Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1983
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Effects of various exposure levels of 2-phenylethanol on fetal development and survival in long-Evans Rats
Author:
R. F. Mankes , R. LeFevre , H. Bates & R. Abraham
Year:
1983
Bibliographic source:
Journal of Toxicology and Environmental Health, 12, 235-244

Materials and methods

Test guideline
Qualifier:
no guideline available
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Long-Evans
Details on test animals and environmental conditions:
The test animals were sourceed from Blue Spruce Farm in Altamont, NY. After mating the females were housed in wire-topped plastic cages. Food and water were available ad ibitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Aqueous suspensions of 2-phenyIethanol were freshly prepared, and daily doses of 20 ml/kg were given by gavage to female Long-Evans rats based on their current body weights. The exposure period was from d 6 to 15 of gestation, the so-called "critical
period" of organogenesis in the rat. Distilled water served as the control.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
The presence of vaginal sperm was defined as d 0 of gestation. Rats that did not mate and those that did not become pregnant were excluded from the analysis.
Duration of treatment / exposure:
The exposure period was from day 6 to 15 of gestation.
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group I - 19 pregnant rats as controls
Dose / conc.:
432 mg/kg bw/day (nominal)
Remarks:
Group II - 5 pregnant rats
Dose / conc.:
43 mg/kg bw/day (nominal)
Remarks:
Group III - 7 pregnant rats
Dose / conc.:
4.3 mg/kg bw/day (nominal)
Remarks:
Group IV - 7 pregnant rats
No. of animals per sex per dose:
See above.
Control animals:
yes, concurrent vehicle
Details on study design:
The exposure levels were chosen as fractional doses (24, 2.4, or 0.24%) of the available LD50 values for phenylethanol, 1 log interval apart (Owston et al., 1981). The large number of pregnant rats were assigned to group 1 controls to account for intralitter variability.

Examinations

Maternal examinations:
Dams were observed daily for signs of toxicity and lethality. Maternal body weights were recorded on d 0-15 and 20 of gestation.
Ovaries and uterine content:
The following observations and weights were recorded at day 20: total uterine weight, total litter weight, individual pup weights, number of live pups, stillbirths, résorptions, implantation sites, sex distribution, crown-rump length, and number of corpora lutea.
Fetal examinations:
All live pups were examined for gross malformations at birth: soft-tissue (internal) defects were evaluated by the method of Wilson (1965), while skeletal variations were detected by the method of McLeod (1980).
Statistics:
All data generated in the course of the study were entered, archived, and statistically analyzed on a DEC System 10 computer. Statistical analyses of the data were performed according to the methods of Dixon and Brown (1977), using both the litter and fetus as experimental units. The f-squared (BMDP3D) analysis was used to compare uterine weights, litter weights, pup weights, litter sizes and crown-rump length. The two-way frequency count routine (BMDP1F) was applied to embryonic deaths (résorptions), total of dead and malformed, and incidences of malformations, as described earlier (Mankes et al., 1981, 1982).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Signs of severe maternal intoxication were observed immediately following ingestion of 2-phenylethanol at 432 mg/kg bw. These signs persisted overnight and were observed after each daily dose. Lower dose levels (43 or 4.3 mg/kg bw) were asymptomatic.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One dam (of group II) died from intratracheal intubation.
Body weight and weight changes:
not specified
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Dead fetuses:
effects observed, treatment-related
Description (incidence and severity):
100% of the Group 2 pups (432 mg/kg bw) were dead or malformated.
Changes in pregnancy duration:
not specified

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
43 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
4.3 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Reduction in number of live offspring:
effects observed, treatment-related

Applicant's summary and conclusion

Conclusions:
The highest no observed adverse effect level (NOAEL) for maternal toxicity is 43 mg/kg/bw/day. The NOEAL for development, teratogenecy and fetotoxicity is 4.3 mg/kg/bw/day.
Executive summary:

Pregnant Long-Evans rats were treated with 4.3, 43, 430 mg/kg/day 2 -phenylethanol from day 6 to day 15 of gestation. Dams were monitored daily for signs of toxicity and lethality and all pups were examined for malformation. The results showed that the highest dosage (430 mg/kg/day) caused maternal toxicity. Examination of the offspring showed that all dosage levels caused malformations. Fetal death rate showed an increase at 43 mg/kg/day at 18% compared to 6% in the control group. The highest no observed adverse effect level (NOAEL) for maternal toxicity is 43 mg/kg/bw/day. The NOEAL for development, teratogenecy and fetotoxicity is 4.3 mg/kg/bw/day.