5-butoxy-2-[4-(4-butoxy-2-hydroxyphenyl)-6-(2,4-dibutoxyphenyl)-1,3,5-triazin-2-yl]phenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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

According regulation (EC) No 1907/2006: the screening for reproductive/developmental toxicity does not need to be conducted if a pre-natal developmental toxicity study [...] is available. A developmental study on a structural analogue is available. The compounds share high similarity in structure and have a comparable molecular weight.

Moreover, oral administration of the test item to Wistar rats at doses of 50, 200 and 1000 mg/kg/day, for 28 days, resulted in no effects on mortality, clinical signs, food consumption, body weight, organ weights, hematology and clinical biochemistry, urinalysis, macroscopic and microscopic findings. There were also no histopathological findings or any changes on mammary gland area, ovaries, pituitary gland, prostate gland, testes, uterus and vagina of the treated animals. Oral administration of the structural analogue at doses of 100, 500 and 1000 mg/kg bw/day for 92 days to rats resulted in no effects on mortality, clinical signs, food consumption, body weight, organ weights, hematology and clinical biochemistry, urinalysis, macroscopic and microscopic findings. There were also no histopathological findings or any changes on mammary gland area, prostate glands, pituitary glands, testes, uterus, vagina and seminal vesicles. The functional observation battery did also not reveal any changes in neurobehaviour.

In addition, due to its very low solubility in water and the large molecular weight only a small amount of the article is expected to be absorbed in the gastrointestinal tract. Almost the entire ingested test item is expected to pass the intestines unchanged and to be excreted directly via faeces. With respect to the very small part of the substance resorbed, most is expected to become directly glucuronidated in the liver and excreted via the bile. It is therefore not expected that repeated dose administration to male and female rats influences fertility, mating behaviour or gestation. It is furthermore not expected that a fertility study in rats would give new insights or would reveal any effects leading to classification. Thus, in accordance with EC 1907/2006, III, chapter 1, article 25, animal welfare and with regard to the points mentioned above a screening for reproductive/ developmental toxicity (OECD 421) will not be conducted.

Effects on developmental toxicity

Description of key information

A pre-natal developmental toxicity study on a structural analogue in rats is available (according to OECD 414). The analogue was applied to mated Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at doses of 60 200, 300 and 600 mg/kg bw/day. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. Thus, the test item is not teratogenic in rats.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Effect level:

600 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: abscence of adverse effects for the tested doses

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

Under the conditions of the prenatal developmental toxicity study in an analogue substance, the oral administration to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 600 mg/kg bw/d caused evidence of maternal toxicity, such as reduced gross and corrected (net) body weight gain.
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 300 mg/kg bw/d. The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 600 mg/kg bw/d, the highest tested dose.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

600 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 the prenatal developmental toxicity study the analogue test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential for maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. The test substance caused neither mortality nor clinical symptoms of systemic toxicity in any of the exposed groups. Two females of the high-dose group (600 mg/kg bw/d) showed transient (up to 10 minutes) salivation at two occasions during the treatment period (GD 14 and GD 17). Such transient salivation shortly after dosing most likely reflects a reaction of the animals to the taste and smell of the test substance. It is not considered to be a sign of systemic toxicity. The high-dose of the test substance (600 mg/kg bw/d) caused a decrease in body weight gain as well as a significant decrease in the corrected (net) body weight gain. These effects are considered minimal, but treatment-related and adverse. No toxicologically relevant clinical effect was noted for the animals exposed to 60, 200 or 300 mg/kg bw/d of the test substance. No differences of toxicological relevance between the control and the treated groups (60, 200, 300 or 600 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. Thus, the test item is not teratogenic in rats.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008, as amended for the thirteenth time in Regulation (EU) No 2018/1480. As a result the substance is not considered to be classified for reproductive toxicity under Regulation (EC) No. 1272/2008.