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Description of key information

Oral NOAEL: 523.9 mg/kg bw/day (chronic; rat)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
523.9 mg/kg bw/day
Study duration:
chronic
Species:
rat

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

Reliable data on repeated dose toxicity after oral subacute and chronic exposure of rats are available for CAS 16090-02-1.

Subacute: in a GLP compliant subacute 28-day toxicity study following OECD testing guideline 407, the test substance was administered daily by gavage to SPF-bred Wistar rats. The test substance was administered to 4 groups each of 5 male and 5 female SPF-bred Wistar rats by oral gavage at daily doses of 0, 50, 200, 1000 mg/kg bw/day (corresponding to 0, 41, 165 and 825 mg/kg bw/day of active ingredient) for 28 consecutive days. Two groups of 5 male and 5 female rats were treated accordingly at 0 and 825 mg/kg bw/day for 28 days followed by a 14-day treatment free recovery period. The dose levels used in this study are based on data from acute and subacute studies, especially a subacute 5-day range-finding study, in which dose levels of 0, 200 and 1000 mg test substance per kg body weight and day were administered to rats. There were no compound related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, urinalysis, organ weights, or gross and histologic pathology observed after 4 weeks of treatment nor at termination of the treatment-free recovery period when the results from the animals of the test article treated groups were compared to those of the control animals. Based upon the results obtained in this study, the "No-Observed-Adverse-Effect-Level" of the test substance is 1000 mg/kg body weight (825 mg/kg bw/day active ingredient) for male and female rats when administered orally by gavage for a period of 28 days followed by a treatment-free 14-day recovery period. The various statistically significant differences observed (increase/decrease) in food consumption (absolute/relative) and organ weights (relative) were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested (Research & Consulting Company AG, 1991).

Subchronic: the subchronic toxicity of the test item was investigated in a feeding study with rats. 25 male and female animals received for 90 days 50, 500 and 5000 ppm of the test substance, corresponding to 250 to 500 mg/kg. Body weight and food consumption were monitored continuously; blood urea from the transaminases SGPT, red and white blood cells, haemoglobin and differential count were measured at regular intervals. After 3 months the animals were killed and examined macroscopically. The weight of spleen, adrenal glands, kidneys, testes/ovaries and liver were measured in 10 animals and recorded as percent of body weight. The removed organs were used for histological examination.

The analyses did not revealed significant abnormalities respect to the control and the No Observed Adverse Effect Level can be stated at 5000 ppm for both male and female rats (Pharma-agroforschung, 1969).

 

Chronic: in the chronic toxicity study the test substance was administered to 50 Wistar rats/sex/dose in diet at dose levels of 100, 1000, 10000 ppm (10000 ppm = 791 mg/kg bw/day for females and 524 mg/kg bw/day for males) for 24 months. There were no compound related effects in mortality, clinical signs, body weight, food consumption, haematology, clinical chemistry, urinalysis, organ weights, or gross and histologic pathology; thus, the NOAEL for females was 791 mg/kg bw/day and for males 524 mg/kg bw/day. The various statistically significant differences observed (increase/decrease) in organ weights (absolute in males), number of reticulocytes/trombocytes, and ALAT (GPT) activities and serum protein were considered to be of no toxicological relevance and did therefore not provide any evidence of toxicity of the test substance at any of the dose levels tested (Bayer AG, 1978).

Further studies were reported in literature, performed directly on the substance CAS 16090-02-01: the repeated dose toxicity was tested in a non-GLP study in the rat (Industrial Bio-Test Laboratories, 1973; Keplinger et al., 1974; Lyman et al., 1975). Rats were fed with 40, 200 and 1000 ppm in the diet (approximately 2, 8 and 40 mg/kg bw/day) for 2 years. The NOAEL was the highest dose tested. Additionally, repeated dose studies in the rat and dog were conducted by Industrial Bio-Test Laboratories and are not considered to be valid to assess the endpoint.

Several studies for CAS 13863-31-5 and CAS 16090-02-1 were performed by Industrial Bio-Test Laboratories, which was closed down in 1978 after a routine inspection by the FDA in 1976 uncovered gross deficiencies in study conduct and recordkeeping. None of the studies were subjected to an external audit. However, as a weight of evidence, they confirm the non toxic behaviour of the substance in long term studies at high concentrations and the similar outcome between the category members. Both the substance CAS 13863-31-5 and CAS 16090-02-1 were fed to rats and dog for 90 days at 10000 ppm (262 and 310 mg/Kg bw) with no adverse effects upon body weights, food consumption, survival and reactions, clinical parameters or gross and microscopic pathologic findings.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Two studies are available on Repeated dose toxicity: a 28 subacute and a chronic study, both equally reliable. The Chronic study has been selected for Chemical Safety Assessment.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), 3.9 Specific target organ toxicity - repeated exposure section, substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values, which take into account the duration of exposure and the dose/concentration, which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as:

- oral (rat): 10 < C ≤ 100 mg/kg bw/day

The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats.

The No Observed Adverse Effect Level was established at 523.9 mg/kg bw/day, on the basis of the results from the chronic study of 24 months, on rats.

In conclusion, the available experimental data are adequate for classification and labelling and the substance is not classified for repeated dose toxicity according to the CLP Regulation (EC 1272/2008).