Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
neurotoxicity: short-term oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Functional observation battery was investigated in the course of a 28-day repeated dose toxicity study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Guideline:
other: OECD 407
Principles of method if other than guideline:
Functional observational battery (FOB) as well as measurement of motor activity (MA) were carried out after 4 weeks of treatment.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(3-hydroxypropyl)oxazolidin-2-one
EC Number:
431-840-1
EC Name:
3-(3-hydroxypropyl)oxazolidin-2-one
Cas Number:
87010-29-5
Molecular formula:
C6 H11 N O3
IUPAC Name:
3-(3-hydroxypropyl)oxazolidin-2-one
Details on test material:
- Name of test substance: 3-(3-Hydroxypropyl)-oxazolidin-2-on
- Test substance No.: 03/0046-1
- Batch identification 73653056 PO
- Date of production: August 09, 2002
- Purity: 94.0 9/1 00 g (analytical report 03L00170)
- Homogeneity: homogeneous (analytical report 03L00170)
- Stability: stable; proven by reanalysis (analytical report 04L00027)
- Physical state 1 color: Iiquid/colourless-yellowish
- Storage conditions: Room temperature

The analyses were carried out at the Analytical Department of BASF AG, Ludwigshafen/Rhein, Germany.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Strain: CrlGlxBrlHan:WI
- Age at study initiation: 35 ±1 days
- Fasting period before study: none
- Housing: singly in type OK III stainless steel wire mesh cages supplied by Becker & Co., Castrop-Rauxel, FRG (floor area about 800 cm2)
- Diet: ground Kliba maintenance diet mouse/rat "GLP", meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland ad libitum
- Water: drinking water (from water bottles) ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24° C
- Humidity (%): 30 - 70%
- Photoperiod (hrs dark / hrs light): 12 hours (12 hours light from 06.00 a.m. - 06.00 p.m., 12 hours dark from 06.00 p.m. - 06.00 a.m.)

Deviations from these ranges did not occur.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SUBSTANCE PREPARATION AND ANALYSES
Preparation
The test substance was weight out and thoroughly mixed with a small amount of food. Thereafter these premixes were adjusted to the desired concentrations with appropriate amounts of food and mixed for about 10 minutes in a Iaboratory mixer.

Analyses
The analytical investigations of the test substance preparations were carried out at the Analytical Chemistry Laboratory of the Experimental Toxicology and Ecology of BASF AG, Ludwigshafen, Germany. The stability of the test substance in the diet over a period of 32 days at room temperature was confirmed before the start of the study. This exceeded the interval from diet preparation to the end of the feeding period. Homogeneity analyses of the test substance preparations were performed in samples of the high and low concentrations at the start of the administration period. These samples also served for concentration control analyses. Additional concentration control analyses were performed with a sample drawn from the mid concentration at the start of the administration period.


Food analyses
The food used in the study was assayed for chemical and microbiological contaminants by the supplier.

Drinking water analyses
The drinking water is regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and the Technical Services of BASF AG as well as for the presence of microorganisms by a contract Iaboratory.

Bedding analyses
The bedding is regularly assayed for contaminants (chlorinated hydrocarbons and heavy metals).
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days with an additional recovery period
Frequency of treatment:
continuously
Doses / concentrations
Remarks:
Doses / Concentrations:
750; 3000; 12000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
0 (vehicle control) 10 animals per sex (5 animals per sex in the recovery group)
750 ppm dosing group: 5 animals per sex
3,000 ppm dosing group: 5 animals per sex
12,000 ppm dosing group: 10 animals per sex (5 animals per sex in the recovery group)
Control animals:
yes, concurrent no treatment

Examinations

Observations and clinical examinations performed and frequency:
Clinical observations
The animals were examined tor overt signs of toxicity or mortality twice a day (in the morning and in the late afternoon) from Mondays to Fridays and once a day (in the morning) an Saturdays, Sundays and public holidays. Additionally, further clinical examinations were carried out daily, as well as once a day during the recovery period. Detailed clinical observations were performed in all animals prior to the administration period and thereafter at weekly intervals. The findings were ranked according to the degree of severity, if applicable. The animals were transferred to a standard arena (50 x 37.5 cm with sides of 25 cm high). The following parameters were examined:

1. abnormal behavior during handling
2. fur
3. skin
4. posture
5. salivation
6. respiration
7. activity/arousal level
8. tremors
9. convulsions
10. abnormal movements
11. impairment of gait
12. lacrimation
13. palpebral closure
14. exophthalmos
15. feces (appearance/consistency)
16. urine
17, pupil size

Food consumption
Individual food consumption was determined weekly over a period of 7 days and calculated as mean food consumption (g/animal/day).

Water consumption
Water consumption was observed daily by visual inspection of the water bottles for any overt changes in volume.

Body weight data
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period and the recovery period the body weight was determined an day 0 (start of the administration period) and thereafter at weekly intervals. The difference between the body weight an the respective day of weighing and the body weight an day 0 was calculated as body weight change.

Food efficiency
Food efficiency (group means) was calculated based upon individual values for body weight and food consumption:

(BWx – BWy) / (FC y to x) x 100 = Food efficiency for day x

BWx = body weight on day x (g)
BWy = body weight on day y (last weighing date before day x) (g)

FC y to x: mean food consumption from day y to day x; calculated as mean daily food consumption on day x, multiplied with the number of days from day y to day x.

Intake of test substance
The mean daily intake of test substance (group means) was calculated based upon individual values for body weight and food consumption.

(FCx x C) / (BWx) = Substance intake for day x

BWx = body weight on day x [g]
FCx = mean daily food consumption on day x [g]
C = concentration in the diet on day x [mg/kg]

Neurobehavioural examinations performed and frequency:
Functional observational battery (FOB)
A functional observational battery was performed in all animals at the end of the administration period starting at about 10.00 a.m. The FOB started with passive observations without disturbing the animals, followed by removal from the home cage, open field observations in a standard arena and sensorimotor tests as well as reflex tests. The findings were ranked according to the degree of severity, if applicable. The observations were performed at random

Home cage observations:
The animals were observed in their closed home cages; any disturbing activities (touching the cage or rack, noise) were avoided during these examinations in order not to influence the behavior of the animals. Beside other findings attention was paid to:
1. posture
2. tremor
3. convulsions
4. abnormal movements
5. impairment of gait
6. other findings

Open field observations:
The animals were transferred to a standard arena (50 x 50 cm with sides of 25 cm high) and observed for at least 2 minutes. Following parameters were examined:
1. behavior when removed from cage
2. fur
3. skin
4. salivation
5. nose discharge
6. lacrimation
7. eyes/pupil size
8. posture
9. palpebral closure
10. respiration
11. tremors
12. convulsions
13. abnormal movements
14. impairment of gait
15. activity/arousal level
16. feces (number of fecal pellets/appearance/consistency) within two minutes
17. urine within two minutes
18. number of rearings within two minutes
19. other findings

Sensorimotor Tests/Reflexes:
The animals were removed from the open field and subjected to following sensorimotor
or reflex tests:
1. approach response
2. touch response
3. vision (“visual placing response")
4. pupillary reflex
5. pinna reflex
6. audition (“startle response")
7. coordination of movements (“righting response")
8. behavior during “handling"
9. vocalization
10. pain perception (“tau pinch")
11. grip strength of forelimbs
12. grip strength of hindlimbs
13. landing foot-splay test
14. other findings

Motor activity assessment
Motor activity was measured on the same day as FOB was performed. The measurement was performed in the dark using the Multi-Varimex-System (Columbus Instruments Int. Corp., Ohio, USA) with 4 infrared beams per cage. During the measurement the animals were kept in Polycarbonate cages with absorbent material. The animals were put into the cages in a randomized order. The measurements started at about 12.45 p.m. in the main groups and at about 2.00 p.m. in the recovery groups. The number of beam interrupts were counted over 12 intervals, each lasting 5 minutes. Measurement did not commence at the same instant tor all cages; the period of assessment tor each animal started when the first beam was interrupted by pushing the cage into the rack (staggered start). Measurements ended exactly 60 minutes thereafter. During the measurements the animals received no food and no water.

Results and discussion

Results of examinations

Details on results:
Functional observational battery
Deviations from “zero values" were obtained in several animals. However, as most findings were equally distributed between treated groups and controls, were without a dose-response relationship or occurred in single animals only, these observations were considered to have been incidental.

Home cage observations:
No substance-related findings were observed.

Open field observations.
No substance-related findings were observed.

Sensorimotor tests/reflexes:
No substance-related findings were observed.

Quantitative parameters:
No substance-related findings were observed.

Motor activity measurement
Regarding the overall motor activity (summation of all intervals) no substance-related findings were measured in both sexes.
Comparing the single intervals with the control groups, the motor activity was statistically decreased in males group 1 at interval 2, in females group 1 at interval 8 and group 3 at interval 7. These single occurrences were clearly not related to the treatment with the test substance.

Effect levels

Dose descriptor:
NOAEL
Effect level:
3 000 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
other: Generation: maternal (migrated information)

Applicant's summary and conclusion