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Effects on fertility

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

In a non-GLP study, the effect of dietary treatment with 40, 200 or 1000 ppm (ca. 50 mg/Kg bw) on reproduction of three different generations of rats was assessed and indicated that up to 1000 ppm the tested material did not have any adverse effects on either parental generation or their progeny (Industrial Bio-Test Laboratories, Inc., 1973). The study validity cannot be ensured since it was not audited and additionally no three-generation studies were conducted within the category members, which would confirm the results recorded. Nevertheless, it was mentioned for completeness sake.

A teratogenicity study was conducted on the substance to be registered (CAS 16090-02-1), where reproductive parameters were recorded at a concentration of 30 mg/Kg bw. No influence on fertility, implantation or resorption was observed (secondary sources: Burg et al. 1977 and Keplinger et al. 1974; original reference: Ciba-Geigy Corporation, 1972).

Furthermore, no abnormalities of the reproductive organs were recorded in the two year chronic study on CAS 16090-02-1.

The abovementioned studies on the substance were performed at doses, which are too low to exclude a potential classification; therefore, the following studies on analogue substances are here reported.

A range-finding test (MPI Research Inc., 2000) on reproduction toxicity in Sprague-Dawley rats as dose range finding for the two -generation study is available (CAS 16470-24-9). 10 rats/sex/dose were dosed with 30, 100, 300 or 1000 mg/kg bw/day by oral gavage during premating, mating, gestation and lactation. Males were killed after mating and females and pups were killed on day 4 of lactation. No substance-related finding was noted in any of the parental animals or pups at any dose level, thus a NOAEL of 1000 mg/kg bw/day for parental and offspring toxicity was established.

In the definitive two-generation rat study (MPI Research Inc., 2001), 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.

Both the tests were performed on a similar substance within the category of Stilbene Fluorescent Whitening Agents: the analogous dihydroxyethyl derivative tetrasulphonated sodium salt, CAS 16470-24-9.

In order to select the most ‘biologically active’ surrogate for 16090-02-1 for further reproduction and developmental toxicity testing and in order to generate data to help establish dosage levels, two pilot prenatal developmental toxicity studies were performed in rabbits and rats with CAS 32466 -46 -9 (the free acid form of CAS 16090-02-1) and with CAS 16470-24-9 administered via oral gavage. According to the agreed decision tree within SOCMA (Stilbene Whitener Task Force toxicology testing program) the most biologically active surrogate was selected and two main prenatal developmental toxicity studies performed in rabbits and rats as well as a two-generation reproductive toxicity and fertility study in rats.

Based on the excessive maternal toxicity observed in rabbits treated with CAS 16470-24-9 at 1000 mg/kg bw/day, the test substance was concluded to be more biologically active than CAS 32466-46-9 under the employed experimental conditions and therefore was selected for the definitive two generation toxicity studies in rats and rabbits. The appropriateness of this choice was confirmed by the U. S. Environmental Protection Agency (U. S. EPA) in its letter dated June 4, 1998.

Therefore, the outcomes from the studies conducted on CAS 16470-24-9 can be taken as representative reference also for 16090-02-1.

The review of all the available information on the category members seems provide enough evidences in order to avoid the performance of a specific reproduction test on the substance to be registered, for sake of animal welfare.

 

It has to be noticed that in the described conditions of use the potential human exposure is negligible. In fact, the substance is used as fluorescent whitening agent in the detergency field, where no oral exposure is involved, neither inhalation exposure of worker or consumer due to the fact that the substance is a solid, with very low vapour pressure.

Based on the described uses, the only possible consumer contact scenario is identified in direct skin contact with the final consumer product through pre-treated clothes or hand-wash laundry. Indirect skin contact may occur via residual deposits on clothing or by inhalation of detergent dust during consumer product handling and oral ingestion from residues on dishes or from accidental product ingestion.

Though toxicokinetic studies on rats indicate very low dermal or intestinal absorption rates of 0.1 % of the administered dose, for the consumer exposure estimates worst case absorption rates of 10 % were assumed for dermal absorption since no experimental data are available for repeated contact or application scenarios.

The maximum exposure was estimated occurring by skin contact during pre-treatment of clothes (spot pre-treatment) (HERA 2004 - Substance: Fluorescent Brightener FWA-1): 0.21 mg/Kg bw/day.


Short description of key information:
No effects concerning reproduction toxicity observed at highest dose tested in a two-generation study in rats performed according to OECD testing guideline 416 and under GLP. The NOAEL was 300 mg/kg bw/day for parental toxicity and 1000 mg/kg bw/day for reproductive performance and offspring toxicity (MPI Research Inc., 2001).

Justification for selection of Effect on fertility via oral route:
Study conducted according to internationally accepted testing guidelines and performed according to GLP.
Justification for Read Across is reported in the endpoint summary and in the Category Justification Report attached to the Section 13 of this dossier.

Effects on developmental toxicity

Description of key information
Pilot developmental toxicity study in rabbits: NOAEL developmental toxicity 1000 mg/kg bw/day test mat
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Additional information

In a non-GLP study, the effect of dietary treatment with 40, 200 or 1000 ppm (ca. 50 mg/Kg bw) on reproduction of three different generations of rats was assessed and indicated that up to 1000 ppm the tested material did not have any adverse effects on either parental generation or their progeny (Industrial Bio-Test Laboratories, Inc., 1973). The study validity cannot be ensured since it was not audited and additionally no three-generation studies were conducted within the category members, which would confirm the results recorded. Nevertheless, it was mentioned for completeness sake.

A teratogenicity study was conducted on the substance to be registered (CAS 16090-02-1), where reproductive parameters were recorded at a concentration of 30 mg/Kg bw. No influence on fertility, implantation or resorption was observed (secondary sources: Burg et al. 1977 and Keplinger et al. 1974; original reference: Ciba-Geigy Corporation, 1972).

In order to select the most ‘biologically active’ surrogate for 16090-02-1 for further reproduction and developmental toxicity testing and in order to generate data to help establish dosage levels, two pilot prenatal developmental toxicity studies were performed in rabbits and rats with CAS 32466-46-9 (the free acid form of CAS 16090-02-1) and with CAS 16470 -24 -9 administered via oral gavage. According to the agreed decision tree within SOCMA (Stilbene Whitener Task Force toxicology testing program) the most biologically active surrogate was selected and two main prenatal developmental toxicity studies performed in rabbits and rats as well as a two-generation reproductive toxicity and fertility study in rats.

Based on the excessive maternal toxicity observed in rabbits treated with CAS 16470-24-9 at 1000 mg/kg bw/day, the substance was concluded to be more biologically active than CAS 32466-46-9 under the employed experimental conditions and therefore was selected for the definitive prenatal developmental toxicity studies in rats and rabbits. The appropriateness of this choice was confirmed by the U. S. Environmental Protection Agency (U. S. EPA) in its letter dated June 4, 1998.

Two studies on developmental toxicity and teratogenicity, according to EPA Guideline OPPTS 870.3700 and under GLP conditions, were performed in rats and rabbits with CAS 16470-24-9.

In the rat study (MPI Research Inc., 1999), 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 discoloured faeces at 400 and 1000 mg/kg bw/day. At skeletal examination of foetuses, 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, also this border finding 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 foetal toxicity is the highest dose tested (1000 mg/kg bw/day).

In the rabbit study (MPI Research Inc., 2000), 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 discoloured faeces also occurred in some dams at 400 mg/kg bw/day. The foetal body weights were lower in the 400 mg/kg bw/day group than compared to controls, and it is considered to be secondary to maternal toxicity. At visceral examination of foetuses, 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 foetal examinations. The NOEL for both maternal and foetal toxicity therefore was established as 100 mg/kg bw/day.

The review of all the available information on the category members seems provide enough evidences in order to avoid the performance of a specific reproduction test on the substance to be registered, for sake of animal welfare.

 

It has to be noticed that in the described conditions of use the potential human exposure is negligible. In fact, the substance is used as fluorescent whitening agent in the detergency field, where no oral exposure is involved, neither inhalation exposure of worker or consumer due to the fact that the substance is a solid, with very low vapour pressure.

Based on the described uses, the only possible consumer contact scenario is identified in direct skin contact with the final consumer product through pre-treated clothes or hand-wash laundry. Indirect skin contact may occur via residual deposits on clothing or by inhalation of detergent dust during consumer product handling, and oral ingestion from residues on dishes or from accidental product ingestion.

Though toxicokinetic studies on rats indicate very low dermal or intestinal absorption rates of 0.1 % of the administered dose, for the consumer exposure estimates worst case absorption rates of 10 % were assumed for dermal absorption since no experimental data are available for repeated contact or application scenarios.

The maximum exposure was estimated occurring by skin contact during pre-treatment of clothes (spot pre-treatment) (HERA 2004 - Substance: Fluorescent Brightener FWA-1): 0.21 mg/Kg bw/day.


Justification for selection of Effect on developmental toxicity: via oral route:
The study was conducted on the free acid form of the CAS 16090-02-1.

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 toxicity according to CLP Regulation (EC 1272/2008).