Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

NOAEL for fertility ≥ 750 mg/kg bw/day (based on the sub-acute studies on OB 4 -MSA and OB 3a-A(Na))

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 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

The substance under registration OB 3c-MSA belongs to the category of Stilbene Fluorescent Whitening Agents. No studies assessing the reproductive toxicity of this substance are available, for this reason data deriving from analogue substance within the category was taken into account.

Following oral exposure by gavage, the similar substances show no toxicological effects on the reproduction parameters, therefore, considering the high structural similarity and the comparable physicochemical/toxicokinetic profile between this category’s substances, the use of these studies to fulfill the data gap is justified. Details on the Read Across approach for category are reported in a document attached in IUCLID section 13.

Recently, Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening (OECD 422), following GLP’s principles, were also performed on other category’s members.

OB 3b-A was administered in the form of a solution in aqua pro iniectione to Wistar rats. Oral application by stomach tube was performed daily and the animals were without feed two hours before application and two hours after application of the test item. The study included 3 treated groups (doses 80, 250, 750 mg/kg/day) and one control group (vehicle only) and two satellite groups of animals - one control group (vehicle only) and one treated group (750 mg/kg/day).Each main group consisted of 12 males and 12 females; each satellite group consisted of 6 males and 6 females.

The body weight of parental males and females was not affected by the test item application. Evaluation of the absolute and relative weight of reproductive organs of male and female, as well as the weight of pituitary and thyroid gland, did not reveal any statistically significant differences in organ weight.

Mean concentrations of T4 hormone was statistically significantly increased at the dose level 750 mg/kg/day, but in range of historical control. Mean concentrations of TSH hormone at all dosed groups were comparable with control group at all dose levels.

Test item treatment did not affect male ability to produce sperm that can fertilise eggs and ability of females to become pregnant. Examination of sperm motility and morphology in treated parental males did not show any differences in comparison with the control males.

Microscopic examination of reproductive organs, thyroid gland and pituitary gland in males revealed tubular degeneration in testicles in one control male and in three males at the dose level 750 mg/kg/day. Because the relative weight of testicles and spermiogenesis of the males were not affected with the test item treatment, this change was considered as non-specific, unrelated to the effect of the test item treatment. The incidence of other microscopical findings were in most cases spontaneous or agonal changes, or sporadic, not associated with the test item treatment. Microscopic examination of reproductive organs, thyroid gland and pituitary gland in females did not reveal presence of treatment related changes. Sporadic findings were of spontaneous origin.

The ability of parental animals to successfully mate, to achieve pregnancy and to give birth live pups was not influenced by the test item administration. The number of implantations was statistically significantly increased at the dose level 750 mg/kg/day, but without toxicological significance. The post-implantation losses were very slightly increased in treated groups in comparison with the control.

The test item did not affect the number of pups and their development. The total number of pups and their mean body weights at first litter check after parturition and during the next intervals were not negative affected by the test item treatment.

Macroscopical examination of pups did not show negative effect of the test item administration on development of pups. No differences in postnatal developmental were observed in pups at the treated groups – presence of nipples in male pups was not recorded. Corrected anogenital distance in treated pups was comparable to the control pups.  

No adverse effect of the test item treatment was observed during examination of thyroxine and rat thyroid stimulating hormone blood concentration in pups. Microscopical evaluation of thyroid gland of pups did not show any findings related to the test item treatment.

According to the study results, the NOAEL value for reproduction and development was established as 750 mg/kg body weight/day in both sexes, since no biologically significant changes were observed.

Another Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening (OECD 422), following GLP’s principles, was performed on OB 4-MSA at doses of 80, 250 and 750 mg/kg/bw.

No toxicologically adverse effects of the test item on growth of animals, food consumption and health condition of animals, were detected in both sexes.

During the biometry of organs, statistically significantly increased relative weight of testes and statistically insignificantly increased absolute and relative weight of pituitary gland in males were found out. Examination of sperm motility and morphology did not show any significant changes. During pathological inspection of reproductive organs, no changes were detected in animals of both sexes. During histopathological examination, only spontaneous change in prostate gland (chronic inflammation) was found out. The findings, which related to previous gravidity in uterus (presence of hemosiderin and focal accumulation of lipophages and siderophages in the mesometrium) were found out in females. These findings were not related to the treatment of the test item.

In females the number of implantation sites was increased. One female with abort was detected. The fertility parameters were not changed compared to control group.

All changes in reproductive parameters observed in parental males and females at all dose levels were considered to be of no toxicological significance. The NOAEL for reproduction was therefore established as 750 mg/kg body weight/day.

A further Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening is available on OB 3a-A(Na), with the same conditions and doses as the one performed for OB 4-MSA.

Repeated oral administration of the test item, to rats by gavage did not cause any mortality (except one male from the dose level 250 mg/kg/day). This death was accidental and not treatment-related.

The body weight of parental males and females was not affected by the test item administration.

Evaluation of the absolute and relative weight of reproductive organs of male and female, as well as the weight of pituitary and thyroid gland, did not reveal any statistically significant differences in organ weight.

Test item treatment did not affect male ability to produce sperm that can fertilise eggs and ability of females to become pregnant.

No adverse effect of the test item treatment was observed during examination of thyroxine and rat thyroid stimulating hormone blood concentration in males.  

Histological examination did not reveal negative effect of the test item on collected organs of reproductive organs (pituitary and thyroid gland). Spermatogenesis in the testes of the high dose administered males was without any pathological findings. Epididymides of both control and high dose males were without any pathological findings. Sporadic findings were of spontaneous origin. The administration of test item did not cause pathological changes in the organs. Examination of sperm motility and morphology in treated parental males did not show any differences in comparison with the control males. The administration of test item did not cause damage of sperms.

The number of implantations was comparable between treated and control groups. The test item did not affect the number of pups and their development.

Under test condition, the NOAEL (No Observed Adverse Effect Level) value for REPRODUCTION was established as 750 mg/kg body weight/day.

In conclusion, the NOAEL values found in all the studies above mentioned confirmed an analogous behavior of this category of substances after prolonged repeated oral exposure.

Effects on developmental toxicity

Description of key information

NOAEL for developmental toxicity ≥ 750 mg/kg bw/day (based on the sub-acute studies on OB 4-MSA and OB 3a-A(Na))

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 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

The substance under registration OB 3c-MSA belongs to the category of Stilbene Fluorescent Whitening Agents. The investigation on developmental toxicity potential is not a standard requirement for the tonnage band registration of this substance. However, with regard to this endpoint the category was extensively explored and no significant adverse treatment-related maternal or developmental effects were observed Details on the Read Across approach for category are reported in a document attached in IUCLID section 13.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), 3.7 Reproductive toxicity section, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

The available experimental data are adequate for classification and labelling and the substance is not classified for reproductive and developmental toxicity according to the CLP Regulation (EC 1272/2008).

Additional information