Brightener 0503E

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Additional information

The objective of this study was to evaluate the effects of the analogue substance 2 (refer to IUCLID chapter 13) on the integrity and performance of male and female reproductive systems, including gonadal function, estrous cycle, mating behaviour, conception, gestation, parturition, lactation, weaning, and growth and development of the offspring.

Based on a two-generation range-finding study with the analogue substance 2 (refer to IUCLID chapter 13)

in the definitive 2-generation rat study according to EPA Guideline OPPTS 870.3800 / OECD 416 and performed under GLP, 26 Sprague-Dawley rats per sex per group were administered 100, 300 or 1000 mg/kg bw/day by oral gavage. In parental animals, the only test substance-related effect noted was an increased kidney weight. In F0 animals, an increased kidney weight (absolute and relative to body and brain weight) was observed in females at 1000 mg/kg bw/day. In F1 parental animals, there was an increase in kidney weight in males (absolute and relative to body weight) and females (absolute and relative to body and brain weight) at 1000 mg/kg bw/day as well as an increase in kidney weight (relative to body weight) in females at 300 mg/kg bw/day. The statistical change in 300 mg/kg bw/day was considered to be spurious since no changes in absolute weight or kidney weight relative to brain weight were seen, and similar increases were not observed in 300 mg/kg bw/day males. There were no test substance-related effects on reproductive performance noted for either parental generation. No adverse, test substance-related changes in growth or development of offspring were observed in either the F1 or the F2 generations.

Based on the results of this study, the NOAEL for parental toxicity was 300 mg/kg bw/day. For parental reproductive performance, the NOAEL was 1000 mg/kg bw/day. For offspring growth and development, the NOAEL was also 1000 mg/kg bw/day [ETAD, 795 -006, 2001].

Short description of key information:
Based on the available data neither in the OECD 416 nor in the OECD 414 study specific substance related effects on reproduction performance are deducible. Signs of general toxicity were without indications on the reproductive behavior up to the mid dose of 300mg/kg bw/day. No reproductive toxic effects at all were observed in rats at the high dose treatment with 1000 mg/kg bw/day which therefore is considered a NOAEL (fertility). The effect level for developmental toxicity (NOAEL developmental) is considered to be 100 mg/kg bw/day.

Effects on developmental toxicity

Description of key information

Two studies were performed using an analogue substance 2 (refer to IUCLID chapter 13). 
1) A prenatal developmental toxicity study according to EPA OPPTS 870.3700 in rats (Sprague-Dawley) treated via oral gavage. The dose range was 100, 400, and 1000 mg/kg bw (actual ingested) applied on 7 days/week. Animals were exposed from day 6 through day 19 of gestation. 
2) A prenatal developmental toxicity study according to EPA OPPTS 870.3700 in rabbits (New Zealand White) treated via oral gavage. The dose range was 100, 400, and 800 mg/kg bw (actual ingested) applied on 7 days/week. Animals were exposed from day 7 through day 28 of gestation. Both studies revealed no evidence of teratogenicity in rats and rabbits. (GLP-compliant OECD 414 studies (ETAD, 795-003, 1999 and ETAD, 795-004, 2000))

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

100 mg/kg bw/day

Additional information

Two studies on developmental toxicity and teratogenicity according to EPA Guideline OPPTS 870.3700 and under GLP conditions have been performed in rats and rabbits with an analogue substance 2 (refer to IUCLID chapter 13).

In the rat study, 30 pregnant Sprague-Dawley rats per group were dosed with 100, 400 or 1000 mg/kg bw/day by oral gavage on gestation days 6-19. The only substance-related effect observed was discolored feces at 400 and 1000 mg/kg bw/day. At skeletal examination of fetuses, the incidence of misaligned sternebra was slightly increased in all dose groups but was well within historical control range and not dose-related and therefore not considered to be test substance related. The incidence of rudimentary ribs was slightly above the historical control range at 100 and 1000 mg/kg bw/day. As the difference from the concurrent control group was not statistically significant and the increase was not dose-related, these findings were not considered biologically significant or test substance-related. The number of vertebral malformations at 1000 mg/kg bw/day (litter incidence 7.1 %) was very slightly above the historical control range (0 - 7 %) and not statistically different from the vehicle controls. Therefore, this border finding too was considered to be within normal variation and unrelated to test substance administration. As there were no adverse maternal or developmental effects seen at any dose level, the NOAEL for both maternal and fetal toxicity is the highest dose tested (1000 mg/kg bw/day) (ETAD 1999).

In the definitive rabbit study, 7 pregnant New Zealand White rabbits per group were dosed with 100, 400 or 800 mg/kg bw/day by oral gavage on gestation days 7 - 28. The application of 800 mg/kg bw/day resulted in excessive maternal toxicity as exhibited by death, abortion, increased incidence of clinical and gross pathological findings, and a marked decrease in food consumption and body weight gain. As a consequence this group was terminated prior to study. Abortion or early delivery and soft stool and discolored feces also occurred in some dams at 400 mg/kg bw/day. The fetal body weights were lower in the 400 mg/kg bw/day group than compared to controls which is considered to be secondary to maternal toxicity. At visceral examination of fetuses, the litter incidence of hemorrhagic iris at 400 mg/kg bw/day was slightly above the historical control range while the slightly increased incidences of gallbladder agenesis, hypoplasia of the gallbladder and azygous lobe of lung absent were within historical control range. Since all the above findings were within or slightly above historical control range, the findings were considered to be spontaneous in nature and unrelated to test substance. Also, no substance-related effects were noted at external and skeletal examinations. At a dose level of 100 mg/kg bw/day no substance-related effects were seen in dams or at fetal examinations. The NOAEL for both maternal and fetal toxicity therefore was established as 100 mg/kg bw/day (ETAD 2000). There was no indication that the test article caused increases in malformations and, consequently, was not considered to be teratogenic in rabbits. Both tests consistently yielded negative results indicating that Stilbene fluorescent whitening agents have no potential for teratogenicity. It is concluded that these negative findings can also be transferred to the substance registered

Justification for classification or non-classification

Based on data from two OECD 414 developmental studies and one two-generation study with an annalogue substance 2

(refer to IUCLID chapter 13) no classification is indicated.