Registration Dossier

Administrative data

Endpoint:
neurotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: FOB segment in full guideline subchronic oral study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guideline
Guideline:
other: FOB in subchronic oral study
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test substance: n-Butyl Methacrylate
- Batch Identification: 1271192067
- CAS No.: 97-88-1
- Purity: 99.8% (analysis was carried out at EVONIK Röhm GmbH)
- Homogeneity: given (visual)
- Stability: The stability of the test substance in drinking water containing 1% CMC + Cremophor EL + one drop Hydrochloric Acid (1mol/L) for a period of 4 hours was proven.
- Date of production: unknown
- Physical state/Appearance: liquid/colorless, clear
- Storage conditions: ambient (RT); avoid temperatures > 30°C

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 34 ± 1 day
- Weight at study initiation:
- Fasting period before study: No
- Housing: in groups of 5 animals per cage (Polysulfonate cages supplied by TECNIPLAST, Hohenpeißenberg, Germany; floor area about 2065 cm²)
- Diet: ground Kliba maintenance diet mouse/rat “GLP”, meal, ad libitum (Provimi Kliba SA, Kaiseraugst, Switzerland)
- Water: ad libitum
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 pm - 6.00 am dark; 6.00 am - 6.00 pm light)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test substance was administered as an emulsion. The appropriate amount of test substance was weighed out depending on the desired concentration. Thereafter, the vehicle (drinking water containing 1% carboxymethyl cellulose) was filled up to the desired volume + Cremophor EL + one drop Hydrochloric Acid (1mol/L) and subsequently mixed using a magnetic stirrer. The test-substance preparations were produced daily.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration control analyses of the test-substance preparations in samples of all concentrations were performed at the start of the administration period and thereafter weekly.
Duration of treatment / exposure:
about three months
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
60, 120 and 360 mg/kg/day
Basis:
nominal conc.
in vehicle
No. of animals per sex per dose:
Control and high dose groups: 15 animals per sex per group (thereof 5 animals per sex per group for 28-day recovery)
Low and mid dose groups: 10 animals per sex per group.
Control animals:
yes, concurrent vehicle
Details on study design:
- Post-exposure recovery period in satellite groups: 28 days (5 rats/sex of control and high dose groups only)

Examinations

Observations and clinical examinations performed and frequency:
Functional observation battery (FOB) was carried out on the assigned animals once before the exposure period and once against the end of the exposure period. Motor activity was measured on the same day and with the same animals as FOB was performed.
Neurobehavioural examinations performed and frequency:
rearing, grip strength forelimbs, grip strength hindlimbs, foot-splay test, and motor activity.
Sacrifice and (histo)pathology:
NECROPSY
All animals were sacrificed by decapitation under Isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology.

WEIGHT PARAMETERS
The following weight determinations were carried out on all animals: anesthetized animals, liver, kidneys, adrenal glands, testes, epididymides, ovaries, uterus, spleen, brain, heart, thymus, thyroid glands.

HISTOPATHOLOGY
After the organs were fixed, processing, examination by light microscopy and evaluation of findings in the following tissues of all control and high-dose animals of the main groups were performed: salivary glands (mandibular and sublingual glands), esophagus, stomach (forestomach and glandular stomach), duodenum, ileum, jejunum (with Peyer’s plaques), cecum, colon and rectum, liver, pancreas, brain, pituitary gland, sciatic nerve, spinal cord (cervical, thoracic and lumbar cords), eyes, adrenal glands, thyroid glands, parathyroid glands, trachea, lungs, nose (nasal cavity/level III), aorta, heart, bone marrow (femur), lymph nodes (mesenteric and axillary lymph nodes), spleen, thymus, kidneys, urinary bladder, testes, ovaries, oviducts, uterus and vagina, prostate, seminal vesicle and epididymides, female mammary gland, skin.
Additionally, nose tissue (nasal cavity/level III) was examined in all low- and mid-dose animals of the main groups and in all control and high-dose animals of the recovery groups. Furthermore, all gross lesions were examined in all affected animals of all groups.
Other examinations:
standard 90 d guideline examinations
Statistics:
KRUSKAL-WALLIS test (two-sided)/Wilcoxon-test (two-sided)

Results and discussion

Results of examinations

Behaviour (functional findings):
no effects observed
Details on results:
Up to the highest dose tested (360 mg/kg/day) there were no effects in the functional observational battery and no effects on motor activity.

Effect levels

Dose descriptor:
NOAEL
Effect level:
360 mg/kg bw (total dose)
Sex:
male/female
Remarks on result:
other:

Any other information on results incl. tables

Up to the highest dose tested (360 mg/kg/day) there were no effects in the functional observational battery and no effects on motor activity.

Applicant's summary and conclusion

Conclusions:
Up to the highest dose tested (360 mg/kg/day) there were no effects in the functional observational battery and no effects on motor activity.
Executive summary:

n-Butyl methacrylate acid was tested for subchronic oral toxicity. Up to the highest dose tested (360 mg/kg/day) there were no effects in the functional observational battery and no effects on motor activity.