Black HM 2482

Endpoint summary

Description of key information

NOAEL (oral; sub-acute; rat) = 200 mg/kg bw/day

NOAEL (dermal; sub-acute; rat) = 1000 mg/kg bw/day

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

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 adverse effect observed

Dose descriptor:

NOAEL

1 000 ng/kg bw/day

Study duration:

subacute

Additional information

The repeated oral toxicity of test item was assessed following OECD Guideline 407, Repeated Dose 28 -Day Oral Toxicity in Rodents.
Oral administration of test item to Wistar rats at doses of 50, 200 and 1000 mg/kg body weight/day for 28 days resulted in no deaths, no adverse test item-related clinical signs, no test item-related effects upon the parameters of the functional observational battery including grip strength, no changes in mean daily food consumption, no test item-related differences in hematology and clinical biochemistry and no macroscopic changes.
Test item related findings of toxicological relevance were generally restricted to: Lower body weight gains in males treated with 200 mg/kg/day (15th day of treatment) and males and females treated with 1000 mg/kg/day (males: 8th and 15th day of treatment and during recovery, females: 8th day of treatment), elevated erythrocyte and leucocyte counts in the urine of males and females treated with 200 and 1000 mg/kg/day, increased kidneyto-body weight ratios in males and females treated with 1000 mg/kg/day and males treated with 200 mg/kg/day and, microscopically, tubular cell damage in males and females treated with 1000 mg/kg/day (tubular cell necrosis in males and tubular basophilia in females).
The increased erythrocyte and leucocyte counts in the urine were considered to be a consequence of renal cell damage and the tubular basophilia can be understood as sequel to tubular damage.
Based on the results of this study, 200 mg/kg body weigh/day of test item was established as the no-observed-adverse-effect-level

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 1 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur at or below the guidance values:
- oral (rat): (C) ≤10 mg/kg bw/day
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
For a 28-day study the guidance values above mentioned are increased by a factor of three.

Two repeated dose toxicity studies are available on the the test substance.
In a sub-acute dermal repeated dose toxicity study the NOAEL was found to be 1000 mg/kg bw/day, thus no classification for the test substance is proposed according to this study.
In a sub-acute oral repeated dose toxicity study the NOAEL was found to be 200 mg/kg bw/day. Test-item related findings of toxicological relevance were related to elevated erythrocyte and leucocyte counts in the urine of males and females treated with 200 and 1000 mg/kg/day, increased kidney-to-body weight ratios in males and females treated with 1000 mg/kg/day and males treated with 200 mg/kg/day. Further treatment-related findings were judged as non adverse and consisted of increased incidence and severity of hyaline droplets in the kidneys of male animals in all treated groups, tubular cell swelling in a single male treated with 1000 mg/kglday and in females treated with 200 (one single animal) and 1000 mg/kg/day.
The occurrence of hyaline droplets was considered to be a typical male rat specific effect and is not considered relevant for human. Furthermore no test item-related differences were noted in the mean absolute or relative organ weights after 2 weeks' recovery. The effects at 1000 mg/kg bw/day all are recovered except the erythrocyte count in the urine of females treated with the highest test dose concentration. So even at concentrations around 300 mg/kg bw/day all effects are expected to be recovered as per 200 mg/kg bw/day, thus no classification for the test substance is proposed.