4-(vinyloxy)butan-1-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

repeated dose toxicity: oral, other

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-(vinyloxy)butan-1-ol

EC Number:

241-793-5

EC Name:

4-(vinyloxy)butan-1-ol

Cas Number:

17832-28-9

Molecular formula:

C6H12O2

IUPAC Name:

4-(ethenyloxy)butan-1-ol

Details on test material:

purity: 99.4%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

test animal source: Male and female Wistar rats, strain Crl:WI(Han), Charles River Laboratories, Research Models and Services, Germany GmbH
housing temperature: 20-24 °C
humidity: 30-70%
air change rate: 15 times per hour
day/night cycle: 12 hours light from 6:00 h to 18:00 h and 12 hours dark from 18:00 h to 6:00 h

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE. The stability of the test substance in Olive oil Ph. Eur./DAB at room temperature was given for a period of 7 days (analytical report: Project No.: 01Y0107/098019).

Duration of treatment / exposure:

males: 30 days
females: 53 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150, 450 mg/kg bw/day
Basis:
other: Olive oil Ph. Eur./DAB

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week postmating in males, and the entire gestation period as well as 4 days of lactation in females. After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females.

Examinations

Observations and examinations performed and frequency:

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0-7, 7-14, 14-20 and lactation days 1-4. Body weights of F0 parents were determined once a week, in males throughout the study
and in females during premating and mating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the parturition day (postnatal day [PND] 0) and on PND 4. The pups were sexed and examined for macroscopically evident changes on PND 0. They
were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed with CO2 and examined macroscopically for external and visceral findings. Clinicochemical and hematological examinations as well as urinalyses were performed in 5
randomly selected parental animals of either sex towards the end of the administration period. At the end of the administration period a functional observational battery was performed and motor activity was measured in 5 randomly selected parental males and females per group.

Sacrifice and pathology:

All surviving F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed. At necropsy on PND 4, all pups were sacrificed with CO2 and examined macroscopically for external and visceral findings.

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

450 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reproductive performance, fertility and developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: systemic toxicity (adverse clinical findings (males + females), decreased body weight gain (males))

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

450 mg/kg bw/d

F0 Parental animals (clinical examinations/reproductive performance/clinical pathology/pathology): Abdominal position after first treatment in 2 male and in 3 female animals; decreased body weight gain in male animals during study week 3-4 and in summary for the entire treatment; decreased motor activity in male animals in interval 4 and in summation (intervals 1-12)

F1 pups (clinical examinations/gross findings): no test substance-related adverse findings

150 mg/kg bw/d

F0 Parental animals: no test substance-related adverse findings

F1 pups: no test substance-related adverse findings

50 mg/kg bw/d

F0 Parental animals: no test substance-related adverse findings

F1 pups: no test substance-related adverse findings

Applicant's summary and conclusion

Conclusions:

Under the conditions of this reproduction/developmental toxicity screening test the NOAEL (no observed adverse effect level) for reproductive performance, fertility and for developmental toxicity is 450 mg/kg body weight/day, the highest dose tested.
The NOAEL for general, systemic toxicity of the test substance is 150 mg/kg body weight/day for the F0 parental animals based on adverse clinical findings (males + females) and decreased body weight gain (males) at 450 mg/kg body weight/day.

Executive summary:

The test substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at doses of 50, 150, and 450 mg/kg body weight/day. Control animals were dosed daily with the vehicle (Olive oil Ph. Eur./DAB). The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week postmating in males, and the entire gestation period as well as 4 days of lactation in females. No adverse effects on fertility of the F0 parental animals of both sexes at dose levels of 50, 150 and 450 mg/kg bw/d were observed. The test substance caused also no impairments of the reproductive performance. Mating behaviour, conception, gestation, parturition, as well as sexual organ weights and gross and histopathological findings of these organs were not influenced. Slight general systemic toxicity was noted in the F0 parents at 450 mg/kg bw/d. Some males and females showed abdominal position exclusively when they were treated with the test substance for the first time. Furthermore, motor activity was slightly decreased in the high-dose males. Although no other effects were noted in daily cageside, detailed clinical examinations in an open field and detailed observations in a functional observational battery (FOB) these findings might indicate a minimal sedative potential of Hydroxybutylvinylether. They are considered as treatment-related. An additional clinical finding was a decreased body weight gain in high-dose males. Concerning clinical pathology no treatment-related, adverse effects were observed up to a dose of 450 mg/kg bw/d. Regarding pathology there were no substance-related organ weight changes, gross lesions, or microscopic findings. Under the conditions of this study the NOAEL for reproductive performance, fertility and for developmental toxicity is 450 mg/kg body weight/day, the highest dose tested. The NOAEL for general, systemic toxicity of the test substance is 150 mg/kg body weight/day for the F0 parental animals based on adverse clinical findings (males + females) and decreased body weight gain (males) at 450 mg/kg body weight/day.