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Administrative data

Description of key information

In the Combined Repeated Dose Oral Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, conducted according to an appropriate OECD test guideline and in compliance with GLP,  the reported NOAEL value for general systemic toxicity for [2-(perfluorohexyl)ethyl]triethoxysilane was 50 mg/kg bw/day (Eurofins, 2017).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
peripheral nervous system
Organ:
other: brachial, femoral and sciatic nerves

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In the Combined Repeated Dose Oral Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, conducted according to an appropriate OECD test guideline and in compliance with GLP,  the reported NOAEL value for general systemic toxicity for [2-(perfluorohexyl)ethyl]triethoxysilane was 50 mg/kg bw/day (Eurofins, 2017).

The test item was administered daily in graduated doses (50, 100 and 150 mg/kg bw/day) to 4 groups of 10 male and 10 female test animals and additional 6 male and 6 female rats in the control and high dose recovery group, one dose level per group for a treatment period of up to 54 days. In order to allow a detection of possible delayed occurrence or persistence of or recovery from toxic effects, additional animals in recovery groups were observed for a period of 14 days (males) or 16 days (females) following the last administration. Animals of the HD group were treated with the higher initial dose of 150 mg/kg bw/day from the start of treatment. Due to observed morbidity and mortality surviving HD animals were treated with a reduced dose of 125 mg/kg bw/day from the respective premating day 14 / mating day 1 onwards.

During the period of administration, the animals were observed each day for signs of toxicity.

Functional observations including sensory reactivity to different stimuli, grip strength, motor activity assessments and other behaviour observations were performed once before the first treatment and at the end of the treatment and the recovery period.

Body weight and food consumption were measured weekly, except for food consumption measurements which were not taken during the mating period in females and the mating and post-mating period in males.

Adult animals that died were examined macroscopically and at the conclusion of the test, all surviving animals were sacrificed and observed macroscopically. The wet weight of a subset of tissues was taken and a set of organs/tissues was preserved.

Haematological and clinical biochemistry evaluations and coagulation measurements were performed on blood samples collected at terminal sacrifice from five randomly selected males and females from each group. Urinalysis was performed on samples collected at terminal sacrifice from five randomly selected males and females from each group.

A full histopathological evaluation of preserved organs/tissues was performed in 5 randomly selected males and females of the control and HD group and in all animals that died prematurely during the course of treatment. These examinations were extended to five randomly selected animals of all other dosage groups for brachial nerves, sciatic nerves, tibial nerves, peroneus nerves, soleus nerves, femoral nerves, eyes with optic nerve, spleen, thymus, heart and liver. These examinations were also extended to animals subjected to necropsy at the end of the recovery period. Testes, epididymides, ovaries, uterus with cervix, vagina and accessory sex organs were examined in all animals from the main groups. For the testes, a detailed qualitative examination was made. Any gross lesion macroscopically identified in any animal was examined microscopically.

Dose-dependent, test item-related morbidity and mortality occurred in the course of treatment in the MD and the HD group was observed.

Predominant clinical signs related to the neuromuscular system were progressive ataxia, paresis (mainly hindlimbs) and hypotonia in the MD and the HD group from treatment day 10 onwards and ultimately abnormal breathing before euthanasia. Furthermore, general signs of reduced health condition such as reduced spontaneous activity, wasp waist and piloerection were noted dose-dependently in the MD and the HD group. Impairments of the neuromuscular system were also seen at weekly detailed clinical observations and in the functional observation battery for several parameters tested such as number of rearings, ataxic and hypotonic gait, reduced equilibrium reflex, positional passivity, visual placing, grip strength, sensitivity to pinching the tail, limb tone, hind limb reflex, toe pinch reflex, righting reflex on the ground and/or air righting reflex. Clinical signs did mostly not fully recover during the treatment-free recovery period of this study.

Dose-dependent, test item-related adverse effects were also noted on body weight and body weight development including significant loss of body weight in the MD and the HD group in the course of treatment. Correlating effects on food consumption were seen in the HD group.

Histopathologically, progressive polyneuropathy was noted in peripheral nerves (brachial, femoral and sciatic nerves including distal extensions) with focal nerve fiber swellings, swellings of Schwann cells, myelin break down, multifocal axonal fragmentation and in more advanced lesions with Bügner’s bands. Caudal nerves were more affected than cranial nerves. The microscopic findings in the peripheral nerves were recorded in both decedent and surviving animals of the MD and the HD group. They are indicative for an induced primary, distal axonopathy. In animals with high severity affection, also the nerve roots of the spinal cord were affected, but less in severity. Findings did not recover in surviving animals that underwent the treatment-free recovery period. Findings in skeletal muscles (quadriceps and gastrocnemius) at the end of the treatment period in terms of minor severity degrees of myofiber atrophy and/or degeneration are of secondary nature. A lung disease consisting of an unusual increase of subacute peri-/vasculitis was noted in the HD group. In the heart of one decedent animal a peri-/arteritis in an intramural coronary artery was noted, which might also be related to the peri-/vasculitis observed in the lungs.

Test item-related findings in the liver consisted of hepatocellular hypertrophy and minimal to slight hepatocellular necrosis in few animals of the MD and the HD group. These findings were not observed after the recovery period.

Justification for classification or non-classification

Based on the available data for [2-(perfluorohexyl)ethyl]triethoxysilane, a classification for STOT RE (peripheral nervous system) Category 2 is required according to Regulation (EC) No 1272/2008.