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Administrative data

Key value for chemical safety assessment

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

A Dominant Lethal Study was conducted on the test substance in order to evaluate the potential for cytotoxic or mutagenic effects on male germinal cells. Mice were administered by oral gavage with a single dose of 1650 and 5000 mg/kg. The data on mating ratio, on the numbers of implantations and embryonic deaths are comparable for all groups. No signs of intolerability were noted in the males (see Genetic Toxicity section for the end point summary) (Ciba-Geigy Ltd., 1974).

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 2-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.

This substance has similar organic functionalities, with a higher sulphonation degree respect the substance under registration (CAS 13863-31-5). The sulphonation degree has an impact on the solubility of the substance, nevertheless both CAS 16470-24-9 and CAS 13863-31-5 can be considered water soluble and completely dissociated in water. From a metabolic point of view the two substances share the same metabolic pathway, since they have in common the monohydroxyethylamoni derivative as the main first pass metabolite; therefore it can be assumed that the test result will be representative of the substance under registration.

The tested substance has a very high purity (> 88 %), and the remaining components are inorganic salts, therefore no influence of impurities on toxicity results is expected.

 

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 under registration, 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.

For the substance under registration CAS 13863-31-5 the calculated value is 0.172 mg/Kg bw/day, while the consumer dermal DNEL was calculated as 30 mg/Kg bw day. As a consequence the dermal RCR = 0.006.


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:
The most conservative NOEAL on Parental toxicity has been reported.

Effects on developmental toxicity

Description of key information
Two studies revealed no evidence of teratogenicity in rats and rabbits: rat: NOAEL = 1000 mg/kg bw/day (maternal and foetal toxicity); rabbit: NOEL = 100 mg/kg bw/day (maternal and foetal toxicity). NOAEL = 400 mg/kg bw/day (teratogenicity) GLP-compliant OECD 414 studies (MPI Research Inc., 1999 and 2000).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
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

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, which 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.

 

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.

This substance has similar organic functionalities, with a higher sulphonation degree respect the substance under registration (CAS 13863-31-5). The sulphonation degree has an impact on the solubility of the substance, nevertheless both CAS 16470-24-9 and CAS 13863-31-5 can be considered water soluble and completely dissociated in water. From a metabolic point of view the two substances share the same metabolic pathway, since they have in common the monohydroxyethylamoni derivative as the main first pass metabolite; therefore it can be assumed that the test result will be representative of the substance under registration.

The tested substance has a very high purity (> 88 %), and the remaining components are inorganic salts, therefore no influence of impurities on toxicity results is expected.

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 under registration, for sake of animal welfare.

In order to select the most ‘biologically active’ surrogate 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 both in rabbits and rats on CAS 16470-24-9 and CAS 32466-49-6 (the acid form of 16090-02-1) 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 2-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, it was concluded to be more biologically active than 32466-49-6 under the employed experimental conditions and therefore it 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.

It has to be taken into account the result of the study on rabbits presents some inconsistencies: rabbit is regarded as a too sensitive specie for repeated dose toxicity, and this is also confirmed by the number of mothers died for gavage mistakes. Since the observed effects on pups (weight gain loss) is reported to a maternal toxicity effect, it has to be evaluate if the test is appropriate to assess Reproductive toxicity for the category members.

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.

For the substance under registration CAS 13863-31-5 the calculated value is 0.172 mg/Kg bw/day, while the consumer dermal DNEL was calculated as 30 mg/Kg bw day. As a consequence the dermal RCR = 0.006.


Justification for selection of Effect on developmental toxicity: via oral route:
Two developmental studies are available on rats and rabbits. Rabbits have been revealed as more sentitive, since in the same testing conditions demonstrated systemic effects and toxicity at maternal level.

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 is adequate for classification and labelling and the substance is not classified for reproductive toxicity according to the CLP Regulation (EC 1272/2008).