Barium oxide, obtained by calcining witherite

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: see discussion

Explanation for the modification of the dose descriptor starting point:

see discussion

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Value:

6

Acute/short term exposure

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - workers

To properly assess the substance in question, its nature and natural occurrence should be taken into consideration. Barium is a naturally occurring metal, mainly found in barite (barium sulfate) and witherite (barium carbonate). Both substances are not well soluble, nevertheless barium can be found in varying concentrations in drinking water (depending on the area), for example the average concentration in the drinking water of the 100 largest cities in the USA was 0.43 mg/liter whereas in certain areas of Sweden up to 20 mg barium can be found in each liter of municipal water. In sea water up to 37 mg/liter barium were detected in the equatorial region of the Atlantic ocean (IOMC 2001). Thus, humans are constantly exposed to low doses of barium in the environment. The average daily intake was estimated to be from 0.18 mg up to 1.24 mg per person (IOMC 2001).

Barium oxide rapidly reacts to barium hydroxide upon contact with water. Ba(OH)₂is a strong base, thus barium oxide has corrosive properties besides releasing barium ions. The corrosive testing of barium was performed employing a Corrositex® assay and resulted in classification of BaO as corrosive Cat. 1B. However, the results do not allow for threshold determination, thus risk assessment for the corrosive properties of BaO will be performed on a qualitative basis. Due to the potential of barium intoxication after contact with BaO, another soluble barium salt, BaCl₂, was used as analogue substance for assessment of barium toxicity, which will be the focus of this discussion.

Accidental human exposure to soluble barium resulted in paralysis, arrhythmias potentially leading to heart attacks, and kidney damage (IOMC 2006). Animal studies were conducted in which both rats and mice were administered soluble barium in the form of barium chloride in the drinking water (NTP 1994, Dietzet al. 1992, Tardiffet al. 1980). Of the human intoxication signs, these studies were able to only reproduce barium nephropathy, but not the other symptoms. Therefore, animal data alone are not sufficient to establish a reliable exposure limit for barium and human data will have to be taken into consideration. DNELs for barium will be calculated from both approaches and the values will be compared and discussed.

Relevant dose descriptor:

In an NTP study from 1994, rats and mice were administered BaCl₂ in the drinking water for 15 days, 90 days, or two years. In the 15-day rat study, the NOAEL was set at ≥115 mg barium/kg bw/day, which was the highest dose tested. Testing in mice for 15 days resulted in a NOAEL of≥70 mg/kg bw/day, also the highest dose tested. In none of the dose level groups were any adverse effects observed. Testing for 90 days in rats revealed signs of kidney damage in the high dose group, changes in organ weights and body weight. The LOAEL was determined to be 115 mg barium/kg bw/day, and the NOAEL was set at 65 mg barium/kg bw/day. In mice, consumption of barium for 90 days resulted in reduced liver weights in both males and females and reduced thymus weight in females. On the basis of these findings, the LOAEL was set at 200 mg/kg bw/day and the NOAEL was determined at 100 mg/kg bw/day. Two other studies (Dietzet al., Tardiffet al.) assessed barium toxicity in rats (Dietzet al. also investigated mice) after 90 days and came to similar conclusions. However, due to better documentation, the DNEL calculation will be based on the data reported in the NTP study. The two year study is considered the most relevant endpoint for DNEL calculation among the animal studies due to the length of exposure as well as the detailed documentation of the study. Chronic exposure of rats to barium led to reduced drinking water consumption and reduced body weight in the high dose level group (LOAEL at 60 mg barium/kg bw/day). A NOAEL for chronic barium toxicity of 30 mg barium/kg bw/day could be derived. In parallel, treatment of mice for 2 years with barium-containing drinking water led to increased mortality, nephropathy and lymphoid depletion at 160 mg/kg bw/day. Based on these findings, a NOAEL was determined to be 75 mg/kg bw/day. Therefore, rats are the more sensitive species and the chronic NOAEL of 30 mg barium/kg bw/day (corresponding to 33.5 mg BaO/kg/day) will be used as dose descriptor starting point for the following DNEL calculations.

For the worker, the following DNELs were derived:

For derivation of the long-term systemic inhalative DNEL for BaO, the oral NOAEL for barium of 30 mg/kg bw/d was adapted to the corresponding value for barium oxide: 33.5 mg/kg bw/d. This number was converted into a corrected inhalative NOAEC of 29.5 mg/m³according to the procedure recommended in the current guidance document (R8, ECHA 2012). Applying all assessment factors, the inhalative long-term systemic DNEL was set at2.4mg/m³for the worker.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL (BaO): 33.5 mg/kg bw/day
Step 2) Modification of starting point	50%/100%       0.38 m^3/kg bw       6.7 m^3/10 m^3	Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)   Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)   Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m^3/10 m^3)
Modified dose-descriptor	NOAEC corrected inhalative = 33.5 * (50/100) * (1/0.38) * (6.7/10) = 29.5 mg/m^3
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2012.
Remaining differences	2.5	Standard assessment factor according to R8 ECHA 2012
Intraspecies	5	Standard assessment factor according to R8 ECHA 2012
Exposure duration	1	chronic study as starting point for DNEL derivation
Dose response	1	Starting point of DNEL derivation is a NOAEL
Quality of database	1	well documented NTP study
DNEL	Value
	29.5 / (1 x 2.5 x 5 x 1 x 1 x 1) =2.4 mg/m^3

 

Importantly, the animal studies conducted could only reproduce one of three major symptoms of human barium ingestion. Thus, if risk assessment were conducted from animal data alone, adverse effects on humans at levels of or below the DNEL could not be excluded. Therefore, human data has to be taken into account.

Besides case reports, only one well-documented study exists that systematically addressed the effect of barium exposure in 18 welders (Zschiescheet al.1992). The test persons were healthy and had not been in contact with barium for at least 10 days prior to start of the study. They were split into 3 groups (A-C) of 8, 5, and 5 men. Subjects in group A performed arc welding with barium-containing stick-electrodes. Group B and C performed arc welding with barium-containing self-shielded flux cores wires, however group C was issued welding guns with built-in ventilation whereas group B was working with standard tools. Barium levels in the air were measured by sensors attached to the inside of the face shield, thus monitoring the air directly breathed by the welders. The welding of barium-containing materials was conducted for 1 week, about 4 hours per day. Thursday and Friday of the week before the barium welding as well as the Monday after, the welders worked with barium-free material. Biomonitoring was set up to start on the Thursday before the welding with barium-containing materials and continue up to the Monday after the barium-welding week. Thus, baseline levels for urine and plasma could be established and the reversibility of barium contact could be assessed. The study found that welding without exhaust system led to average total fumes of 13.2 mg/m³for stick electrodes and 12.3 mg/m³for flux cored wires. The concentrations of barium were at 4.4 mg/m³and 2.0 mg/m³, respectively. The barium levels in plasma and urine of the workers fluctuated before and after the shifts, being low before welding and strikingly increased after. Over the course of the week, the plasma baseline for barium increased, but also decreased over the following free weekend. None of the symptoms reported by the workers could be correlated with barium exposure, no exposure-related trend in the pulse rate was found and auscultation of the lungs did not result in irregular findings in any welder. Thus, no major symptoms could be detected and daily exposure to 4.4 mg/m³barium fumes for 4 hours was well tolerated. Based on the biokinetic monitoring, a biological half-life of 10-18 hours could be determined, however in literature biological half-life times of up to 48 hours are reported (NTP 1994).

Using the symptom-free dose of 4.4 mg barium/m³(corresponding to 4.9 mg BaO/m³) as dose descriptor starting point for derivation of a DNEL via the inhalation route, some considerations have to be applied by means of assessment factors. The intraspecies assessment factor of 1 is justified, since the study was conducted with human volunteers. However, the study size was quite small and the statistical power is difficult to assess. Nevertheless, since there were no adverse effects associated with exposure to barium, an assessment factor of 2 is considered sufficient to account for the small cohort size. The exposure time was only 5 days and considering reports of biological half times for barium of up to 48 hours, the flux balance between the external and internal concentrations might take up to 10 days to arrive at an equilibrium. Thus, a factor of 2 needs to be applied to compensate for short exposure duration in the study (considering free time on weekends). Finally, the welders worked with the material for 4 hours per day instead of 8 hours, which can be considered a normal work day. Thus, an assessment factor of 2 is considered justified to account for the differences in exposure time. Conclusively, a total assessment factor of 8 would need to be applied to account for potential insecurities from the study design.

For derivation of the long-term systemic inhalative DNELfor BaO based on human data, the inhalative NOEC for barium of 4.4 mg/m³was adapted to the corresponding value for Barium oxide based on molecular weight: 4.9 mg/m³. Applying all assessment factors, the inhalative long-term systemic DNEL was set at0.6mg/m³for the worker.

 

Long-term – inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOEC (Ba): 4.9 mg/m^3	NOEC was determined in a human study
Step 2) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied since the relevant dose descriptor was derived from a human study.
Remaining differences	1	Standard assessment factor according to R8 ECHA 2012
Intraspecies	2	Safety factor due to small cohort size required, but 2 is considered sufficient since no adverse effects were observed.
Exposure duration	4	Exposure time was 4h instead of 8h per day and study period was relatively short
Dose response	1	Starting point of DNEL derivation is NOEC
Quality of database	1	well documented study
DNEL	Value
	4.9 / (1 x 2.5 x 5 x 1 x 1 x 1) =0.6 mg/m^3

 

The calculations conducted above result in the following values:

External worker DNEL_long-termfor the inhalation route of 2.4 mg barium/m³(animal studies)

External worker DNEL_long-termfor the inhalation route of 0.6 mg barium/m³(human study)

Since the DNEL obtained from the human study is lower and therefore also more sensitive than the DNEL derived from animal studies, it is considered more appropriate. This determined value closely correlates with anIndicative Occupational Exposure Limit Value(IOELV), set by the Scientific Committee on Occupational Exposure Limits (SCOEL), as well as anOccupational Exposure Limitset by the German Government (Directive 2006/15/CE and TRGS 900 Liste of baua). The IOELV and German OEL are both exposure thresholds that are accepted in regulatory context and are set at 0.5 mg/m³for soluble barium compounds. The value was determined on the basis of empirical expertise and since it is lower than the calculated DNELs from both animal and human studies, it will be adopted for risk assessment of BaO. 

Derivation of the short-term systemic inhalative DNELis not required since the long-term DNEL is considered adequately low to avoid short-term effects.

Derivation of the long-term and short-term systemic and local dermal DNELis not significant since the corrosive properties of barium oxide were tested using a Corrositex® assay, the results of which do not allow for threshold determination. Already small amounts of BaO are expected to cause corrosive effects on the skin, systemic exposure is not expected in amounts sufficient to cause adverse effects. Altogether, a qualitative risk assessment is considered more appropriate for dermal exposure with BaO.

Derivation of local DNELsis not required, since the corrosive properties of BaO are considered prevalent and thus will be assessed in a qualitative risk assessment.

In summary, the following DNELs for barium are relevant and derived:

DNEL_long-termfor exposure via the inhalation route: 0.5 mg/m³

 

 

 

 

References:

Concise International Chemical Assessment Document No. 33 (2001)Barium and Barium Compounds.Inter-organization Programme for the sound Management of Chemicals (IOMC), WHO 2001.

Dietz DD, Elwell MR, Davis WE Jr, Meirhenry EF (1992)Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water.Fundamental and Applied Toxicology, 19:527-537.

National Toxicology Program (1994)NTP technical report on the toxicology and carcinogenesis of barium chloride dihydrate (CAS no. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). Research Triangle Park, NO, US Department of Health and Human Services. National Institutes of Health, National Toxicology Program (Toxicity Report Series No. 432).

Zschiesche W, Schaller KH, Weltle D (1992) Exposure to soluble barium compounds: an interventional stuy in arc welders.Intl Arch Occup Environ Health 64:12-23.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

DNEL related information

Additional information - General Population

The intended uses for BaO are strictly industrial, exposure of the general population is not to be expected. Therefore, only worker DNEL values are derived.