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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

An extended one-generation reproductive toxicity study is waived as the 90-days oral repeated dose toxicity studies did not indicate adverse effects on reproductive organs or tissues.

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reason / purpose:
data waiving: supporting information
Reproductive effects observed:
not specified
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
According to REGULATION (EC) No 1907/2006, an Extended-One Generation Reproductive study shall be initially performed if there are results available from repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with
The substance was administered as feed admix during 13 weeks in a study according OECD TG 408. Four test groups each consisting of 12 rats per sex were formed. The animals received 0, 200, 450, and 1000 mg active ingredient per kg body weight per day. Mortality, general symptoms, and body weights were recorded. Haematology and clinical chemistry determinations were performed. All rats were autopsied. Organs and tissues of the control rats and rats treated with 1000 mg/kg bw/day were microscopically examined.
Deaths related to treatment did not occur throughout the test period. Two female rats died as a result of anaesthesia. Treatment-related clinical symptoms were not observed. The treatment with BMDBM did not have an effect on the weight development and feed consumption. The number of red blood cells was decreased in female rats treated with 1000 mg/kg bw/day. The results of the urinalysis were normal. No findings were observed in eyes of control rats and rats treated with 1000 mg/kg bw/day. No treatment-related necropsy findings were seen. The liver weights of male rats treated with 1000 mg/kg bw/day and of females treated with 200, 450, and 1000 mg/kg bw/day were higher than those of the control groups. The liver weight increase in the animals treated with 200 mg/kg bw/day could be attributed to their higher body weight compared to the control animals, but the effect in the higher dose groups must be considered as related to treatment. After a treatment-free period of 4 weeks, the high dosed male and female rats had a normal liver weight. With the exception of hepatic parenchyma cells which became hypertrophic in females treated with 1000 mg/kg bw/day, no histopathological changes were considered to be related to treatment. No histopathological changes could be detected in uterus, testes or epididymides. The organs weights of uterus, ovaries, testes and prostate were not changed compared to the untreated control. Under the conditions of this study, the maximum oral dose level producing no toxic effect (NOAEL) was considered to be 450 mg/kg bw/day. The increase of liver weights as well the increase of hepatic parenchyma cells were interpreted as a process of liver adaption to treatment.
In conclusion, no toxic effects on reproductive organs have been reported after repeated exposure. Therefore, and because of animal welfare reasons an Extended-one Generation Reproductive study is not required.
Reason / purpose:
data waiving: supporting information
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Description of key information

An OECD 414 developmental toxicity study with the rat via the oral route revealed a NOAEL of 1000 mg/kg bw/day. The NOAEL value correspond to the highest dose level tested.

Link to relevant study records
Reference
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
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
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
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).
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.
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).
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
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
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
Key result
Abnormalities:
not specified
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.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: embryotoxicity
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
no
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.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
similar to OECD TG 414
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The substance was tested for embryotoxic and teratogenic action in the rat in a study similar to OECd TG 414. 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 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.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

Based on the available data, the test item does not need to be classified for effects on fertility and developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.