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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

In a 28 day subacute oral study in the rat there were no effects of toxicological significance.  The NOEL is 1000 mg/kg bw/day.

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
Reliability:
1 (reliable without restriction)
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
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: Barriered Animal Breeding Unit, Zeneca
- Age at study initiation: 5 weeks
- Weight at study initiation: mean weight = 190g males, 160g females
- Housing: stainless steel cages 26.5 x 50.0 x 20.7 cm, 5 animals per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%):40-70%
- Air changes (per hr): 25-30
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) hydroxypropylmethylcellulose in 0.1% (w/v) aqueous polysorbate 80
Details on oral exposure:
Dosing formulations were shaken then stirred using a magnetic stirrer prior to and during dosing. Rats were dosed by gavage at 1.0ml/100g according to their daily individual bodyweights. Rats were dosed sequentially within group order at approximately the same time each day.


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Portions of sample were dissolved in 25ml DMF and further diluted with methanol to give concentrations of approximately 40ug/ml HMBDA. Solutions were analysed by HPLC using a spherisorb S50DS1 column, mobile phase water/methanol/ammonium acetate (700:300:5 g/l), UV detection at 220nm. The sample concentrations were calcualted by reference to the interspersed calibration standard.
Duration of treatment / exposure:
Single oral gavage dose
Frequency of treatment:
Daily dosing for 28 consecutive days
Remarks:
Doses / Concentrations:
50 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
250 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes, concurrent vehicle
Details on study design:
Dose levels for the study were selected on the basis of a preliminary sighting study.
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Daily

FOOD CONSUMPTION: Yes
- Food consumption for each group of animals wasa recorded continuously and calculated on a weekly basis

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Termination
- Method: Cardiac puncture
- Parameters: haemoglobin, total white cell count, red cell count, mean cell colume, mean cell haemoglobin concentration, haematocrit, platelet count, prothrombin and kaolin-cephalin times, differential white cell count, red cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Termination
- Method: Cardiac puncture
- Parameters: plasma urea, creatinine, glucose, albumin, total protein, cholesterol, triglycerides, total bilirubin, sodium, potassium, chloride, calcium, phosphorous, plasma alkaline phosphatase, alanine transaminase, creatine kinase, aspartate transminase, gamma-glutamyl transferase









Sacrifice and pathology:
GROSS PATHOLOGY: Yes
- Organs weighed: Testes, adrenal glands, kidneys, liver

HISTOPATHOLOGY: Yes
- Organs examined by light microscopy: Adrenal glands, epididymis, heart, kidney, liver, spleen, testis, macroscopically abnormal tissue
Statistics:
Body weights were considered by analysis of covariance.
Haematology and blood clincial chemistry were considered by analysis of variance.
Organ weights were considered by analysis of variance and analysis of covariance on final bodyweight.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
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:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified

The achieved concentrations of test substance in vehicle were within 6% of nominal values. The homogeniety and stability of the dose formulation were shown to be satisfactory.

Conclusions:
In a subacute oral study in the rat there were no effects of toxicological significance. The NOEL is 1000 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Sufficient to meet data requirements. The sub-chronic endpoint has been waived in accordance with Annex IX, 8.6.2 column 2 paragraph 4 of the REACH regulation.

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

In a 28 day subacute study, there were no mortalities, no adverse treatment related effects on clinical signs, bodyweight, food consumption, haematology or blood clinical chemistry. There was no evidence of any effect on the weights of specific organs and no pathological effects attributable to treatment were observed. The NOEL is 1000 mg/kg bw/day. The requirement for a 90 day sub-chronic study has been waived in accordance with Annex IX, 8.6.2 column 2 paragraph 4 of the REACH regulation. HMBDA is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity from the existing 28 day sub-acute study. In addition, human exposure will not be significant.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available. The study is Klimisch 1.

Justification for classification or non-classification

There were no effects of toxicological significance in the available repeated dose study and therefore the substance is not classified.