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Description of key information

Repeated dose toxicity (oral, subacute): NOEL (male/female) = 250 mg/kg bw/day; NOAEL (male/female) = 1000 mg/kg bw/day (Annex V; Method B7)

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
other: SNIF
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
All information in this endpoint has been provided by the ECHA using the 12-year rule, this is data not owned by the registrant. The reliability is assumed to be at level 2. Therefore the following reliability statement can be used: Study conducted in accordance with generally accepted scientific principles, possibly with incorect reporting or methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Principles of method if other than guideline:
Information from migrated NONS file, as per inquiry number 06-0000021057-76-0000, permission to refer granted by ECHA.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Charles River Crl : CD(SD)BR strain
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: 1 % aqueous methyl cellulose
Duration of treatment / exposure:
Test duration: 28 days
Frequency of treatment:
7 days per week
Dose / conc.:
62.5 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
5 males
5 females
Control animals:
yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Mean haemoglobin concentration decreased (p <0.05) in top dose females relative to controls, and was marginally lower than the lower end of the historical value range.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Details on results:
One animal died during blood sampling (anaesthetic trauma).
Dose descriptor:
NOEL
Effect level:
250 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No effects noted
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
haematology
Critical effects observed:
no
Conclusions:
In a sub-acute toxicity study in Charles River Crl:CD(SD)BR rats, the NOEL (male/female) was 250 mg/kg bw/day and the NOAEL (male/female) was 1000 mg/kg bw/day.
Executive summary:

In a sub-acute toxicity study (Annex V; Method B7), DL-N33 was administered by oral gavage to Charles River Crl:CD(SD)BR rats (5/sex/group) in 1% aqueous methylcellulose at 0, 62.5, 250 or 1000 mg/kg bw/day for 28 days, 7 days per week.

No treatment-related deaths or clinical signs of toxicity. Mean haemoglobin concentration decreased (p <0.05) in top dose females relative to controls, and was marginally lower

than the lower end of the historical value range. No other treatment-related effects were observed. No gross or microscopic treatment-related effects were observed.

The NOEL (male/female) was 250 mg/kg bw/day and the NOAEL (male/female) was 1000 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
There is one study available and it has a Klimisch score of 2.

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

Repeated dose toxicity (oral)

There is one 28 day repeated dose toxicity study in rats available.

In a sub-acute toxicity study (Annex V; Method B7), DL-N33 was administered by oral gavage to Charles River Crl:CD(SD)BR rats (5/sex/group) in 1% aqueous methylcellulose at 0, 62.5, 250 or 1000 mg/kg bw/day for 28 days, 7 days per week. No treatment-related deaths or clinical signs of toxicity. Mean haemoglobin concentration decreased (p <0.05) in top dose females relative to controls, and was marginally lower than the lower end of the historical value range. No other treatment-related effects were observed. No gross or microscopic treatment-related effects were observed. The NOEL (male/female) was 250 mg/kg bw/day and the NOAEL (male/female) was 1000 mg/kg bw/day.

This study is acceptable to use in the human health risk assessment.

Justification for classification or non-classification

Based on the available information in the dossier, the substance DL-N33 (CAS No. 104815-18-1) does not need to be classified as specific target organ toxicity (repeated) when considering the criteria outlined in Annex I of 1272/2008/EC.