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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study wqs conducted according to O.E.C.D. Testing Guideline 407 following the GLP regulations with analytical verification of concentration and stability.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
Vehicle = water/PEG 200 50/50 (v/v). Samples prepare once per week.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis showed that achieved concentrations and stability were acceptable in all cases.
Duration of treatment / exposure:
28 days
Frequency of treatment:
5.0 ml/kg/day
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
10 mg/kg/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
30 mg/kg/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
100 mg/kg/d
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
7
Control animals:
yes
Positive control:
5.0 ml/kg/d vehicle = water/PEG 200 50/50 (v/v

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: NOAEL for systemic endpoints was 30 mg/kg/day. The NOAEL for local irritational events was 30 mg/kg/day.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

There was no treatment related effect on survival.

The only clinical sign seen in this study was atransient effect. Immediately after dosing the 100 or 300 mg/kg/day test formulations, rats were observed to sneeze and produce a dark nasal discharge. This transient behaviour probably resulted from a mild irritant effect of the volatile acid test substance on nasal mucosa.

A slightly lower bodyweight in the 300 mg/kg/day dose group females was considered to be of uncertain relation to treatment.

There was no effect on male bodyweight , food intake, haematological parameters, or histopathological observations at any dose level.

Changes in alkaline phosphatase, cholesterol, creatinine and bilirubin in females suggested a slight change in liver function at the 100 and 300 mg/kg/day dose level, however, there was no associated histopathalogical changes.

Minor differences in hepatic macroscopic appearance, liver weight and kidney weight were not accompanied by any histopathological change. These differences were considered to be related to adaptive or functional changes and not a toxic effect.

There was no evidence of a cumulative toxic effect at any dose level. However, transient irritancy or adaptive changes were seen at 30, 100 and 300 mg/kg/day.

Additionaly, minor differences in liver and kidney weight were seen at 10 mg/kg/day, these were of uncertain relationship with treatment.

The no adverse effect level for treatment with pivalic acid was 30 mg/kg/day for systemic and 30 mg/kg/day for local irritation

Applicant's summary and conclusion

Conclusions:
The NOAEL for systemic effects was 30 mg/kg/day. The NOAEL for local irritational effects was 30 mg/kg/day.