Registration Dossier

Administrative data

Description of key information

NOAEL in male rats 750 mg/kg bw/day

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The substance under registration OB 3c-MSA belongs to the category of Stilbene Fluorescent Whitening Agents.

As for the standard requirements of this registration, the repeated dose toxicity potential is assessed throughCombined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening (OECD 422).

No data on the substance under investigation are available, for this reason data from analogue substances within the category was used for the assessment of the repeated dose toxicity via oral route.

Following oral exposure by gavage, the similar substances show no toxicological adverse effects, even on the reproduction parameters, therefore, considering the high structural similarity and the comparable physicochemical/toxicokinetic profile between this category of substances, the use of this 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, a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening, according to the OECD guideline 422, following GLP’s principles, was performed on OB 4-MSA at doses of 80, 250 and 750 mg/kg/bw (report n. 20-243, 2020).

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 was therefore established as 750mg/kg body weight/day.

A further Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening is available and was carried out on OB 3a-A(Na), with the same conditions and doses as the one performed for OB 4-MSA (report n. 20-217, 2020).

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 was established as 750 mg/kg body weight/day.

A subacute toxicity study is also available on a further OB substance, namely OB 2-A (report n. 288505, 1991). No toxic effects were observed and the NOAEL value was set at 825 mg/kg bw/day.

Three additional combined repeated dose studies, according to the OECD guideline 422, on OB 3b-A, OB 3a-DSA and OB 2-DSA are still in progress and data will be updated as soon as results are available.

In conclusion, no adverse effects were seen in none of the studies above described and the NOAEL value for OB 3c-MSA is assumed to be as 750 mg/kg body weight/day.

 

 

 

 

 

 

Justification for classification or non-classification

According to the CLP Regulation (EC) No. 1272/2008, substances are classified as specific target organ toxicants following repeated exposure, and are placed in one of two categories, depending on the nature and severity of the effect(s) observed. Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure, are classified in Category 1 for target organ toxicity (repeat exposure). Classification in Category 1 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at low concentrations (< 10 mg/kg bw/day in oral studies, and < 20 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.2).

Substances which can be presumed to have the potential to be harmful to human health following repeated exposure, based on evidence from animal studies, are classified in Category 2. Classification in Category 2 is applicable when significant toxic effects are observed in a 90-day repeated-dose animal study at generally moderate exposure concentrations (10 to 100 mg/kg bw/day in oral studies, and 20 to 200 mg/kg bw/day in dermal studies) (CLP Regulation (EC) No. 1272/2008: Annex 1, Part 3, Table 3.9.3).

Equivalent guidance values for an equivalent 28-day study period raises the concentration values for classification by three-fold: classification in category 1 is applicable at low concentrations (< 30 mg/kg bw/day in oral studies; < 60 mg/kg bw/day in dermal studies) and in Category 2 at generally moderate concentrations (30 to 300 mg/kg bw/day in oral studies, 60 to 600 mg/kg bw/day in dermal studies).

Based on the short-term, repeated dose toxicity study (combined with reproductive and developmental toxicity) according to the OECD Guildeline 422, the test item did not produce adverse toxicity in male or female rats when administered at 750 mg/kg bw/day. Therefore, no classification of the test item is warranted for specific target organ toxicity – repeated exposure according to the CLP Regulation (EC) No. 1272/2008.