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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: scientifically acceptable and well documented

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1993
Reference Type:
publication
Title:
Frequency and relationships of clinical chemistry and liver and kidney histopathology findings in 13-week toxicity studies in rats
Author:
Travlos GS, Morris RW, Elwell MR, Duke A, Rosenblum S, Thompson MB
Year:
1996
Bibliographic source:
Toxicology 107, 17-29

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Groups of 10 rats of each sex received TCPA (tetrachlorophthalic anhydride) in corn oil vehicle by oral gavage (5 days/week) at doses of 0, 94, 187, 375, 750, and 1500 mg/kg. All animals were observed twice daily for morbidity and mortality and detailed clinical signs. Food consumption was recorded weekly and individual body weights were recorded at study initiation and then weekly thereafter until study term. The examinations performed included reproductive system, clinical pathology, and histopathologic evaluations.
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:
corn oil
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 94, 187, 375, 750 or 1500 m/kg/d
Basis:
actual ingested
No. of animals per sex per dose:
Ten (10) male and 10 female F344 rats/dose
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
LOAEL
Effect level:
94 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on microscopic kidney lessions in males and females

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The deaths of 5 male rats and 1 female rat in the 1500 mg/kg dose group and 1 female rat in the 750 mg/kg dose group were considered due to chemical toxicity. Mean final body weights and body weight gains were depressed in male rats in the 375, 750, and

1500 mg/kg groups and in all groups of female rats receiving TCPA. No clinical pathology changes or hematological changes were clearly associated with chemical exposure.

Relative liver weights were slightly increased in males and females at doses of 187 mg/kg and higher, although a dose relationship was not apparent. Heart weights of surviving male rats in the high-dose group were also increased. Male and female rats exhibited dosedependent increases in kidney weights and in the incidence and severity of renal tubule necrosis and/or dilation.

Applicant's summary and conclusion

Executive summary:

Groups of 10 rats of each sex received TCPA (tetrachlorophthalic anhydride) in corn oil vehicle by oral gavage (5 days/week) at doses of 0, 94, 187, 375, 750, and 1500 mg/kg. All animals were observed twice daily for morbidity and mortality and detailed clinical signs. Food consumption was recorded weekly and individual body weights were recorded at study initiation and then weekly thereafter until study term. The examinations performed included reproductive system, clinical pathology, and histopathologic evaluations.

The deaths of 5 male rats and 1 female rat in the 1500 mg/kg dose group and 1 female rat in the 750 mg/kg dose group were considered due to chemical toxicity. Mean final body weights and body weight gains were depressed in male rats in the 375, 750, and

1500 mg/kg groups and in all groups of female rats receiving TCPA. No clinical pathology changes or hematological changes were clearly associated with chemical exposure.

Relative liver weights were slightly increased in males and females at doses of 187 mg/kg and higher, although a dose relationship was not apparent. Heart weights of surviving male rats in the high-dose group were also increased. Male and female rats exhibited dosedependent increases in kidney weights and in the incidence and severity of renal tubule necrosis and/or dilation.

In summary, clear evidence of organ toxicity following administration of TCPA in corn oil by gavage for 13 weeks was limited to the kidney of rats. The no-observed-adverseeffect level for histopatholologic lesions in this tissue was not achieved with doses as low as 94 mg/kg per day.