Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

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: Proprietary study, also published in a peer-reviewed journal.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1973
Reference Type:
study report
Title:
Unnamed
Year:
1972

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The study was conducted prior to development of the guidelines, but is essentially a repeated dose 90-Day oral toxicity study in male rats.
GLP compliance:
no
Remarks:
older proprietary study, pre-dates GLP
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Dimethyl terephthalate manufactured by the Tennessee Eastman Company, and described as a white crystalline solid.

Test animals

Species:
rat
Strain:
Long-Evans
Sex:
male
Details on test animals and environmental conditions:
120 weanling male, hooded Long Evans rats purchased from Blue Spruce Farms, Inc., Altamont, New York were randomly divided into four groups of 30 animals each. The animals were housed five per cage in wire-bottomed cages. Water and the appropriate diet were available ad lib.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
Dimethyl terephthalate was fed for 91 days at concentrations of 0.25, 0.5 and 1.0% in a basal diet of ground Purina Laboratory Chow to which 2.0% Mazola corn oil (w/w) had been added. The compound was added to the measured amount of corn oil and put into solution by adding 1000 g of chloroform and heating. This solution was added to the ground chow and homogenised using an automatic food mixer. The diets were then spread onto shallow open trays to allow the chloroform to evaporate. A control diet was handled similarly except for the addition of compound.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
There are no details given on analytical verification of doses.
Duration of treatment / exposure:
91 days
Frequency of treatment:
Daily - ad libitum feeding
Doses / concentrations
Remarks:
Doses / Concentrations:
0.25, 0.5 and 1.0%
Basis:
nominal in diet
No. of animals per sex per dose:
30 animals per dose were used. Only male rats were used.
Control animals:
yes
Details on study design:
Dose levels were chosen based on previous testing conducted at the laboratory, which indicated that DMT has a very low oral toxicity in rats and mice. A preliminary feeding study was conducted at a level of 5% for 28 days, in 5 rats. Administration resulted in a continuous loss of body weight resulting in the death of all animals. It was concluded that feeding 5% DMT resulted in food refusal with death by starvation. Based on this data, a top dose of 1% was selected for the 96 day study.

Interim necropsies were performed on ten rats from each group on or about the 96th day of feeding. Blood was collected from these rats on approximately feeding day 90 for haematology and clinical chemistry determinations.

Haematology and clinical chemistry determintions were performed on 15 rats on approximately the 55th day of feeding (rats designated for necropsy on the 96th day were not sampled at this time).

The remaining animals were used in additional studies, the reproductive toxicity study is reported in IUCLID section 7.8.1.
Positive control:
A positive control was not included and is not required.

Examinations

Observations and examinations performed and frequency:
Individual body weights and group (5 rats/cage) feed consumption were recorded at weekly intervals for 91 days of the feeding period. Feed efficiency was calculated.

The following clinical chemistry and haematology parameters were determined on selected rats on the 55th and 90th days of feeding: haematocrit, haemoglobin, total and differential white cell counts, serum protein, serum glutamic oxaloacetic transaminase, serum alkaline phosphatase, blood urea nitrogen, blood glucose and ornithine carbamyl transferase.
Sacrifice and pathology:
Ten rats per group were sacrificed on the 96th day using CO2 (the remaining 20 rats/group continued onto another study, see IUCLID section 7.8.1). Tissue samples from all major organ systems were fixed in 10% buffered formalin and processed for histologic examination. Livers and kidneys were weighed for organ weight comparisons.
Other examinations:
Reproductive toxicity - reported in section 7.8.1.
Statistics:
Students t-test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No clinical signs were reported. No treatment related deaths occurred (one animal was accidentally killed).

BODY WEIGHT AND WEIGHT GAIN
The mean body weight gain over the 91 day feeding period was reduced dose dependently when compared to the controls, and this difference at the high dose group (1.0%) was statistically significant (p=0.05).

FOOD CONSUMPTION
Feed consumption was comparable across all groups.

FOOD EFFICIENCY
The diet efficiency of the 1.0% was lower than the control group.

HAEMATOLOGY
No effects were detected on the haematology parameters determined.

CLINICAL CHEMISTRY
No effects were detected on the clinical chemistry parameters determined.

ORGAN WEIGHTS
Relative and absolute liver and kidney weights did not differ significantly from control values.

GROSS PATHOLOGY
No abnormalities detected.

HISTOPATHOLOGY: NON-NEOPLASTIC
No abnormalities detected.

Effect levels

Dose descriptor:
NOEL
Effect level:
5 000 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Body weights were reduced at the 1% level

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No further remarks on results.

Applicant's summary and conclusion

Conclusions:
The 96-day dietary NOEL can be considered to be 0.5% . The effects at the highest dose level of 1.0% were limited to reduced weight gain and food efficiency.
Executive summary:

Dimethyl terephthalate incorporated into the diet at a concentration of 0.25, 0.5 and 1.0% had little effect on male Long-Evans rats following 96 days exposure. The only noticeable effect was a significant reduction in average body weight gain at a concentration of 1.0%. Therefore the 96-day dietary NOAEL can be considered to be 0.5% (5000 ppm; equivalent to 500 mg/kg bw/d).