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Administrative data

Link to relevant study record(s)

Description of key information

Short description of key information on bioaccumulation potential result: 
Assessment of Toxicokinetics behavior for substance FAT 40841/A TE
According to the available data for substance FAT 40841/A TE, a qualitative assessment of toxicokinetics behavior is generated and presented in this dossier.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1.           Physico-chemical data:

FAT 40841/A TE is an odorless dark blue organic powder and a multi-constituent substance used in industrial dyeing for garments. The substance has a MMD smaller than 9.9µm, with a water solubility of 60440 mg/L and a log Pow < - 4.4 at 20. The substance is relatively quickly hydrolyzed at room temperature and in neutral pH conditions;however, the hydrolysis is much slower at acidic or basic conditions at room temperature.

2.           Toxicological data:

FAT 40841/A TE was tested for its acute oral and dermal toxicity, for skin and eye irritation, for skin sensitization, for sub-acute oral toxicity, for genetic toxicity and for reproductive toxicity.

a)           For acute toxicity no classification is required according to EU CLP regulation.

For testing of acute oral toxicity, the substance was administrated by oral gavage at a dosage of 2000 mg/kg body weight.All animals survived until the end of the study period. In three animals blue feces were observed on test day 2. No other clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

In an acute test for dermal toxicity, a single dose of 2000 mg/kg bodyweight of the test substance dissolved in water was applied topically. Animals were observed during a period of 14 days after removal of the dressing. No deaths occurred during the study. No clinical signs were observed. Due to a persisting blue staining of the skin a reliable assessment of potential skin irritating effects was not possible during the first study days. Thereafter, when the staining had vanished no reddening of the skin was seen. No gross findings were recorded during necropsy at the termination of the study at day 15. In conclusion, no adverse effects in rats were seen after the application of a single dermal dose of FAT 40481/A TE at a dose level of 2000 mg/kg bodyweight.

b)           Skin irritation/corrosion was tested using human skin model EpiDerm(TM) and by application to rabbits. Both tests showed that the substance is not corrosive to skin and the test on rabbits in addition showed the substance is not irritant.

During the test with human skin model, after treatment with the substance, the relative absorbance values were not relevantly decreased both after 3 minutes and after 1 hour treatment. The positive control showed a decrease in the relative absorbance as compared to the negative control both for the 3 minutes treatment interval and for the 1 hour treatment interval ensuring the validity of the test system. Therefore, the substance is not considered corrosive.

During the test with rabbits, topical semi-occlusive application of 0.5 g substance to the intact left flank of rabbits was carried out. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48 and 72 hours as well as 7, 10 and 14 days after removal of the dressing.

A marked blue staining produced by the substance was observed on the skin of all animals at the 1-hour reading which persisted as slight up to 14 days after treatment, the end of the observation period. Due to this staining of the skin produced by the substance (blue dye), an assessment of the formation of erythema was not possible in all animals at the1-hour reading and additionally in two animals at the 24-hour evaluation.

When assessable, neither erythema nor swelling (oedema) or any other skin reactions were noted in any animal. Thus, the individual mean score for erythema/eschar and oedema for each of the three animals was 0 at any of the observation times where an assessment was possible. No corrosive effects were noted on the treated skin of any animal at any of the measuring intervals and no clinical signs were observed. No oedema was present in all animals during the whole observation period. Thus, the substance was not irritating concerning the oedema assessment. Furthermore, the substance is suggested to be not irritant concerning also erythema because a severe reaction would have been observed despite the staining and would not have disappeared completely from 24 to 48 hours. Therefore, the substance is “not irritating” to rabbit skin.

c)                 In the eye irritation test using BCOP, the substance caused opacity and permeability of the corneas compared with the results of the negative control and is considered to be a very severe eye irritant. However, during the test, the substance caused coloring of the cornea which could not be rinsed off even after stringent washing. Therefore the positive effect may be caused by the coloring effect.

Further study in rabbits indicates not to classify the substance as “causing severe ocular lesions”. The instillation of the substance into the eye resulted in mild, early-onset and transient ocular changes, such as reddening of the conjunctivae and sclerae with or without discharge. These effects were reversible and were no longer evident 24 or 48 hours after treatment. No abnormal findings were observed in the cornea or iris of any animal at any of the examinations. No corrosion was observed at any of the measuring intervals. The substance (blue dye) produced a slight blue staining of the eye which was visible up to the end of the observation period (21 days) in all animals. Additionally, blue remnants were noted in two animals at the 1-hour reading. No clinical signs were observed throughout the observation period. Thus, the substance did not induce significant or irreversible damage to the rabbit eye and the substance is considered to be “not irritating” to the rabbit eye.

d)                In the skin sensitization test (LLNA), the substance was found to be a sensitizer.

e)                 In the sub-acute (28-day) oral toxicity test, the substance was administered daily by oral gavage at dose levels of 50, 200 and 1000 mg/kg body weight/day.

All animals survived until scheduled necropsy. Dark feces were observed with dose-related speed of onset and mean severity. This was considered to be common following oral administration of dyestuffs and of no toxicological relevance. No findings of toxicological relevance were noted during the Detailed Clinical Observations (weeks 1-3). and the Functional Observational Battery (week 4). The mean fore- and hind- limb grip strength and the mean daily food consumption of the substance-treated rats compared favorably with those of the respective controls. Minor differences in the mean locomotor activity were considered to be unrelated to the substance. No substance­related differences in the mean body weights or mean body weight gain values were noted at any dose level. For Hematology / Clinical Biochemistry / Urinalysis, after four weeks’ treatment, no differences of toxicological relevance were noted at any dose level. All differences remained within the ranges of the historical control data, were dose-unrelated, were largely due to aberrant control values, or were not accompanied by concomitant changes in related parameters and therefore considered to be incidental. After two weeks’ recovery, none of the observed differences were considered to be late effects. No substance-related effects upon the mean absolute or relative organ weights were noted. After four weeks of treatment, dark discoloration of several organs (tongue, stomach, jejunum, ileum, cecum, colon, rectum, kidneys, and mesenteric lymph nodes) was noted macroscopically at various dose levels and considered to be related to the substance. After two weeks of recovery, persistent dark discoloration of the kidneys was noted in previously treated rats. Microscopically, no findings of toxicological relevance were noted in animals necropsied after four weeks of treatment. After two weeks of recovery, blue pigment (engulfed in pulmonary phagocytes) were noted in three animals.

Based on the results of this study, a no-observed-effect-level (NOEL) for FAT 40841/A could not be established, but the no-observed-adverse-effect-level (NOAEL) was considered to be 1000 mg/kg body weight/day.

f)                  In the genetic toxicity tests, the substance shows non-mutagenic in a bacterial reverse mutagenic assays and in anin vivomammalian bone marrow micronucleus assay. Though it is considered to be clastogenic in anin vitrochromosome aberration test in the absence and presence of metabolic activation.

g)                In the reproductive toxicity test, the repeated dose administration of the substance to pregnant female rats at dosages of 160, 400 and 1000 mg/kg body weight from gestation day 5 to 19 revealed no major toxicological findings in females and fetuses. Based on the data generated from this study, The NOAEL for both maternal toxicity and fetal toxicity of FAT 40841/A TE inWistarrats was 1000 mg/kg body weight.

No substance related clinical observations were observed in any of the dose group females during the entire period of the treatment when compared with controls. Body weight, body weight change and food consumption remained unaffected throughout the treatment period. Statistical analysis of prenatal data revealed no significant effect on prenatal parameters like terminal body weight, gravid uterus weight, adjusted maternal weight, number of corpora lutea, implantations, live fetuses, dead fetuses, resorptions, percent preimplantation loss and post implantation loss in the treated groups when compared with controls.

Statistically significant increase in group mean number of male fetuses in MD and HD group and sex ratio in HD group was observed when compared with controls. Group mean number of females was decreased in MD and HD group without reaching statistical significance. Statistically significant increase in group litter mean weight and male litter weight was also observed in MD and HD when compared with controls. There was also decrease in female litter weight observed in HD when compared with controls. Group mean number of males was increased in MD and HD and group mean number of females was decreased in MD and HD as compared to controls. However, total number of fetuses remained unaffected in treated groups when compared with controls. Decrease in pregnancy rate was observed in control group (73.08%), LD (80.00%), and MD (80.77%) as compared to HD (92.00%). The significant difference in various parameters was attributed to the gender imbalance and reason for this effect could not be established in this study.

Few gross external abnormalities were seen among the control and treatment groups.

Skeletal examination of the Alizarin red stained fetuses revealed a range of abnormalities which were of a type or which occurred at an incidence comparable in treated groups when compared with controls. Statistically significant increase in incidence of incomplete ossification of 5th and 6th sternebra and significant decrease in incidences of absent 4th metacarpal (bilateral) was observed in LD and HD respectively. However, due to lack of dose dependency in this effect indicates no relevance with treatment. There was no indication of a compound related trend in the type and incidences of other abnormalities and they were therefore considered to be spontaneous in nature.

Internal observation of the fetal viscera by free hand microdissection technique revealed a range of visceral abnormalities in all groups including control. There was a statistically significant decrease in kidney- hydronephrosis (Left) in LD and MD group. Since these visceral abnormalities observed in treated groups were in frequencies comparable or even less in numbers to controls, no toxicological significance can be attributed to these findings and they are considered to be spontaneous in nature.

Craniofacial examination by razor blade serial sectioning technique revealed a range of visceral abnormalities in all groups including controls. Therefore, these findings are not to be considered as treatment related and solely spontaneous in nature.

The terminally sacrificed animals belonging to the control and treatment groups revealed lesions like kidney cyst, pale kidneys, lung with white spots. There was an increased number of incidences of blue/green discoloration of various visceral organs observed in treated groups. The pattern of gross pathological lesions at necropsy in very few animals from different treatment groups suggested that the lesions were of spontaneous/ incidental in nature.

3.           Absorption, distribution, metabolism and excretion:

The substance has a high water solubility (60440 mg/L) and a partition coefficient of Log Pow   < - 4.4, which indicates the passive absorption through the bio-membrane to be relatively low; so is the dermal absorption. However, according to the findings from the sub-acute and reproductive toxicity tests, discoloration of various visceral organs and tissues, such as kidney and mesenteric lymph nodes, were observed after administration of the substance. Also, after two weeks of recovery, persistent dark discoloration of the kidneys was noted, which indicate the substance to be mainly excreted via urine.

The MMD of this substance is smaller than 9.9 µm, which implies a possibility of inhalative exposure. Considering that the substance is imported into the EU in a formulated form as a dust-free powder, the inhalation route of exposure is unlikely, thus the study on acute inhalation toxicity is being waived. However, during the sub-acute toxicity test by oral gavage, after two weeks of recovery blue pigments in pulmonary phagocytes were found in three animals. All lesions recorded during the microscopic investigation were within the range of background alterations that may be recorded in this type of study, and in rats of this strain and age.

The substance and its metabolites are anticipated to be distributed from the portal vein blood into the liver and into the kidneys where the soluble metabolites are further metabolized and excreted. The substance is not likely to be accumulated into the fatty tissue due to its high hydrophilicity and low Log Pow.



Date: 28.01.2011