Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented publication which meets basic scientific principles. The justification for the Read Across approach has been attached to the Section 13.
Principles of method if other than guideline:
No available information on method used.
GLP compliance:
not specified
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
No available data
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
F0 generation

Exposition premating period: 10 weeks
Exposition mating period: 2 weeks


Exposition premating period: 10 weeks
Exposition mating period: 2 weeks
Exposition during gestation and lactation: Yes

F1 generation

Exposition premating period: 10 weeks
Exposition mating period: 2 weeks


Exposition premating period: 10 weeks
Exposition mating period: 2 weeks
Exposition during gestation and lactation: Yes
Details on mating procedure:
The F0 generation was sacrificed after the pups were weaned
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No available data
Duration of treatment / exposure:
Premating period: 10 weeks
Mating period: 2 weeks
For female exposition to the test substance during gestation and lactation.
Frequency of treatment:
Daily
Details on study schedule:
No available data
Remarks:
Doses / Concentrations:
10 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
No available data
Control animals:
yes, concurrent vehicle
Details on study design:
No available data
Positive control:
No available data
Parental animals: Observations and examinations:
No available data
Oestrous cyclicity (parental animals):
No available data
Sperm parameters (parental animals):
No available data
Litter observations:
No available data
Postmortem examinations (parental animals):
No available data
Postmortem examinations (offspring):
No available data
Statistics:
No available data
Reproductive indices:
No available data
Offspring viability indices:
No available data
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day group: T4 lower (F0 ♂ ♀); T3 lower (F0 ♂);
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day group: T4 lower (F1 ♂ ♀); 100 mg/kg bw/day group: T4 lower (F1 ♂ ♀)
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
no effects observed
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 1 000 mg/kg bw/day
Based on:
not specified
Sex:
male/female
Reproductive effects observed:
not specified

The F0 generation was sacrificed after the pups were weaned, and decreases in T4 levels were found at the high dose in males and females. In the F1 generation, lower serum T4 concentrations were observed in both sexes at 100 and 1000 mg/kg. T3 serum levels were significantly lower only in F0 males of the 1000 mg/kg group. No changes in serum TSH levels, compared to vehicle control animals, were observed in any of the treated groups.

Conclusions:
NOAEL = 1000 mg/kg bw/day
Executive summary:

Method

The effects on reproductive performance and fertility were evaluated in a 2 generation study. The substance was administered daily by oral gavage. Sprague Dawley rats were exposed to 10, 100, or 1000 mg/kg bw/day in the F0 generation during 10 weeks premating and during a 2-week mating period. Females were treated also during gestation and lactation. The same treatment regime as in F0 animals was also applied in F1 animals.

Observations

The F0 generation was sacrificed after the pups were weaned, and decreases in T4 levels were found at the high dose in males and females. In the F1 generation, lower serum T4 concentrations were observed in both sexes at 100 and 1000 mg/kg. T3 serum levels were significantly lower only in F0 males of the 1000 mg/kg group. No changes in serum TSH levels, compared to vehicle control animals, were observed in any of the treated groups.

Results

No treatment-related histopathologic changes were observed. The substance has no toxicologically significant effects in fertility or reproductive performance at doses of up to 1000 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In order to evaluate the effects of AP 1300S on reproductive performance and fertility, a study on Similar Substance 02 (CAS 79-94-7), a precursor/metabolite of AP 1300 S, has been considered; further information on the justification for the read across approach are attached at the section 13.

The test considered is a 2 generation study. The substance was administered daily by oral gavage. Sprague Dawley rats were exposed to 10, 100, or 1000 mg/kg bw/day in the F0 generation during 10 weeks premating and during a 2-week mating period. Females were treated also during gestation and lactation. The same treatment regime as in F0 animals was also applied in F1 animals.

Serum T3, T4 and TSH concentration have been determined, and lower serum T4 concentrations were observed in both sexes at 100 and 1000 mg/kg in the F1 generation. In the F0 generation decreases in T4 levels were found at the high dose in males and females and T3 serum levels were significantly lower only in F0 males of the 1000 mg/kg group. Nevertheless No treatment-related histopathologic changes were observed. The substance has no toxicologically significant effects in fertility or reproductive performance at doses of up to 1000 mg/kg bw/day.

Taking into account the great similarity between AP 1300 S and Similar Substance 02, AP 1300 S is expected to have a NOAEL for reproduction of 1000 mg/kg bw/day.


Short description of key information:
NOAEL = 1000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
Well-documented study. Cited in a reliable internationally accepted source.

Effects on developmental toxicity

Description of key information
NOAEL > 2500 mg/kg bw/day
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented publication which meets basic scientific principles. The justification for the Read Across approach has been attached to the Section 13.
Principles of method if other than guideline:
No available information on method used.
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
No available data
Route of administration:
oral: unspecified
Vehicle:
olive oil
Details on exposure:
No available data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No available data
Details on mating procedure:
No available data
Duration of treatment / exposure:
For the gestation period (animals sacrified 20 days)
Frequency of treatment:
Daily
Duration of test:
Animals sacrified during gestation: 20 days for
Animal not sacrified during gestation: Gestation period
Offspring: 21 days post-natal
Remarks:
Doses / Concentrations:
280 mg/kg bw/day
Basis:
no data
Remarks:
Doses / Concentrations:
830 mg/kg bw/day
Basis:
no data
Remarks:
Doses / Concentrations:
2500 mg/kg bw/day
Basis:
no data
No. of animals per sex per dose:
22 to 24
Control animals:
yes, concurrent vehicle
Details on study design:
No available data
Maternal examinations:
ANIMAL SACRIFIED
Gross pathology

ANIMAL NOT SACRIFIED
N. of live and dead offspring
Sex of offspring
Presence of any abnormalities
After sacrifice: Gross pathology
Ovaries and uterine content:
N. of corpora lutea, implants, surviving foetus, early fetal deaths, late fetal deaths

Fetal examinations:
Body weights of surviving foetus
Sex of fetuses
Presence or absence of external abnormalities in foetus
Skeletal abnormalities
Visceral abnormalities

OFFSPRING
During post natal 21-days: Bodyweight, state of growth and general state.
After sacrifice: Skeletal abnormalities and n. of implants.
Statistics:
No available data
Indices:
No available data
Historical control data:
No available data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No toxicologically significant effects in the treated maternal animals throughout gestation. In the early stages of pregnancy in the treated dams there was a slight increase in body weight gain above that of the control animals; by day eight onwards the increase in body weight gain was similar in all groups. In early pregnancy food consumption was significantly reduced in all of the TBBP-A dosed groups, but from mid pregnancy food consumption was increased in the 2500 mg/kg group.
No other differences were evident during the dosing period. With the exception of kidney stones and the resultant deformation of one kidney in one animal in the 830 mg/kg group (clearly not treatment-related), no abnormalities were observed in the dams on gross pathological examination.
Dose descriptor:
NOAEL
Effect level:
> 2 500 mg/kg bw/day
Based on:
no data
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effect on the length of the gestation period and no toxicologically significant effects on fetal development. In the fetuses examined on gestational day 20, on external observation, examination of the internal organs and skeletal observations, there were no findings of toxicological significance. In the offspring that were delivered normally and reared to day 21, no difference in development was observed between the treated and control groups.
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
NOAEL > 2500 mg/kg bw/day
Executive summary:

Method

The effects on development were evaluated in Pregnant Wistar rats (Noda et al., 1985[1]). The substance was orally administered in olive oil throughout gestation, from day 0 once a day (280, 830 and 2500 mg/kg bw/day). The doses were established from the results of a preliminary study in which no toxicologically significant effects were observed at the top dose of 2500 mg/kg.

Observations

On gestational day 20, approximately two thirds of the animals were sacrificed and examined.

For the animals that were allowed to deliver their offspring naturally, the gestation period was calculated. Offspring were kept up until weaning on post-natal day 21 and then killed and examined for the presence of any abnormalities. The dams were also killed on day 21 post-partum and then examined.

Results

The substance did not produce adverse effects on development in the rat at dose levels up to 2500 mg/kg. Although this dose did not produce maternal toxicity, it is considered sufficiently high to adequately assess developmental toxicity effects by the oral route.

[1]Noda T, Morita S, Ohgaki S and Shimizu M (1985) Safety evaluation of chemicals for use in household products (VII) teratological studies on tetrabromobisphenol-A in rats. Annual report of the Osaka Institute of Public Health and Environmental Sciences 48, 106-112.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 500 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

In order to evaluate the effects of AP 1300S on reproductive performance and fertility, a study on Similar Substance 02 (CAS 79-94-7), a precursor/metabolite of AP 1300 S, has been considered; further information on the justification for the read across approach are attached at the section 13.

 

The substance was orally administered in olive oil throughout gestation, from day 0 once a day (280, 830 and 2500 mg/kg bw/day). On gestational day 20, approximately two thirds of the animals were sacrificed and examined.

For the animals that were allowed to deliver their offspring naturally, the gestation period was calculated. Offspring were kept up until weaning on post-natal day 21 and then killed and examined for the presence of any abnormalities. The dams were also killed on day 21 post-partum and then examined.

 

The substance did not produce adverse effects on development in the rat at dose levels up to 2500 mg/kg. Although this dose did not produce maternal toxicity, it is considered sufficiently high to adequately assess developmental toxicity effects by the oral route.

 

Taking into account the great similarity between AP 1300 S and Similar Substance 02, AP 1300 S is expected to have a NOAEL for developmental toxicity greater than 2500 mg/kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
Well-documented study. Cited in a reliable internationally accepted source.

Justification for classification or non-classification

According to the CLP Regulation (EC n. 1272/2008) for the porpoise of classification for reproductive toxicity, substances are allocated on one of two categories.

The Table 3.7.1(a) set out the Hazard categories for reproductive toxicants:

Category 1: Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans.

Category 2: Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1.

Considering the whole data set AP 1300 S is expected to be non classified for reproductive toxicity according to the CLP Regulation (EC n. 1272/2008).