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Administrative data

Description of key information

Oral: NOAEL = 300 mg/kg bw/d (OECD 407)
Oral: NOAEL = 343 mg/kg bw/d (recalculated from Boron uptake; chronic study)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2005-06-10 - 2005-10-17
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study according GLP
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Service, CH-Füllinsdorf, Switzerland
- Age at study initiation: 6 weeks
- Weight at study initiation: mean 143.4 g (males), mean 120.0 g (females)
Housing: In groups of five in Macrolon type-4 cages with wire mesh tops and standard softwood bedding (“Lignocell”, Schill AG, CH-4132 Muttenz, Switzerland
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch No. 54/03 and 78/03 (Provimi Kliba AG, CH-4303 Kaiseraugst, Switzerland); ad libitum
- Water (e.g. ad libitum): Community tap water from Füllinsdorf; ad libitum
- Acclimation period: 7 days, under test conditions after health examination



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 10 -15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
Desiccated corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test substance was daily freshly prepared by weighing into a glass beaker and mixing with vehicle.The mixture was perpared using magnetic stirrer and used at room temperature (15-25°C)


VEHICLE
- Justification for use and choice of vehicle (if other than water): Since test usbstance decomposes in water, desiccated corn oil was chosen as vehicle.
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): Charge 11570660
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability (after 2 hours) of the dose formulations were determined in samples taken after experimental start. Concentration and homogeneity of dose formulations were determined during week 3 of treatment.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
30, 100 and 300 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
30 mg/kg bw/d: 5 males and 5 females
100 mg/kg bw/d: 5 males and 5 females,
300 mg/kg bw/d: 5 males and 5 females; additionally 5 males and 5 females for recovery group
Control: 5 males and 5 females; additionally 5 males and 5 females for recovery group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: doses were selected based on results of a 5-day oral toxicity study (Report A05308)
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for clinical signs once before administration, twice daily on days 1-3, once daily during days 4-28 and during recovery period on days 29-42
- Cage side observations checked in table were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: in random sequence once before administration and once weekly during weeks 1-3

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during acclimatization, treatment and recovery and before necropsy

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks (all groups), after 6 weeks (recovery groups), early in the morning
- Anaesthetic used for blood collection: Yes (Isoflurane)
- Animals fasted: Yes (approx. 18 h)
- How many animals: all animals of the designated groups
- Parameters checked in table were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks (all groups), after 6 weeks (recovery groups)
- Anaesthetic used for blood collection: Yes (Isoflurane)
- Animals fasted: Yes (approx. 18 h)
- How many animals: all animals of the designated groups
- Parameters checked in table were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: after 4 weeks (all groups), after 6 weeks (recovery groups)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (approx. 18 h)
- Parameters checked in table were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4
- Dose groups that were examined: All animals
- Battery of functions tested: sensory activity / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Follwing statistical methods were used for analysis of grips strenght, locomotor activity, body weights, organ weights and ratios:
- Dunnett-test
-Steel-test
- Fisher's exact test

Follwing statistical method was used for analysis of clinical laboratory data:
- One-way ANOVA
- DunnettTest
-Kruskal-Wallis test
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
observed in the moribund rats
Mortality:
mortality observed, treatment-related
Description (incidence):
observed in the moribund rats
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
observed in the moribund rats
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
observed in the moribund rats
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Two males pf the high dose group died before scheduled necropsy, one on day 2 and one was killed on day 12 for ethical reasons.
No test-related clinical signs were noted. Only noted findings included piloerection, salivation, hunched posture, sedation, rales, emaciation and distended abdomen in the male sacrificed for ethical reasons.

BODY WEIGHT AND WEIGHT GAIN
No changes in body weight an all animals of all dose groups were compared to control groups were noted.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
During treatment and recovery period, the mean daily food consumption values of treated animals of all dose groups were unaffected.

HAEMATOLOGY
After the end of the treatment and recovery period, no differences of toxicological relevance were seen in all treated animals.

CLINICAL CHEMISTRY
After the end of the treatment and recovery period, no differences of toxicological relevance were seen in all treated animals.

URINALYSIS
After the end of the treatment and recovery period, no differences of toxicological relevance were seen in all treated animals.

FUNCTIONAL OBSERVATION BATTERY
No clinical signs of toxicological relevance were evident. The mean fore- and hindlimb grip strength values of all treated animals were unaffected. No substance-related changes in locomotor activity was seen.

ORGAN WEIGHTS
No substance-related changes were noted after treatment or recovery periods in the mean absolute or relative organ weights in all treated animals.

GROSS PATHOLOGY
With exception of the two animals sacrificed before scheduled necropsy, all macroscopical changes noted in the remaining substance-treated animals were considered to be in the range of normal background lesions seen in rats of this strain and age. Thus the noted lesions were considered incidental reflecting the usual individual variability and not substance-related.
The male died on day 2 had incomplete lung deflation and dark red discoloration of the mandibular lymph nodes and salivary glands. The animals sacrificed for ethical reasons had distension of the entire digestive tract with multiple crateriform red to dark-red retractions of the stomach fundus and hyposplenia which was considered to the reactive nature of the substance.

HISTOPATHOLOGY: NON-NEOPLASTIC
No substance-related microscopical changes were noted after treatment or recovery periods in all treated animals, except the animal sacrificed for ethical reasons. This animal had several foci of mucosal necrosis with mild gastric haemorrhage , mild luminal dilation of the ileum and colon and minimal luminal dilation of the rectum. No substance-related microscopic findings were evident in rats necropsied after recovery period.

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of substance-related systemic effects
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of substance-related systemic effects
Critical effects observed:
not specified
Conclusions:
Based on the absence of substance-related systemic effects in male and female Wistar rats treated for 28 days, the NOAEL of 300 mg/kg bw/d was determined for Sodium triacetoxyborohydride.
Executive summary:

Oral toxicity of Sodium triacetoxyborohydride after repeated dosing for 28 day was evaluated in a GLP study performed according OECD guideline 407. Groups of 5 male and female Wistar rats received 30, 100 and 300 mg/kg bw/d in desiccated corn oil by gavage for 28 days. Additional groups were treated with control only and 300 mg/kg bw/d for 28 days had a recovery period of 14 days. Clinical signs and mortality, body weight, food consumption, clinical chemistry data and functional observation battery was analysed during and at the end of the treatment period. After necropsy macroscopic and microscopic changes were recorded. Two males of the high dose groups died prior to scheduled necropsy, but the effects were considered to the reactive nature of the substance. No substance related systemic effects were noted on all the other treated animals. Based on these findings, the NOAEL was determined to be 300 mg/kg bw/d, the highest dose tested.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A lower NOAEL was derived in the subacute study with the test substance compared to the calculated value resulting from a reliable chronic study, peer reviewed and used for international risk assessment with the hydrolysis product boric acid. However, both NOAEL values are within the same range.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral toxicity of Sodium triacetoxyborohydride after repeated dosing for 28 day was evaluated in a GLP study performed according OECD guideline 407. Groups of 5 male and female Wistar rats received 30, 100 and 300 mg/kg bw/d in desiccated corn oil by gavage for 28 days. Additional groups were treated with control only and 300 mg/kg bw/d for 28 days had a recovery period of 14 days. Clinical signs and mortality, body weight, food consumption, clinical chemistry data and functional observation battery was analysed during and at the end of the treatment period. After necropsy macroscopic and microscopic changes were recorded. Two males of the high dose groups died prior to scheduled necropsy, but the effects were considered to the reactive nature of the substance. No substance related systemic effects were noted on all the other treated animals. Based on these findings, the NOAEL for Sodium triacetoxyborohydride was determined to be 300 mg/kg bw/d, the highest dose tested.

Boric acid was evaluated in a two year feeding study, where Sprague-Dawley rats were dosed with 0, 670, 2000, and 6690 ppm boric acid, equivalent to 0, 33, 100, 334 mg boric acid/kg bw/day (equivalent to 0, 5.9, 17.5 and 58.5 mg boron/kg bw/day). Observed clinical signs included coarse hair coats, hunched position, and inflamed bleeding eyes, desquamation of the skin of the tail and the pads of the paws which were also swollen, marked respiratory involvement, as well as reductions in body weight were observed in males and females of the highest dose group. Further the scrotum of all males of the high dose group was of shrunken appearance. Blood samples were taken after 1, 2, 3, 6, 12, 18 and 24 months and observed changes in haematological parameters were decreased red cell volume and haemoglobin. Although the observations on haematology over time were not always consistent at the end of the study the values in all dosed animals were reduced compared to control. Testicular atrophy and seminiferous tubule degeneration was observed at 6, 12 and 24 months at the highest dose level whereas microscopic examination of the tissue revealed atrophied seminiferous epithelium and decreased tubular size in the testes. No effects were observed in control, low and mid dose groups. Based on the testicular atrophy and the haematological effects observed at the highest dose tested a NOAEL for chronic effects of 17.5 mg boron/kg bw/day (equivalent to 100 mg boric acid /kg bw/day) could be derived.

When calculated to the corresponding value for Sodium triacetoxyborohydride, the resulting NOAEL is 343 mg/kg bw/d, which is in line with the dose level of 300 mg/kg bw/d found in the subacute study with Sodium triacetoxyborohydride itself.

Based on thi, the lower NOAEL value of 300 mg/kg bw/d was used for risk assessment.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Reliable guideline study according to GLP

Justification for classification or non-classification

The available data on repeatded dose toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.