Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March - April 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
: administration on days 7 - 16 inclusive of gestation
Principles of method if other than guideline:
Deviations not affecting the validity of the study.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material : BMDBM

Test animals

Species:
rat
Strain:
other: Füllinsdorf-Albino SPF
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute for Biological and Medical Research, Füllinsdorf, Switzerland
- Weight at study initiation: 167 - 225 g
- Housing: 2 females were housed in wire-mesh cages during acclimatization and mating and in macrolon cages during gestation and lactation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: minimum of 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): about 22 °C
- Humidity (%): about 50 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: SSV (0.5 % carboxymethylcellulose, 0.9 % NaCl, 0.5 % benzyl alcohol, 0.4 % Tween 80 in water)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test compound was formulated in one batch for the whole treatment period in the vehicle and stored in a refrigerator. High shear mixing was used during formulation and the suspension was kept homogeneous during dosing by the use of a magnetic stirrer.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1 (exceptionally 1/2)
- Length of cohabitation: over night
- Proof of pregnancy: vaginal plug, referred to as day 1 of pregnancy
Duration of treatment / exposure:
day 6 to day 17 of gestation (12 days)
Frequency of treatment:
daily
Duration of test:
One half of the animals were sacrificed on day 21 of gestation, the other half of the females were allowed to litter spontaneously and to rear their young up to weaning (lactation day 23).
Doses / concentrationsopen allclose all
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
36 mated females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Outcome of a preliminary study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: on gestation day 1, 7, 17, and 21

FOOD CONSUMPTION AND COMPOUND INTAKE: No

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No
Statistics:
In the tables, median and interquartile range are reported.
a) All groups together are tested by a simultaneous test against trend (Jonckheere test or Armitage test).
b) In the case of a non-significant result of the trend test, the same groups are tested by a simultaneous test without trend alternative (Kruskal-Wallis test or Chi2test).
c) In the case of a significant result for test b), all dose groups are separately tested against control (U test or Fisher test).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No adverse clinical observation could be made on the dams of any dose group which is considered to be treatment-related.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No compound-related maternal death occurred in any treatment group during pregnancy and lactation.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight development of the treated animals was comparable to controls in all dose groups.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects: no effects

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity

Maternal abnormalities

Key result
Abnormalities:
not specified

Results (fetuses)

Changes in sex ratio:
no effects observed
Description (incidence and severity):
The distribution of fetuses by sex was normal in all dose groups.
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related skeletal malformations were observed in the controls and the 500 and 1000 mg/kg dose groups. One case of a fusion of two sternal elements was revealed in the 250 mg/kg dose group. Single occurrence of this malformation was also observed in animals of former control groups and therefore drug-relation is not taken into account. A slight incidence of delayed ossification of neural arches and sternebrae was observed in the 500 mg/kg dose group fetuses, but not in fetuses of the 250 and 1000 mg/kg dose groups. Because of this lack of dose dependence a drug relation seems to be questionable.
Visceral malformations:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
In the rearing group all measured parameters like resorption rate, birth rate, gestation length, survival and weight development of the pups compared well to concurrent and historical control group values.
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects

All reproductive parameters examined in the necropsy sub-groups compared well to concurrent control group results. Only one case of complete resorption of embryos was observed in the 250 mg/kg dose group. Because of its single occurrence in the lowest dose group it is considered to be a random finding without biological significance. The examination for soft tissue abnormalities revealed in the 500 mg/kg dose group one fetus with missing right ovarium and uterus. Because of its isolated occurrence in the middle dose group this finding is considered to be accidental.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Key result
Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
It can be concluded, that under the conditions of the present study butyl methoxydibenzoylmethane (BMDBM) is neither embryotoxic or teratogenic nor impairs postnatal development of rat offspring up to a dose of 1000 mg/kg bw/day.
Executive summary:

Butyl methoxydibenzoylmethane (BMDBM), an UV-A absorber, was tested for embryotoxic and teratogenic action in the rat. In order to determine postnatal manifestations of prenatal administration of the test compound, this investigation included concurrent rearing of the offspring until weaning. Doses of 250, 500 and 1000 mg/kg body weight were administered daily by oral gavage from day 7 to 16 of gestation. A control group received the vehicle (SSV) only.

The test compound in general was well tolerated in all dose groups. All reproductive parameters examined in the necropsy subgroups compared well to control group results. No treatment-related skeletal malformations were observed in the controls and the treatment groups. One pup with two fused sternal elements was revealed in the lowest dose group. In the middle dose group a slight increase of incised neural arches and sternebrae was assessed. The soft tissue examination displayed one fetus of the 500 mg/kg dose group with unilateral missing ovarium and uterus. All these observations show no dose-dependence and are considered to be fortuitous findings without drug relation. In the rearing group all measured parameters were well comparable to concurrent control group values.

It may be concluded that under the conditions of the present study BMDBM, when applied orally to pregnant rats up to a dose of 1000 mg/kg bw/day is neither embryotoxic or teratogenic nor impairs the postnatal development of the offspring.