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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
No reproductive toxicity data are available. A NOAEL of 5000 ppm (350 mg/kg bw/d) is reported for testicular effects in a good quality 90-day study.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No reproductive toxicity data are available.

In the 90-day oral toxicity study performed with the substances in the rat (Lamb, 1993), male rats at the highest dietary concentration of 10000 ppm showed testicular aspermatogenesis and an absence of spermatocytes in the epididymal tubules. Mean absolute and relative (to brain weight and bodyweight) testes weights were also significantly lower in males in this group and the testes were observed to be small and/or soft at gross necropsy. The effects seen in this study at the highest dietary concentration of 10000 ppm (equivalent to a mean achieved intake of the substance of 707 mg/kg bw/d; 62 mg/kg bw/d boron equivalents) are comparable to those reported in studies with boric acid at a dose level of 334 mg/kg bw/d (59 mg/kg bw/d boron equivalents). In a reproductive toxicity study, administration of this dose level of boric acid was associated with sterility of male rats. Based on the comparability of testicular effects seen in 90-day studies with barium diboron tetraoxide and boric acid, and the similarity of dose levels resulting in these effects, it is concluded that the testicular toxicity of barium diboron tetraoxide is attributable to the barium content. Furthermore, it can be assumed that the assessment of barium diboron tetraoxide in a reproductive toxicity study (e.g. EOGRTS) would identify effects comparable to those already identified for boric acid.

Boric acid has a harmonised classification under CLP (1st ATP) for reproductive toxicity of H360FD (Cat 1B), with a specific concentration limit (SCL) of 5.5%. The related substance boric oxide has the same classification, with an SCL of 3.1%; the lower SCL for this substance is due to the higher boron content (31.1%) compared to boric acid (17.5%). 

Column 2 of Annex IX of the REACH Regulation states that testing for reproductive toxicity is not required for substances known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60 [DSD, equivalent to Cat 1A or 1B under CLP], and the available data are adequate to support a robust risk assessment. The data available for barium diboron tetraoxide (the findings of the 90-day rat study, the boron content of the substance and the comparability of effects to those seen with boric acid) indicate that the substance should be classified for reproductive toxicity (Cat 1B) in line with boric acid. The substance should therefore be classified for reproductive toxicity (Cat 1B), with an SCL of 11% (based on a boron content of 8.7%).  Testing of barium diboron tetraoxide for reproductive toxicity is not justified scientifically or on animal welfare grounds.


Short description of key information:
No reproductive toxicity data are available. Testicular toxicity in male rats is reported in a 90-day repeated dose toxicity. Classification of the substance is proposed and a waiver is justified for additional testing.

Justification for selection of Effect on fertility via oral route:
No reproductive toxicity data are available. A waiver is proposed for reproductive toxicity, based on the testicular effects observed in male rats in the 90-day repeated dose toxicity study. Classification for reproductive effects is proposed based on the results of this study and comparability to effects seen in studies with boric acid. Testing of barium diboron tetraoxide for reproductive toxicity is therefore not justified scientifically or on animal welfare grounds.

Effects on developmental toxicity

Description of key information
A developmental toxicity study oral (gavage) rabbit (New Zealand White) is available.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 January, 1992 - 9 March, 1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was carried out under GLP and followed the appropriate guideline. The bodyweights were not measured with the frequency recommended in the guideline, however this is not deemed to affect the scientific integrity of the study.
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, Pennsylvania
- Age at study initiation: approximately 5 months
- Weight at study initiation: 2.344 - 3.710 kg
- Fasting period before study:
- Housing: Individually, stainless steel wire bottom cages suspended above a cage-board
- Diet (e.g. ad libitum): Purina Certified Rabbit Chow #5322 ad libitum
- Water (e.g. ad libitum): Municipal water ad libitum
- Acclimation period: approximately 6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22.2
- Humidity (%): 28-60%
- Air changes (per hr): 10 fresh air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
other: 0.5% aqueous methylcellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
An appropriate amount of the test material was weighed for each group and transferred to a mortar. The test material was triturated with a small amount of the vehicle until a slurry was formed. This was then transferred to a graduated cylinder and a sufficient amount of vehicle was added to attain an appropriate volume for mixing. The suspension was mixed on a mixer for approximately 5 minutes to reduce any large particles.
A magnetic stir bar was added and the mixture was stirred continuously throughout the sampling and dosing procedures. Dosing preparations were dispensed on a daily basis for dose administration. Dosing preparations were prepared twice during the study period and were stored at room temperature.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: Each litre of vehicle was prepared by heating 1000 ml of deionised water to approximately 70 °C and gradually adding 5.0 g of the control material powder. The mixture was stirred until clear. The vehicle was prepared approximately once each week and stored refrigerated between periods of use.
- Amount of vehicle (if gavage): Dosage volume 1 ml/kg
- Lot/batch no. (if required): 50H0209
- Purity: 0.5% aquous methyl cellulose
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to initiation of dosing, duplicate aliquots taken from the top, middle and bottom of the preparations were tested for homogeneity. Two duplicate sets of aliquots were collected for the middle of the preparations for concentration and 14-day stability analysis. Duplicate sets of sample aliquots were collected form the middle of the dosing solutions at dosing initiation for concentration analysis. Analysis was carried out at EPL BioAnalytical Services, Inc.
The dosing preparations were homogenous, contained the amounts of test material specified by the protocol and were stable for 14 days.
Details on mating procedure:
- Impregnation procedure: artificial insemination
- A 0.25 – 0.5 ml aliquot of each diluted semen sample (collected from 10 resident males of the same strain and obtained from the same supplier as the females) was deposited into the anterior vagina of each female with a glass insemination pipette. Immediately following insemination each doe was administered an intravenous injection of human chorionic gonadotropin to ensure ovulation. The day of insemination was designated gestation day 0.
Duration of treatment / exposure:
From gestation days 7-19
Frequency of treatment:
Daily
Duration of test:
Dam gross necropsy examination performed on gestation Day 29
No. of animals per sex per dose:
20 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on the results of a preliminary range-finding study
Five groups of 7 pregnant females were dosed with 20, 55, 90, 125, 160 mg/kg/day Busan 11-M1 daily from gestation day 7-19 by oral gavage. The animals were then observed until gestation day 29 at which point they were sacrificed and gross necropsy examination was performed. Maternal toxicity was exhibited at dose levels of 20 mg/kg/day and greater by mortalities and changes in the general clinical condition of the animals. No developmental toxicity was expressed at any dose level available for evaluation 20, 55, 90 mg/kg/day. Based on these results, the dose levels 2, 10, and 20 mg/kg/day were selected for the definitive developmental toxicity study.

- Rationale for animal assignment (if not random): computer randomisation procedure
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations included: mortality and moribundity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On the first day of dosing, animals were observed one hour following dosing. On the second day of dosing, animals were observed one, two and four hours following dosing. For the remainder of the test, animals were observed one hour following dosing.

BODY WEIGHT: Yes
- Time schedule for examinations: recorded individually on gestation days 0, 7-20, 24 and 29

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day and g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Post mortem findings were correlated with ante mortem clinical finding as and any abnormalities were recorded.

OTHER:
Gross necropsy was performed on females which aborted or died during the course of the study. Maternal tissues were retained for possible future histopathological examination. The number and location of implantation sites and corpora lutea were recorded. Foetal finding for females which aborted were not included in any tabulation or statistical analysis.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
Gravid uterine weight, net body weight (excluding the weight of the uterus and contents) and net body weight change were presented for each gravid female.
- Number of corpora lutea: Yes, in each ovary
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Uteri with no macroscopic evidence of nidation were opened and subsequently placed in 10% ammonium sulfide solution for detection of early implantation loss.
Fetal examinations:
- External examinations: Yes: all per litter, including but not limited to eyes, palate and external orifices. Crown-rump measurements for late resorptions. Sex was determined.
- Soft tissue examinations: Yes: all per litter, heart and major vessels, kidneys
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: all per litter, brain was examined by a mid-coronal slice
Statistics:
All statistical tests were performed by a Digital MicroVAX 3400 computer with appropriate programming. All analyses were conducted using two-tailed tests for a minimum significance level of 5% comparing each treated group to the vehicle control group. Each mean was presented with the standard deviation and the number of animals used.
Foetal sex ratios: Chi-square test with Yate’s correction factor
Malformations and variations: Fishers Exact test
Early and late resorptions, dead foetuses, postimplantation losses: Mann-Whitney U-test
Corpora Lutea, total implantations, viable foetuses, foetal bodyweights, maternal bodyweights and weight changes, maternal net bodyweight changes and gravid uterine weights, maternal food consumption: ANOVA with Dennett’s test
Litter proportions of intrauterine data: Kruskal-Wallis test
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One animal in the 20 mg/kg/day group died on gestation day 16 and was internally normal. No clinical signs were noted in this female during the study. The death was consistent with the mortality observed in the range-finding study.
No other treatment related effects were found in any of the other animals.
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
mortality
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No efffects
Key result
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No effects observed at the highest dose level
Key result
Abnormalities:
no effects observed
Developmental effects observed:
not specified

No further data

Conclusions:
No evidence of teratogenicity or developmental toxicity was seen in this study in the rabbit at dose levels sufficient to cause maternal toxicity.
Executive summary:

In a developmental toxicity study performed by Lamb (1993) groups of 20 pregnant female rabbits were dosed with 2, 10, 20 mg/kg bw/d Busan 11-M1 daily from gestation day 7-19 by oral gavage. The animals were then observed until gestation day 29 at which point they were sacrificed and gross necropsy examination was performed. One animal in the highest dose group died. No other effects attributable to treatment were observed on any of the other animals and no embryotoxic/teratogenic effects attributable to treatment were encountered. Based on the results of this study, the NOAEL for maternal toxicity was considered to be 10 mg/kg/day and the NOAEL for developmental toxicity was considered to be 20 mg/kg/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
Only one study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In a developmental toxicity study performed by Lamb (1993) groups of 20 pregnant female rabbits were dosed with 2, 10, 20 mg/kg bw/d Busan 11-M1 daily from gestation day 7-19 by oral gavage. The animals were then observed until gestation day 29 at which point they were sacrificed and gross necropsy examination was performed. One animal in the highest dose group died. No other effects attributable to treatment were observed on any of the other animals and no embryotoxic/teratogenic effects attributable to treatment were encountered. Based on the results of this study, the NOAEL for maternal toxicity was considered to be 10 mg/kg/day and the NOAEL for developmental toxicity was considered to be 20 mg/kg bw/d.

A study of developmental toxicity in a second species is not required based on the proposed classification of the substance in Category 1B (H360FD) for reproductive toxicity under the CLP Regulation.


Justification for selection of Effect on developmental toxicity: via oral route:
Key study

Justification for classification or non-classification

Boric acid has a harmonised classification under CLP (1st ATP) for reproductive toxicity of H360FD (Cat 1B), with a specific concentration limit (SCL) of 5.5%. The related substance boric oxide has the same classification, with an SCL of 3.1%; the lower SCL for this substance is due to the higher boron content (31.1%) compared to boric acid (17.5%). The substance barium diboron tetraoxide should therefore be classified for reproductive toxicity (Cat 1B), with an SCL of 11% (based on a boron content of 8.7%). 

The RAC opinion on boric acid notes evidence of developmental toxicity in all species tested (mice, rats, rabbits and dogs). The absence of developmental toxicity in the study available for BMBF (Lamb, 1993) does not report any developmental toxicity and does not therefore appear to support the classification of BMBF. The RAC Opinion, however, notes that the rat is the most sensitive species with respect to developmental toxicity. The study available for BMBF may not therefore be in the most sensitive species. Classification of BMBF in Category 1B for developmental toxicity in line with boric acid is therefore proposed.An SCL of 10.7% (11%) is proposed, in line with the SCL values agreed for boric acid (5.5%) and boric oxide (3.1%) and taking into account the lower boron content of BMBF.