Technical Report: Barium Diboron Tetraoxide

Technical report: barium diboron tetraoxide

Agency technical report on the classification and labelling of

Barium diboron tetraoxide

EC Number: 237-222-4 CAS Number: 13701-59-2

Health and Safety Executive Chemicals Regulation Division Redgrave Court Merton Road Bootle L20 7HS [email protected]

Date: MAY 2021

Technical report: barium diboron tetraoxide

Contents

Brief summary ...... 3 Introduction ...... 4 Overview of current and proposed classification and labelling ...... 4 General substance information: ...... 6 Background ...... 6 Scientific assessment of the physical, human health and environmental hazard classes ...... 7 Physical Hazards ...... 7 Health Hazards ...... 7 Acute toxicity ...... 7 Specific target organ toxicity – single exposure (STOT SE)...... 10 Skin corrosion/irritation ...... 10 Serious eye damage/irritation ...... 10 Respiratory sensitisation ...... 10 Skin sensitisation ...... 10 Specific target organ toxicity – repeated exposure (STOT RE) ...... 10 Germ cell mutagenicity ...... 10 Carcinogenicity ...... 10 Reproductive toxicity ...... 10 Aspiration toxicity ...... 14 Environmental hazards ...... 14 Hazardous to the aquatic environment ...... 14 Other hazards ...... 14 Hazardous to the ozone layer ...... 14 Overall conclusion ...... 15 References ...... 16 Glossary of terms used in Agency technical reports ...... 17

Technical report: barium diboron tetraoxide Brief summary The conclusion of the Agency technical report is that barium diboron tetraoxide meets the classification criteria for: Acute tox. 3; H301 (Toxic if swallowed with an ATE value of 100 mg/kg bw) Repr. 1B; H360FD (May damage fertility. May damage the unborn child.)

Is this in agreement with the RAC opinion? NO

RAC concluded that barium diboron tetraoxide should also be classified as Acute Tox. 4; H332 (Harmful if inhaled) with an ATE value of 1.5 mg/L. The conclusion of the Agency technical report is that this classification is not supported by the available data. No classification is warranted for acute toxicity via the inhalation route.

At the time of publication, this mandatory classification and labelling has not been agreed and/or adopted in Great Britain.

Technical report: barium diboron tetraoxide Introduction Under Article 37 of the GB CLP Regulation1, the Agency2 is required to produce a technical report for each substance on which the Committee for Risk Assessment (RAC) of the European Chemicals Agency produces an opinion3.

This technical report documents an independent scientific assessment, conducted by HSE technical specialists, of the classification and labelling of barium diboron tetraoxide.

Table 1. Information considered in the scientific assessment

Document Included in assessment

EU CLH report Yes

Annexes to the EU CLH report Yes

RAC opinion Yes

Background document Yes

Information submitted during the EU public Yes consultation process (RCOM table, including attachments)

RAC minority opinion(s) Not applicable

Other information: No

This information has been evaluated against the classification and labelling criteria set out in the GB CLP Regulation.

1The retained CLP Regulation (EU) No. 1272/2008 as amended for Great Britain 2 HSE acting in its capacity as the GB CLP Agency 3 Under Article 37(4) of Regulation (EU) No 1272/2008 on classification, labelling and packaging of substances and mixtures 4

Technical report: barium diboron tetraoxide

Overview of current and proposed classification and labelling

Table 2. Current and proposed classification and labelling

Classification Labelling

Index International EC No. CAS Hazard Class Hazard Pictogram, Hazard Suppl. Hazard Specific Notes No. Chemical No. and Category Statement Signal Word Statement Statement Concentration Identification Code(s) Code(s) Code(s) Code(s) Code(s) Limits, M- factors GB MCL List 056- barium salts, Acute Tox. 4* H332 GHS07 * A1 entry 002-0 with the Acute Tox. 4* H302 Wng 0-7 exception of barium sulphate, salts of 1-azo-2- hydroxynapht halenyl aryl sulphonic acid, and of salts specified elsewhere in Annex VI of 1272/2008 EU dossier TBD barium 237- 13701- Add Add Add Add Add submitter’s diboron 222-4 59-2 Repr. 1B H360FD GHS08 H360FD oral: proposal tetraoxide ATE = Modify Retain Retain Retain 530mg/kg bw Acute Tox. 4 H302 GHS07 H302

Remove Remove Modify Remove

Technical report: barium diboron tetraoxide

Classification Labelling

EU RAC TBD barium 237- 13701- Add Add Add Add Add opinion diboron 222-4 59-2 Repr. 1B H360FD GHS08 H360FD inhalation: tetraoxide ATE = 1.5mg/L Modify Modify Modify Modify (dusts or mists) Acute Tox. 4 H301 GHS06 H301 oral: Acute Tox. 3 Dgr ATE = Retain Retain 100mg/kg bw H332 H332

Agency TBD barium 237- 13701- Add Add Add Add Add technical diboron 222-4 59-2 Repr. 1B H360FD GHS08 H360FD oral: report tetraoxide ATE = conclusion Modify Modify Modify Modify 100mg/kg bw Acute Tox. 3 H301 GHS06 H301 Dgr Remove Remove Remove Acute Tox. 4* H332 H332 Resulting TBD barium 237- 13701- Repr. 1B H360FD GHS08 H360FD Add MCL entry diboron 222-4 59-2 Acute Tox. 3 H301 GHS06 H301 oral: on GB MCL tetraoxide Dgr ATE = list 100mg/kg bw TBD: To be determined

Technical report: barium diboron tetraoxide

General substance information:

Active substance in Plant Protection Products: ☐

Active substance in Biocidal Products: ☐

Chemical registered under REACH: ☒

Background

Barium diboron tetraoxide is a chemical substance within the scope of Regulation (EC) No 1907/2006. Barium diboron tetraoxide is included in a group entry (Index No. 056-002-00-7) of Annex VI of CLP (and the GB mandatory classification and labelling (MCL) list) for barium salts. The group entry has a harmonised/mandatory classification for acute toxicity (via oral and inhalation exposure). Barium diboron tetraoxide is a metal borate that is used in industry for the manufacture of coating and paints, thinners and paint removers. It is also used by professional workers and consumers.

The dossier submitter (DS; Sweden) submitted a targeted CLH report to ECHA in August 2019, proposing the inclusion of harmonised classification for reproductive toxicity, modification of the existing classification for acute oral toxicity and removal of acute inhalation toxicity. This was based on data from the substance itself (obtained using a commercial form, Busan 11-M1), supported with read-across data from boric acid and borax (disodium tetraborate decahydrate). RAC considered the use of these substances for read- across acceptable against ECHA’s ‘Read-Across Assessment Framework’:

• Formation of compounds: metal borates dissolve in water to form boric acid, which is the predominant species at acidic and neutral pH, and tetrahydroxyborate anion. Therefore, barium diboron tetraoxide is expected to convert to boric acid and barium cations, which can form metal-ion complexes with tetrahydroxyborate, in the stomach. Borax converts to boric acid and sodium cations in the stomach. The chemical and toxicological effects of boric acid and other borates are similar on mol boron/L equivalent basis when dissolved in water or biological fluids at the same pH and low concentration. RAC therefore concluded that comparison on the basis of boron equivalents was justified. • The biological targets for common compounds: all three substances were expected to have the same biological targets because conversion to boric acid occurs prior to absorption. • Exposure to the biological targets for the common compounds: there was no significant quantitative difference in exposure of testes to boric acid when comparing toxicity data of the source and target substances. • The impact of parent compounds: biological targets were not expected to be directly exposed to barium diboron tetraoxide because its solid state and structure prevents its ability to be absorbed. The substance was assumed to hydrolyse to boric acid upon dissolution. • Formation and impact of non-common compounds: Sodium cations released from borax were not expected to contribute to the toxicity of borax at the tested dose levels. The barium cation shows higher general toxicity than borate, but studies did not show it to have any effect on reproduction or reproductive organs. RAC agreed that should similar studies be conducted with barium diboron tetraoxide, the barium

Technical report: barium diboron tetraoxide

cation would likely lead to marked general toxicity, including death, at the higher doses.

Dose levels from the read-across studies were converted from boron equivalents to equivalent barium diboron tetraoxide doses, allowing an estimation of general toxicity. RAC noted that the general toxicity of the barium cation should be considered when evaluating the contribution of read-across studies to classification.

The RAC opinion also refers to the substance by the alternative name of barium metaborate. In this technical report the EC name barium diboron tetraoxide is used throughout.

RAC adopted by consensus an opinion (at EU level) in September 2020. RAC agreed with the proposal to add classification for Repr 1B; H360FD. However, RAC disagreed with the proposals regarding acute toxicity, concluding that classification is to be upgraded to Acute Tox. 3; H301 (oral) and modified to Acute Tox. 4; H332 (inhalation).

Scientific assessment of the physical, human health and environmental hazard classes

Physical Hazards

Not assessed in the CLH report.

Health Hazards

Acute toxicity Classification agreed by RAC:

Read-across was not applied to these endpoints because acute toxicity studies were available for barium diboron tetraoxide via the oral, dermal and inhalation routes. The additional information on the acute toxicity of boric acid, sodium borates and barium chloride did not contradict the classification derived from data on barium diboron tetraoxide.

Oral One study, performed prior to OECD TG and GLP but comparable to OECD TG 401, was available. Sprague-Dawley rats (8/sex/group) were administered barium diboron tetraoxide of unknown purity and in an unknown vehicle by oral gavage, at doses up to 5000 mg/kg bw. In males the LD50 was 850 mg/kg bw; in females the LD50 was 530 mg/kg bw, corresponding to category 4.

RAC also considered information from a 5-day tolerability study in non-pregnant female rabbits (2/group) that was conducted prior to a prenatal developmental toxicity (PNDT) study, in which RAC reported there were no deaths at 100 mg/kg 7

Technical report: barium diboron tetraoxide bw/d of barium diboron tetraoxide. Both animals died at 200 mg/kg bw/d, whilst at 400 mg/kg bw/d one animal was found dead and one was killed in extremis. All the deaths occurred on the day the first dose was administered. The range-finding PNDT study involving pregnant rabbits reported that 50% mortality was reached at 90 mg/kg bw/d. The deaths occurred between gestation days 8 and 16 (doses were administered from gestation days 7 to 19. The study design meant that an LD50 value could not be derived, but RAC considered the LD50 value to be approximately 100 mg/kg bw and agreed this would be appropriate for classification.

RAC noted that humans may be more sensitive to barium compounds than rats because the rat LD50 for barium chloride ranges from 200-650 mg/kg bw, whereas lethal doses of 11 mg/kg bw of this compound have been reported in humans. Consequently, in line with CLP, data from rabbits was used to derive classification as this is the more sensitive species. The rabbit LD50 value, 100 mg/kg bw, is within the classification criteria for category 3 (50 < ATE ≤ 300 mg/kg bw). Therefore, RAC concluded that barium diboron tetraoxide meets the classification criteria for acute oral toxicity in category 3 (with an ATE value of 100 mg/kg bw).

Dermal One study, performed prior to OECD TG and GLP but comparable to OECD TG 402, was available. New Zealand White rabbits (5/sex/group) were administered a single dermal dose of barium diboron tetraoxide of unknown purity and in an unknown vehicle. The study reported the LD50 value as > 2000 mg/kg bw, exceeding the classification criteria for category 4 (1000 < ATE ≤ 2000 mg/kg bw). Therefore, RAC concluded that barium diboron tetraoxide does not meet the classification criteria for acute dermal toxicity.

Inhalation One study, performed prior to OECD TG and GLP but comparable to OECD TG 403, was available. Sprague-Dawley rats (5/sex/group) were exposed to barium diboron tetraoxide of unknown purity and in an unknown vehicle by whole body dust exposure at 2.98 mg/L (MMAD 3.4µm) and 3.54 mg/L (MMAD 2.8µm). Rats were exposed for 4 hours, followed by a 14-day post exposure observation period. The top concentration was the maximum attainable concentration. One male died from the low concentration group (day 2); one female died from the high concentration group (day 1). In the high concentration group, clinical signs were reported on day 1, but all surviving animals were observed as being normal from day 2 through to termination. The study concluded that the LC50 was > 3.5 mg/L. The DS thus proposed to remove the existing classification of Acute Tox. 4* (H332); however, RAC considered that the two deaths occurred at concentrations within the classification criteria for category 4 (1.0 < ATE ≤ 5.0 mg/L).

Again, RAC considered humans may be more sensitive to barium compounds than rats. A case of severe intoxication in humans following inhalation exposure to barium was noted, but information on exposure concentration was not available and oral exposure could not be excluded. Following analysis of available human data, RAC concluded that acute toxicity via the inhalation route was relevant, supporting the

Technical report: barium diboron tetraoxide need for classification. As the basis of the original classification for entry 056-002-00- 7 in Annex VI was unknown, a reliable effect level could not be derived for humans.

RAC stated that the asterisk (*) in the current entry, which indicates the classification was derived from the Dangerous Substances Directive (DSD), could be removed because the borders for classification for Xn; R20 in the DSD mirrors that of inhalation (dusts and mists) category 4 of CLP. As per Table 3.1.2 of Annex I in CLP, RAC agreed that a converted ATE of 1.5 mg/L was appropriate. Therefore, RAC concluded that barium diboron tetraoxide met the classification criteria for acute inhalation toxicity in category 4 (with an ATE value of 1.5 mg/L).

Classification proposed by the Agency:

Oral The Agency agrees with RAC’s assessment of the data. Although an LD50 of 530 mg/kg bw was obtained in a rat study, in a rabbit tolerability study deaths occurred from 200 mg/kg bw, albeit with small group sizes (2 non-pregnant females per group; both animals died at 200 and 400 mg/kg bw). Nevertheless, the increased sensitivity of rabbits compared with rats was also observed in a dose-range-finding study to a PNDT, in which 7 animals per group were dosed by gavage. There is some uncertainty in the relevance of this study to acute oral toxicity classification, since the animals were pregnant, received doses over 13 days and the design was not suitable for the derivation of an LD50. When considering only deaths that occurred in the first 72 hours of the study, the numbers of animals dying were 0/7, 0/7, 1/7, 3/7, 5/7, 6/7 at 0, 20, 55, 90, 125, 160 mg/kg bw/d. Overall, the Agency considers that the rabbit data, with early deaths (50% of animals) occurring from around 100 mg/kg bw support classification in category 3. A converted ATE of 100 mg/kg bw (Annex I Table 3.1.2. of CLP) is also largely consistent with this data. Barium diboron tetraoxide meets the classification criteria for acute oral toxicity in category 3 (with an ATE value of 100mg/kg bw).

Dermal The Agency agrees with RAC’s assessment of the data. Barium diboron tetraoxide does not meet the classification criteria for acute dermal toxicity.

Inhalation The Agency disagrees with RAC’s assessment of the data. The existing classification on Annex VI of CLP is a group entry for barium salts. The basis of the classification for acute inhalation toxicity is not known. In an acute inhalation toxicity study in rats, 1/5 males and 0/5 females died at 2.98 mg barium diboron tetraoxide/L; 0/5 males and 1/5 females died at the next concentration of 3.54 mg/L, which was the highest attainable concentration. The increase in concentration thus did not result in an increased number of deaths. RAC considered that humans might be more sensitive to barium toxicity than rats, but there was no reliable data to support this supposition. The Agency considers that the only conclusion that can be drawn from the available data is that the 4-hour LC50 in rats was > 3.5 mg/L. Since there is no data to indicate that the 4-hour LC50 would be achieved at concentrations ≤

Technical report: barium diboron tetraoxide

5.0 mg/L, barium diboron tetraoxide does not meet the classification criteria for acute inhalation toxicity.

Specific target organ toxicity – single exposure (STOT SE) Not assessed in the CLH report.

Skin corrosion/irritation Not assessed in the CLH report.

Serious eye damage/irritation Not assessed in the CLH report.

Respiratory sensitisation Not assessed in the CLH report.

Skin sensitisation Not assessed in the CLH report.

Specific target organ toxicity – repeated exposure (STOT RE) Not assessed in the CLH report.

Germ cell mutagenicity Not assessed in the CLH report.

Carcinogenicity Not assessed in the CLH report.

Reproductive toxicity Classification agreed by RAC:

Adverse effects on sexual function and fertility One 90-day dietary study (US EPA guideline and GLP compliant) was available. Sprague-Dawley rats (10/sex/group) were administered barium diboron tetraoxide (94.3% purity) in the diet. In the high-dose group (707 mg/kg bw/d in males, equivalent to 63.6 mg B/kg bw/d) statistically significant reductions in body weight (by 10% in males and females) as well as absolute and relative testes weight (61% and 57%, respectively) were reported. Severe aspermatogenesis and no

Technical report: barium diboron tetraoxide spermatocytes in epididymal tubules were observed in 9/10 high-dose males; mild aspermatogenesis and small testes were observed in the remaining high-dose male. In females (high-dose group 794 mg/kg bw/d, equivalent to 71.4 mg B/kg bw/d), no effect on reproductive organs was observed.

RAC noted that doses close to those in the high-dose group in the 90-day study were lethal in the acute oral toxicity study. RAC considered this difference was primarily explained by the different way of administration (diet vs gavage).

The DS supplemented the 90-day study by reading across data from several rat, mouse and dog studies performed with boric acid and borax. These studies consistently showed severe adverse effects on the male reproductive system (including testes atrophy, inhibition of spermiation, reduced epididymal sperm count) and/or on fertility at doses that did not result in excessive parental toxicity.

RAC attempted to compare the general toxicity between those studies and what would be predicted were the studies to use barium diboron tetraoxide. RAC considered that if the studies had been conducted with barium diboron tetraoxide, some of the higher doses might lead to excessive toxicity, including death. This was important because excessive general toxicity makes concurrent reproductive toxicity effects less relevant for classification.

While the general toxicity of barium could be estimated in rat studies from the 90- day dietary study with barium diboron tetraoxide (described above), there was no data to estimate this in mice and dogs. In the 90-day rat study with barium diboron tetraoxide, a dose of approximately 700 mg/kg bw/d caused a 10% reduction in body weight but no clinical signs or deaths. With this in mind, RAC considered that the reproductive effects at 59 mg B/kg bw/d in a three-generation rat study on boric acid and borax and the testicular findings at 38 mg B/kg bw/d in a 9-week rat dietary study on boric acid provided additional support for an adverse reproduction effect of barium diboron tetraoxide.

Studies with barium chloride indicated that the murine threshold for death could be twice that of rats, but RAC acknowledged this was uncertain. No data were available to inform on the general toxicity of barium to dogs, so the testicular findings in a 90- day dog study with boric acid and borax were of unclear relevance for the classification of barium diboron tetraoxide. RAC also noted that an adverse effect on female fertility was reported in a three-generation rat study with boric acid and borax.

The DS presented information from human exposures to boric acid and borate salts. None of these reported reproductive effects, but RAC noted that the highest human exposure levels were below the doses at which such effects occurred in animal studies. Other limitations of the studies affected their reliability and sensitivity.

Overall, RAC concluded that the presence of severe aspermatogenesis in the absence of marked general toxicity in the 90-day dietary study in rats with barium diboron

Technical report: barium diboron tetraoxide tetraoxide, supported with read-across from studies with boric acid or borax, met the classification criteria for category 1B. The ED10 value derived from the 90-day study was 385 mg/kg bw/d, which is within the medium potency group (4 mg/kg bw/d < ED10 < 400 mg/kg bw/d). No modifying factor to reduce the concern could be identified, therefore the medium potency group and generic concentration limit (GCL) of 0.3% were applicable.

Adverse effects on development One US EPA guideline and GLP compliant PNDT study, performed in pregnant New Zealand rabbits (20/group), was available. Up to 20 mg/kg bw/d barium diboron tetraoxide (1.8 mg B/kg bw/d) in aqueous methyl cellulose was administered via oral gavage from GD 7-19. In the high-dose group, one dam died on GD16 (no treatment- related clinical signs reported), one dam aborted on GD22 and two other dams were found not to be pregnant. There was no developmental toxicity in this main study. The top dose was derived from a preliminary study that reported deaths at doses from 20 to 160 mg/kg bw/d (all animals died from 125 mg/kg bw/d). No developmental toxicity was reported in the preliminary study (7 females/group) at the doses available for evaluation, up to 90 mg/kg bw/d (8.1 mg B/kg bw/d).

The dossier submitter also reported information from PNDTs in rats, mice and rabbits and a continuous breeding study in mice with boric acid. Developmental toxicity reported in these studies comprised the following, as compared against the classification criteria. • Death of the developing organism: decreased live birth index and number of litters per pair in a mouse continuous breeding study at 111 mg B/kg bw/d.; markedly increased rates of resorptions per litter (90%) in rabbits at 44 mg B/kg bw/d, which resulted in some maternal toxicity; and increased resorption (36% resorptions per litter versus 4% in controls) in rats at 94 mg B/kg bw/d. • Structural abnormality: in rats, skeletal malformations were seen in the absence of maternal toxicity, including agenesis of rib XIII in 6.2% and 12.5% of foetuses and shortening of rib XIII in 39% and 37% of foetuses, at 58 and 94 mg B/kg bw/day, respectively. Increased incidence of short rib XIII (i.e., by approx. 1.5% at 13.3 mg B/kg bw/day and by approx. 3.4% at 25 mg B/kg bw/day, compared with controls) in the absence of maternal toxicity was also observed in another rat study. In mice, significantly increased incidence of short rib XIII (4% vs. 0% in controls) was reported at 175 mg B/kg bw/day, in the absence of maternal toxicity. Visceral malformations such as enlarged lateral ventricles of the brain in 5.5% of foetuses at 58 mg B/kg bw/day and 26.5% of the foetuses at 94 mg B/kg bw/day, as well as malformations of the eyes (i.e., displaced eyes, convoluted retina) in 11% of the foetuses at 94 mg B/kg bw/day, were also observed in rats. In rabbits, cardiovascular malformations such as interventricular septal defects (57% vs. 0.6% in controls), enlarged aorta (36% vs. 0% in controls), papillary muscle malformations (14% vs. 3% in controls) and double outlet right ventricle (14% vs. 0% in controls) were seen at the highest dose level (43.5 mg B/kg bw/day) together with some maternal toxicity.

Technical report: barium diboron tetraoxide

• Altered growth: statistically significantly reduced mean rat foetal body weights per litter at 13.3 and 25 mg B/kg bw/d in the absence of maternal toxicity. Additionally, a dose-dependent decrease in average rat pup foetal body weight was noted for all dose levels (7, 13, 37 and 50% at 14, 29, 58 and 94 mg B/kg bw/day, respectively). In mice, a statistically significant decrease in foetal body weights occurred at 79 and 175 mg B/kg bw/d, with some maternal toxicity in the high-dose group. RAC noted that the maximum dose of barium diboron tetraoxide administered in the PNDT was lower than the doses (in mg B/kg bw/d) at which the developmental toxicity of boric acid occurred. Again, RAC tried to elucidate the impact of barium on maternal toxicity had the studies been conducted with barium diboron tetraoxide. A rat dietary PNDT study reported malformations at doses equivalent to 970 and 600 mg/kg bw/d barium diboron tetraoxide. RAC estimated the maternal toxicity of barium diboron tetraoxide from the 90-day rat study, where non-pregnant females showed a 10% body-weight reduction but no clinical signs or deaths at approximately 800 mg/kg bw/d. RAC therefore surmised that at least the dose of 58 mg B/kg bw/d (equivalent to 600 mg/kg bw/d barium diboron tetraoxide) that caused agenesis of rib XIII and severe foetal weight reduction (by 37%) was relevant for classification. Other findings at this dose comprised cleft sternum (dose-related increase from the mid-dose group), clubbed limb, a high incidence of short rib XIII and enlarged lateral ventricles of the brain.

A rabbit PNDT study with boric acid reported high embryolethality and teratogenicity at the barium diboron tetraoxide equivalent dose of 450 mg/kg bw/d. In a rabbit (same strain) preliminary study to a PNDT with barium diboron tetraoxide, all animals died from 125 mg/kg bw/d by gavage administration. This suggested that developmental toxicity in rabbits could not be achieved with barium diboron tetraoxide because of excessive maternal toxicity at doses below those potentially causing developmental toxicity. The developmentally toxic dose reported in the murine PNDT study was at a barium diboron tetraoxide equivalent dose that was above the limit dose (1000 mg/kg bw/d). High maternal toxicity could not be excluded.

A human cohort study in women exposed to boron via drinking water reported a statistically significant inverse association between serum boron levels during pregnancy >0.08µg/mL and birth length. Birth weight remained unaffected. However, a contribution of lithium to this effect could not be ruled out. No association between boron exposure and developmental toxicity was reported in other epidemiology data. RAC agreed that the human data did not contradict the animal data because of low exposure levels and/or methodological limitations.

Overall, marked increase in agenesis of rib XIII from the read-across rat PNDT study, supported by observations of short rib XIII, clubbed limb, cleft sternum, enlarged lateral ventricles and 37% reduction in foetal weight, provided justification for classification in category 1B. RAC stated that at the barium diboron tetraoxide dose equivalent of 600mg/kg bw/d, maternal toxicity would not be expected. The ED10

Technical report: barium diboron tetraoxide value for short rib (330 mg/kg bw/d) was the only one to fall within the medium potency range (4 mg/kg bw/d < ED10 < 400 mg/kg bw/d). Short rib XIII is structurally related to agenesis of rib XIII and reached a rate of increased incidence of >10%. Therefore, RAC concluded that the medium potency group and GCL of 0.3% was applicable.

Effects on or via lactation No studies performed using barium diboron tetraoxide or barium salts were available. From data read-across from studies with boric acid and borax no treatment related observations or significant reduction in pup weight or viability attributable to effects on or via lactation were reported. Human mothers administered with boric acid reported 10-285 mg/kg boron in breast milk, but there was insufficient data to conclude whether these levels were toxic. Therefore, RAC concluded that the data for effects on or via lactation did not support classification.

RAC conclusion RAC agreed that the findings related to fertility and development warranted classification. Therefore, RAC concluded that barium diboron tetraoxide met the classification criteria for reproductive toxicity in category 1B for fertility and development (with no specific concentration limit; GCL of 0.3% applies).

Classification proposed by the Agency:

The Agency agrees with RAC’s assessment of the data. Barium diboron tetraoxide meets the classification criteria for reproductive toxicity in category 1B for fertility and development (with no specific concentration limit; GCL of 0.3% applies).

Aspiration toxicity Not considered in the CLH report.

Environmental hazards

Hazardous to the aquatic environment Not considered in the CLH report.

Other hazards

Hazardous to the ozone layer Not considered in the CLH report.

Technical report: barium diboron tetraoxide

Overall conclusion

The Agency has evaluated the RAC Opinion, its rationale and any additional scientific evidence that may have been made available to HSE against the criteria for classification and labelling in the GB CLP Regulation and technical guidance.

The Agency technical report agrees with the classification proposed by RAC for the following hazards:

Acute tox. 3; H301 (Toxic if swallowed; with an ATE value of 100mg/kg bw) Repr. 1B; H360FD (May damage fertility. May damage the unborn child; with no SCL, GCL of 0.3% applies) The Agency technical report disagrees with the classification proposed by RAC for the following hazards:

Acute tox. 4; H332 (Harmful if inhaled; with an ATE value of 1.5mg/L)

The available data do not support this classification. No classification is warranted for acute toxicity via the inhalation route.

Overall, the conclusion is to disagree with the RAC opinion.

Technical report: barium diboron tetraoxide References

For all other references, please see the EU CLH report and the EU RAC opinion (available at: https://echa.europa.eu/registry-of-clh-intentions-until-outcome)

Documents published as part of the EU CLH process: Source: European Chemicals Agency, http://echa.europa.eu/

ECHA (2017) Guidance on the application of the CLP criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures, version 5.0, ref: ECHA-17-G-21-EN. Available at https://www.echa.europa.eu/

ECHA, CLH report (including Annexes): Proposal for Harmonised Classification and Labelling Based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, Part 2. Substance Name: barium diboron tetraoxide; Date: 2019; Accessed date: 05/2021

ECHA, Committee for Risk Assessment (RAC) Opinion (including Annexes) proposing harmonised classification and labelling at EU level of barium diboron tetraoxide; Reference CLH-O-0000006847-60-01/F; Date: 17/09/2020, Accessed date: 05/2021

Technical report: barium diboron tetraoxide Glossary of terms used in Agency technical reports

Agency, the HSE, acting in its capacity as the GB CLP Agency AR Applied radiation ATE Acute toxicity estimate BCF Bioconcentration factor BOD Biological Oxygen Demand bw Body weight CAR Competent Authority Report CAS Chemical Abstracts Service CI Confidence interval CL Confidence limits CLH Harmonised Classification and Labelling CLP Classification, labelling and packaging (of substances and mixtures) CO2 Carbon dioxide COD Chemical Oxygen Demand CV Coefficient of Variation d Day DAR Draft Assessment Report DOC Dissolved Organic Carbon DS Dossier Submitter DSD Dangerous Substances Directive DT Dissipation time OR degradation time (also DissT or DegT where apparent) DT50 Dissipation half-life OR degradation half-life (hours or days), see also above dw Dry weight ECHA European Chemicals Agency ECx x% effect concentration EDx x% effect dose EFSA European Food Safety Authority ErCx x% effect concentration based on growth rate EU European Union GCL Generic concentration limit GD Gestation day GLP Good Laboratory Practice h Hours KOC Organic carbon-water partition coefficient KOW Octanol-water partition coefficient LDx x% lethal effect dose LCx x% lethal effect concentration MCL Mandatory Classification and Labelling M-factor Multiplying factor MW Molecular weight NOEC No-observed effect concentration

Technical report: barium diboron tetraoxide

OECD Organisation for Economic Co-operation and Development PNDT Pre-natal developmental toxicity QSAR Quantitative structure-activity relationship RAC Risk Assessment Committee RAR Renewal Assessment Report RCOM Response to comments document REACH Registration, Evaluation, Authorisation and Restriction of Chemicals regulation STOT-RE Specific target organ toxicity – repeated exposure STOT-SE Specific target organ toxicity – single exposure TG Test Guideline US EPA United States Environmental Protection Agency wt Weight wwt Wet weight