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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Data waiving:
other justification
Justification for data waiving:
other:
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
Additional information

Screening for reproductive/developmental study:

Screening for reproductive/developmental study could be waived since according to REACH (Regulation (EC) No 1907/2006, Annex VIII, column 2, paragraph 8.7.1), this study does not need to be conducted if a pre-natal developmental toxicity study is available.

Two-generation reproductive toxicity:

According to REACH (Regulation (EC) 1907/2006, Annex IX, column 1 paragraph 8.7.3), the two-generation reproductive toxicity study can be waived if in the 28-day or 90-day study no adverse effects on reproductive organs or tissues were observed. In IUCLID section 7.5.1, the 28-day oral repeated dose toxicity study do not show any adverse effects on reproductive organs or tissues.

Short description of key information:

According to REACH (Regulation (EC) No 1907/2006, Annex VIII, column 2, paragraph 8.7.1), the screening for reproductive/developmental toxicity does not need to be conducted if a pre-natal developmental toxicity study is available.

The 28-day oral repeated toxicity study do not show any adverse effects on reproductive organs or tissues, therefore according to REACH (Regulation (EC) 1907/2006, Annex IX, column 1 paragraph 8.7.3), the two-generation reproductive toxicity study can be waived.

Effects on developmental toxicity

Description of key information

NOAEL (maternal/developmental) = 100 mg/kg bw/day Mexoryl SBO

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 2009-06-17 to 2010-10-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline compliant GLP study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Wistar Hannover
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BIOAGRI Laboratórios-DF
- Age at study initiation: thirteen weeks old
- Weight at study initiation: mean of 197.5 g
- Fasting period before study: no data
- Housing: during acclimation period, the rats were housed 2 animals/ cage and after mating, mated animals were housed individually in polypropylene cages wire mesh tops and bedding material.
- Diet (e.g. ad libitum): autoclaved Nuvilab CR-1 diet type for rats supplied by Nuvital Nutrientes Ltda. (Curitiba - PR, Brazil), ad libitum
- Water (e.g. ad libitum): autoclaved drinking water, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 - 23.2
- Humidity (%): 40.5 - 69.0
- Air changes (per hr): 10 - 20
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: 0.5 % CMC (carboxymethylcellulose + 0.1 % of Tween
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
For each dosage group an appropriate amount of Mexoryl SBO was weighed into a precalibrated beaker. The vehicle, 0.5% carboxymethylcellulose (CMC) + 0,1% Tween 80 in purified water, was added in sufficient quantity to achieve the desired concentration. A sufficient quantity of the vehicle was similarly dispensed for administration to control animals. Test suspensions were prepared daily at the Testing Facility, stored at room temperature and used within 4 hours after preparation. The suspensions were stirred continuously during the administration to maintain the homogeneity.

VEHICLE
- Concentration in vehicle: 25, 75 and 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses of test solutions were carried out at analytical laboratories of BlOAGRl Laboratorios-SP by HPLC (High Performance Liquid Chromatography) method.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/2
- Length of cohabitation: from about 4:30 pm to about 8:00 amof the following day
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: the animals were 13 weeks old at mating (instead of approximately 9 weeks old).
Duration of treatment / exposure:
from day 6 through day 19 of gestation, at approximately the same time of the day (in the morning)
Frequency of treatment:
daily
Duration of test:
about 21 days
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dosage levels (in mg/kg body weightlday) were selected in agreement with the Sponsor, on the basis of the results of a 28-day toxicity study by the oral route in rats where the highest dose, 1000 mg/kg/day, induced low toxicity (slight increase in liver weight and size correlating with hepatocellular hypertrophy; slight increase in triglycerides; slight decrease in erythrocytes, hemoglobin and mean cell hemoglobin concentration in male only)
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were examined for clinical symptoms twice a day. Mortality was checked by a trained technician twice a day on working days or once a day on weekends or public holidays. A detailed clinical examination was performed weekly by a veterinary.

BODY WEIGHT: Yes
- Time schedule for examinations: Pregnant animals were weighed on days 0, 3, 6, 9, 12, 15, 18, and 20 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: uterus and ovaries
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- 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 data
Statistics:
One Way Analyses of Variance (ANOVA), followed by Dunnett's Test, was used for statistical evaluation of fetal and maternal body weights, maternal body weight changes, weight of the uterus, placental weights, food consumption, number of implantation, fetuses, corpora lutea, resorption, and pre and postimplantation losses. Wilcoxon Test (non parametric test) was used for data that did not present a normal distribution. Fisher Exact Test and Chi-Square Test was used for statistical evaluation of fetal and maternal findings. The litter was used as the experimental unit for the purpose of statistical evaluation. The level of significance was set at 5%, and the statistical program used was SAS Software.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At 300 mg/kg bw/day:
- moderately lower corrected body weight gain (statistically significant comparing to control),
- slightly lower food consumption from day 9 to 12 of gestation (statistically significant comparing to control).

At 1000 mg/kg bw/day:
- lower body weight gain from day 9 to day 12 of gestation correlated with lower food consumption from day 6 to day 12 of gestation (statistically significant comparing to control),
- moderately lower corrected body weight gain (statistically significant comparing to control).
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No effect on maternal toxicity at this dose level
Key result
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At 300 mg/kg bw/day:
-slightly lower fetal weight (male, female and total): statistically significant comparing to control.

At 1000 mg/kg bw/day:
-slightly lower fetal weight (male, female and total): statistically significant comparing to control,
-higher incidence of fetuses and litters affected by short supernumerary ribs.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: supernumerary rib
Description (incidence and severity):
short supernumeracy ribs noted at 1000 nf/kg bw/day dose level
Developmental effects observed:
not specified
Conclusions:
Based on the study results, NOAEL for maternal toxicity is 100 mg/kg bw/day and NOAEL for developmental toxicity is 100 mg/kg bw/day.
Executive summary:

Mexoryl SBO was tested for prenatal developmental toxicity in Wistar rats. The test item was suspended in 0.5% carboxymethylcellulose (CMC) aqueous solution in purified water + 0,1% Tween 80 and administered by gavage to 20122123 pregnant rats per group at doses of 100, 300 and 1,000 mg/kg bw/day from day 6 through day 19 of gestation. The control group (23 pregnant rats) received the vehicle (0.5% CMC + 0,1% Tween 80 aqueous solution). The animals were checked daily for mortality and weekly for detailed clinical signs. Body weights and food consumption of the females were recorded at 3 days interval throughout gestation period. On day 20 of gestation, all females were sacrificed and assessed for gross pathology. The uterus were removed, weighed and their contents assessed (number of corpora lutea, implantations, resorption, and live and dead fetuses were recorded). The fetuses were sexed, weighed, and observed for any external, soft tissue andlor skeletal findings (malformations or variations). The following substance-related findings were obtained:

Group 3 (300 mg/kg bw/day):

- moderately lower corrected body weight gain;

- slightly lower food consumption from day 9 to 12 of gestation;

- slightly lower fetal weight (male, female and total);

Group 4 (1,000 mg/kg bw/day):

- lower body weight gain from day 9 to day 12 of gestation correlated with lower food

consumption from day 6 to day 12 of gestation;

- moderately lower corrected body weight gain;

- slightly lower fetal weight (male, female and total);

- higher incidence of fetuses and litters affected by short supernumerary ribs;

In conclusion, under the conditions of this study, the administration of Mexoryl SBO to pregnant Wistar rats after the preimplantation period elicited some signs of maternal toxicity at doses of 1,000 and 300 mg/kg bw/day. Fetal evaluation at 1,000 mg/kg bw/day group revealed higher fetal and litter incidence of a skeletal variation (short supernumerary rib). Based on the study results, NOAEL for maternal toxicity is 100 mg/kg bw/day and NOAEL for developmental toxicity is 100 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is GLP conform according 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

Teratogenicity study with Mexoryl SBO was conducted in rat (Pontes, 2010). For Wistar rats the doses of 0, 100, 300 and 1000 mg/kg bw/day were administered by gavage from gestation day 6 to 19. At 300 and 1000 mg/kg bw/day doses of Mexoryl SBO, pregnant rats after preimplantation period elicited some signs of maternal toxicity. Fetal evaluation at 1000 mg/kg bw/day group revealed higher fetal and litter incidence of a skeletal variation (short supernumerary rib) and at 300 mg/kg bw/day, slightly lower fetal weight. Based on study results, NOAEL for maternal and developmental toxicity is 100 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:

Only one study is available for the pre-natal developmental toxicity.

Justification for classification or non-classification

In the 28-day oral repeated dose toxicity study any adverse effects on reproductive organs or tissues were obserwed following exposure to Mexoryl SBO, therefore Mexoryl SBO is deemed not to be toxic to the reproduction and accordingly do not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Based on the above stated teratogenicity study with Mexoryl SBO conducted in rats, the test item could not be classified for developmental toxicity/teratogenicity according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (Regulation (EC) No 1272/2008 of the European Parlaiment and of the Council) as implementation of UN-GHS in the EU.

Additional information

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