acute and DNEL_{long term} 

DNEL_acute

The effects noted in the acute toxicity tests were mainly local irritating effects, predominately at the port of entry. Acute oral toxicity of calcium chloride is low, as evidenced by the studies with rats administered single doses of calcium chloride dissolved in water or in 5% Arabic gum, resulting in LD50 > 2000 mg/kg bw. However, in the acute toxicity studies with rabbits administered anhydrous substance in gelatin capsules at dose levels of 500-1000 mg/kg bw, haemorrhagic trachea and severe ulceration of the stomach were observed. These effects were regarded to be exaggerated by gavage administration. In acute dermal toxicity studies, skin lesions/irritation was noted at or near the administration sites; however, it should be noted that the administered dose was much higher and the application duration much longer in comparison to the testing regime recommended by modern guidelines for skin irritation studies. In a non-reliable inhalation study with rats, irritation of the trachea was noted at test concentrations of 40 and 160 mg/m³.

A DNEL_acute should be established for substances if an acute hazard toxicity (leading to C&L) has been identified and a potential for high peak exposures exists.

 

Eye irritation

Calcium chloride is classified as an eye irritant. Three eye irritation studies with calcium chloride are available, performed with calcium chloride hexahydrate, 33% aqueous solution of calcium chloride, and anhydrous calcium chloride, respectively, demonstrating slight to severe eye irritating properties in rabbits.

 

In accordance with Chapter R.8, appendix R. 8-9 of the REACH Guidance on information requirements and chemical safety assessment, “DNELs for irritation/corrosion can only be derived if dose-response information is available. Acute, sub-acute or sub-chronic toxicity studies in animals by the dermal or inhalation route may be able to provide this information, provided that symptoms of irritation/corrosion are recorded and reported in relevant studies”. No LOAEL or NOAEL can be derived from the available eye irritation studies on different forms of calcium chloride, as these studies were designed to provide only qualitative information on the eye irritation potential of the substances (i.e. whether the substance is irritating or non-irritating). The exposure conditions used in these studies can also not be extrapolated to exposure situations that are relevant for potential human exposure. Furthermore, the observed difference in irritation potential between anhydrous calcium chloride and its hexahydrate is likely not to be the result of a concentration effect, but rather be caused by differences in the physical properties between the two substances, such as the extent of being hygroscopic.

 

Furthermore, Chapter R.8, appendix R. 8-9 of the Guidance states that “In acute, sub-acute and sub-chronic toxicity studies, the eyes of the animal are not intentionally exposed and the symptoms are not systematically reported. Therefore, normally there is no basis for quantitative assessment of the eye irritation/corrosion from these studies. In case signs of eye irritation/corrosion are observed in inhalation toxicity studies, and dose-response information is available, it may be possible to identify a NOAEC or a LOAEC and derive a DNEL. Also, if human data are available, a NOAEC or a LOAEC may be identified from these data.”

For calcium chloride, the single study via the inhalation route is an acute inhalation study with rats reported by Sukhanov et al. (1990). The reliability of this study is insufficient and there is no indication of clinical signs referring to potential eye irritation. Therefore, this study does not allow the derivation of a DNEL for eye irritation.

 

In summary, a (quantitative) DNEL for eye irritation for calcium chloride can not be derived due to the design of the eye irritation studies (i.e. providing only qualitative information on eye irritation potential) and the lack of inhalation studies that sufficiently document eye irritation effects in experimental animals. Therefore, as no DNEL can be derived, a qualitative approach to assessing and controlling the risks is appropriate. For the worker the use of goggles is considered to be an adequate risk management measure.

 

Skin irritation

Anhydrous calcium chloride has not been classified for skin irritation based on the results of the available OECD guideline study. In other studies only slight irritation was noted, however, in these cases the animals were either exposed to the hexahydrate form, or exposed for 24 hours. The rabbit acute dermal study (24 hour exposure) indicated an LD50 of > 5000 mg/kg. Gross pathology revealed skin lesions (scab formation, skin thickening, and inflammation) at or near the treatment site; however, as stated above, the dose applied and the exposure duration significantly exceeded the limits recommended by modern guidelines for skin irritation studies. As no other doses were administered a NOAEL for these local effects could not be determined. A few reports on human skin injuries as a result of incidental contact with calcium chloride are available. However, as no quantitative risk assessment is possible based on these data and calcium chloride is not classified as skin irritant, no DNEL for these effects shall be derived.

 

Respiratory tract irritation

In the limited acute inhalation toxicity study with rats, signs of irritation of the respiratory tract were described at both exposure levels (40 and 160 mg/m³). Because of the insufficient documentation of the study, a NOAEC for the DNEL derivation could not be established.

 

In addition, Vinnikov et al. reported the use of aerosol inhalation of 2-5% aqueous solution of calcium chloride in the treatment of tuberculosis patients. Although in some cases symptoms of mucos membrane of pharynx and throat, as well as an unpleasant sensation in the mouth, were reported, most patients did not experience any adverse effects, suggesting that the toxicity of calcium chloride by inhalation is very low.

 

In accordance with Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, a national OEL can be used in place of a DNEL if an evaluation of the scientific background for its setting has been performed. As discussed above, the systemic toxicity of calcium chloride is very low and no adverse systemic effects are expected to occur upon repeated exposure. In accordance with Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, in case of exposure to inert significantly soluble dusts a general limit of 10 mg/m³(used in setting Occupational Exposure Limits in many countries) can be used as a DNEL. However, there are indications, although from a study with a limited reliability, that anhydrous calcium chloride can induce respiratory tract irritation.The irritant potency of anhydrous calcium chloride is expected to be mainly a physical effect, caused by its strong hygroscopic properties, leading to drying of mucus membranes. An Occupational exposure limit (OEL) for calcium chloride of 5 mg/m³ has been established by the Ministry of Labour, Ontario, Canada, 2002 [5]. No further OELs for calcium chloride have been established; however, ACGIH (2018) [6] has established a TLV-TWA and a STEL values for several substances containing Ca²⁺ and Cl^- ions with low systemic toxicity, based on their respiratory tract irritating properties, namely calcium sulfate, calcium hydroxide and ammonium chloride. Their physico-chemical properties, as well as scientific background for limit values derivation, are briefly discussed below. As the TLV-TWA for calcium hydroxide is partially based on the limit value established by ACGIH for sodium hydroxide based on the available data, the latter substance has been included in the overview for sake of comparison as well.

 

Calcium sulfate

Anhydrous calcium sulfate, similarly to calcium chloride, possesses the high affinity for water and will absorb 6.6% of its weight of water, forming the stable hemihydrate. In contrast to highly soluble calcium chloride (solubility of anhydrous form 745 g/L at 20 ˚C), anhydrous calcium sulfate is only very limitedly soluble in water (ca. 2.1 g/L at 30 ˚C). An available study with human volunteers indicated chemesthetic effects on the nose and throat at the 40 mg/m³ exposure level and above. Nasal secretion, nasal resistance and mucociliary transport were unaffected. A chronic study with guinea pigs with commercial calcined gypsum consisting of 70% hemihydrate, 15% calcite, 10% anhydrite, 2% of other carbonates (magnesium, aluminum and iron) showed no or slight lung effects at airborne levels of 448 million particles per cubic foot. Based on these concentration levels, a TLV-TWA of 10 mg/m³ has been recommended by ACGIH to protect against respiratory health effects, based on upper and lower respiratory tract irritation.

Calcium hydroxide

Calcium hydroxide is a relatively strong base and hence a moderately caustic irritant to all exposed surfaces of the body, including the eyes and respiratory tract. It is slightly soluble in water (1.85 g/L at 0 ˚C). The EU Commission Directive 2017/164 prescribes an 8h limit value of 1 mg/m³ and a short-term limit value of 4 mg/m³. This is considered to be sufficiently low to protect against undue irritation.

 

Ammonium chloride

Ammonium chloride is a somewhat hygroscopic, readily soluble in water (297 g/L at 0˚C) material. According to the available data, the substance is a moderate skin and eye irritant. Although only limited information was available on its inhalation toxicity, a TLV-TWA of 10 mg/m³ and TLV-STEL of 20 mg/m³ was suggested by ACGIH. The recommended values should minimize the potential for ocular and respiratory tract irritation.

 

Sodium hydroxide

Sodium hydroxide has been included in this overview because it was partially used to establish the TLV-TWA value for calcium hydroxide by ACGIH (ACGIH, 2018). It is a hygroscopic alkaline material, which readily absorbs water from air. It is well soluble in water (420 g/L at 0˚C). Depending upon the concentration, sodium hydroxide aerosol can be a severe irritant of the eyes, mucous membranes and skin; the caustic dust of sodium hydroxide is irritating to the upper respiratory tract. Rats that inhaled unmeasured concentrations of sodium hydroxide aerosols for 30 minutes/day suffered pulmonary damage after 2.5 months. In humans, there were two reports indicating noticeable irritation at concentrations of sodium hydroxide aerosol below 2 mg/m³. Accordingly, a TLV-Ceiling of 2 mg/m³ was recommended by ACGIH, based on a concentration that produces noticeable, but not excessive, ocular and upper respiratory tract irritation.

 

In summary, although only limited information on the induction of local effects upon inhalation exposure to calcium chloride is available, the overview of the available limit values established by ACGIH for substances with similar properties shows that the concentration levels below 5 mg/m³ are considered to be sufficient to ensure the protection against the respiratory tract irritation for workers (see Table 1). An exception is sodium hydroxide, for which a TLV-TWA value of 2 mg/m³ has been suggested by ACGIH. However, as sodium hydroxide is a very strong base, classified as corrosive on on Annex VI of Regulation (EC) No 1272/2008 (CLP), the comparison of its properties with those of calcium chloride is not really appropriate. Overall, using the weight of evidence approach, a concentration of 5 mg/m³, which also coincides with the Canadian OEL for calcium chloride, is thought to be sufficient to ensure the protection against possible respiratory health effects by prolonged exposure, and shall be considered as a DNEL_long-term for local effects. For acute exposure, based on the ratio for proposed TLV-TWA and TLV-STEL values for ammonium chloride, a concentration of 10 mg/m³ is proposed, which shall be regarded as a DNEL_acute for local effects.

 

Table 1. Overview of the available TLV values established by ACGIH for Ca(OH)₂, CaSO₄, NaOH and NH₄Cl

Substance	TLV-TWA mg/m^3	TLV-STEL mg/m^3	TLV-Ceiling mg/m^3	Classification (local effects)
Ca(OH)2	4	1	-	Skin irrit. 2, Eye Damm. 1
CaSO4	10	-	-	/
NaOH	-	-	2	Skin corr. 1A
NH4Cl	10	20	-	Eye Irrit. 2

DNELs anhydrous vs hydrate form of Calcium chloride

Risk assessment is based on the anhydrous form of Calcium Chloride anhydrous (CAS 10043-52-44), however other 4 forms of hydrate Calcium chloride are present in the market, namely:

·      calcium chloride monohydrate (CAS 22691-02-7)

·      calcium chloride dihydrate (CAS 10035-04-8)

·      calcium chloride tetrahydrate (CAS 25094-02-4)

·      calcium chloride hexahydrate (CAS 7774-34-7)

 

The anhydrous form was chosen as it would result in the most conservative assessment, as per section 9-10 of the CSR, thus covering also the associated risk to the exposure to the other hydrate forms (Tab.2). Nevertheless, for completeness of information, here are reported the DNELs for the hydrate forms that can be used for a specific risk assessment.

 

Table 2. DNELs for acute and chronic inhalation exposure

	MW CaCl2 g/mol	MW H2O g/mol	sum MW	local acute DNEL mg/m^3	local chronic DNEL mg/m^3
calcium chloride anhydrous (CAS 10043-52-44)	110.98	0	110.98	10	5
calcium chloride monohydrate (CAS 22691-02-7)	110.98	18	128.98	11.6	5.8
calcium chloride dihydrate (CAS 10035-04-8)	110.98	36	146.98	13.2	6.6
calcium chloride tetrahydrate (CAS 25094-02-4)	110.98	72	182.98	16.5	8.2
calcium chloride hexahydrate (CAS 7774-34-7)	110,98	108	218.98	19.7	9.9

 

[1] Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, 1999

[2] Department of Health, UK, 1991

[3] Joint FAO/WHO Expert Committee on Food Additives; 1974, 2001

[4] Scientific Opinion of the EFSA Panel on Food Additives and Flavourings (FAF), Adopted 6 June 2019: Re-evaluation of hydrochloric acid (E507), potassium chloride (E508), calcium chloride (E509) and magnesium chloride (E511) as food additives.

[5] Ministry of Labour, Ontario, Canada (2002) Updated and New OELs in Part 4 of Regulation 833, effective September 30, 2000. Found at http://www.e-laws.gov.on.ca/html/regs/english/elaws_regs_900833_e.htm

[6] ACGIH (2018). TLVs and BEIs based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices. Signature Publications, Cincinnati, Ohio, USA (and references therein)

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:

DNEL (Derived No Effect Level)

Value:

2.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

2

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Overall assessment factor (AF):

2

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:

medium hazard (no threshold derived)

Additional information - General Population

Derivation of DNELs for local and systemic effects by acute and prolonged exposure for calcium chloride for general population

According to the REACH guidance on information requirements and chemical safety assessment a leading DN(M) EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

Systemic effects: DNEL_acuteand DNEL_{long term}

After assessment of the toxicological properties of CaCl₂, it has been concluded that the substance is not expected to cause adverse systemic effects by either acute or repeated exposure (see Discussion in the Section "DNEL derivation for workers". Therefore no DNELs for systemic effects by either acute or prolonged exposure have been derived either for workers or for general population for any exposure route.

Local effects: DNEL_acuteand DNEL_{long term}

Dermal route of exposure

Regarding the local effects, calcium chloride is not classified as irritating to skin; therefore no DNELs were derived for local dermal effects by either acute or prolonged exposure.

Inhalation route of exposure

Available data, albeit of poor quality, indicate that anhydrous calcium chloride may cause respiratory tract irritation due to its intense hygroscopic properties. However, available animal data are not sufficient to derive DNEL for either acute or repeated exposure based on them. Therefore DNELs for respiratory tract irritation by acute or long-term exposure to calcium chloride for workers have been derived by weight of evidence approach, comparing established by ACGIH limit values for occupational exposure for either Ca²⁺ or Cl- containing substances, known to cause respiratory tract irritation. This resulted in the DNEL_local of 5 mg/m³ for long-term inhalation exposure and 10 mg/m³ for acute inhalation exposure for workers. As general population also includes elderly and juvenile citizens, a default assessment factor of 2 is recommended by Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment for the extrapolation of the DNEL from workers to general population. Applying this assessment factor, DNELlocal of 2.5 mg/m³ and DNEL local of 5 mg/m³ are derived for acute and prolonged inhalation exposure, respectively, for general population.

Oral route of exposure

In the available acute oral toxicity studies with rabbits, several irritating local effects were revealed at gross pathology, in particular haemorrhagic trachea and severe ulceration of the stomach.  These effects are regarded to be exaggerated by gavage administration. Taking into account that calcium and chloride are both essential nutrients for humans and a daily intake of more than 1000 mg of each of these ions is recommended, no DNEL needs to be derived for oral route of exposure.

DNELs anhydrous vs hydrate form of Calcium chloride

Risk assessment is based on the anhydrous form of Calcium Chloride anhydrous (CAS 10043-52-44), however other 4 forms of hydrate Calcium chloride are present in the market, namely:

·      calcium chloride monohydrate (CAS 22691-02-7)

·      calcium chloride dihydrate (CAS 10035-04-8)

·      calcium chloride tetrahydrate (CAS 25094-02-4)

·      calcium chloride hexahydrate (CAS 7774-34-7)

The anhydrous form was chosen as it would result in the most conservative assessment, as per section 9-10 of the CSR, thus covering also the associated risk to the exposure to the other hydrate forms(Tab.1). Nevertheless, for completeness of information, here are reported the DNELs for the hydrate forms that can be used for a specific risk assessment.

 

Table 1. DNELs for acute and chronic inhalation exposure

	MW CaCl2 g/mol	MW H2O g/mol	sum MW	local acute DNEL mg/m^3	local chronic DNEL mg/m^3
calcium chloride anhydrous (CAS 10043-52-44)	110.98	0	110.98	5	2.5
calcium chloride monohydrate (CAS 22691-02-7)	110.98	18	128.98	5.8	2.9
calcium chloride dihydrate (CAS 10035-04-8)	110.98	36	146.98	6.6	3.3
calcium chloride tetrahydrate (CAS 25094-02-4)	110.98	72	182.98	8.2	4.1
calcium chloride hexahydrate (CAS 7774-34-7)	110.98	108	218.98	9.9	4.9