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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

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
Details on test material:
- Name of test material (as cited in study report): o-phenylenediamine.
- Physical state: solid.
- Purity: 99%

Test animals

Species:
rat
Strain:
other: ChR-CD
Sex:
male

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
Rats in group A (control) received plain tap water throughout the 28-day test period. During the first seven days of the study, rats in group B received tap water to which was added 4,000 ppm OPD. Group B received plain tap water on test days 7-10. On test day 10, group B was divided into two sub-groups of seven rats each, (B1 and B2). The rats in these groups received drinking water to which OPD was added according to a schedule.

Group B1: Concentrations= 400 ppm on test days 10-14, 1,000 ppm on test days 14-17, 2,000 ppm on test days 17-24, and 4,000 ppm on test days 24-28.

Group B2: concentrations= 1,000 ppm on test days 10-24, and 4,000 ppm on test days 24-28.

Drinking water stock solutions were prepared twice weekly and stored under refrigeration in closed plastic containers until used. Two hundred millimeters of freshly prepared water solutions contained in clean glass bottles were given to the rats in each treatment group on each solution preparation day.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
No. of animals per sex per dose:
14 male rats (control)
7 male rats (B1 treatment protocol)
7 male rats (B2 treatment protocol)
Control animals:
other: water
Details on study design:
The objective of the study was to determine the palatability to male rats of drinking water that contained OPD.

Examinations

Observations and examinations performed and frequency:
Drinking water consumption was estimated at regular intervals during the study.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Estimated at regular intervals
Sacrifice and pathology:
Four weeks after the start of the study, all rats were sacrificed. Pathology examinations were not conducted.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
With the exception of brown, discolored fur on the faces of the test rats and sporadic weight loss, no clinical signs were observed that could be related to the presence of OPD in drinking water.
Description (incidence):
All animals survived the test period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Rats receiving 4000 ppm of OPD in drinking water exhibited immediate and marked weight loss. By the end of the first study week, rats in the 4000 ppm OPD group (B1 + B2) weighed approximately 35% less then rats in the control group and, on the average, weighed approximately 18% less than at the start of the study. When OPD was removed from the drinking water for test days 7-10, group B rats exhibited rapid weight gain. Over the three-day recovery period, the gain was approximately six-times that of the control group. Despite the rapid weight gain, however, body weights of the rats in group B averaged 16% lower than those of the control group when exhibited on test day 10.
Following the recovery period, the rats in group B that were given 400 ppm OPD in drinking water (group B1) continued to gain weight at a rate that was slightly greater than that of the control group. After an increase to 1000 ppm OPD, the rate of weight gain by these test rats was comparable to that of the control group. However, when the concentration of OPD in drinking water was raised to 2000 ppm, the test rats exhibited an immediate decrease in the rate of weight gain, followed later by a marked increase in rate of weight gain when compared to the control group. Overall, mean daily weight gain by rats that received 2000 ppm OPD in drinking water during test days 17-24 was comparable to that of the control rats. An increase to 4000 ppm OPD in drinking water during the last four days of the study resulted in a loss of body weight by the rats in test group B1.
The rats in group B that received 1000 ppm OPD in drinking water following the recovery period (group B2) exhibited decreased rate of body weight gain for four days, increased rates of weight gain during the next three days and rates of weight comparable to control rats over seven more days. When the concentration of OPD in drinking water was increased to 4000 ppm during the last four days of the study period, group B2 rats exhibited marked weight loss.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
The presence of 4000 ppm OPD in drinking water substantially reduced the amount of water consumed by the test rats. The presence of 400, 1000, and 2000 ppm OPD in drinking water tended to reduce to variable degrees the estimated mean amount of water consumed by test rats.

Effect levels

Dose descriptor:
NOAEL
Effect level:
400 ppm

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The results of the study suggest that concentrations of 1000 - 4000 ppm OPD in drinking water are not palatable to rats and, that during a longer term study, the administration to rats of drinking water which contains ≥1000 ppm OPD may result in body weight or other clinical changes that are not related to the toxicity of OPD.
Executive summary:

Male rats received 0, 400, 1000, 2000, or 4000 ppm OPD in drinking water for 3 to 14 days intervals during a 28-day study period. Rats that received 4000 ppm OPD in drinking water exhibited weight losses and consumed smaller amounts of water than did control rats. Rats that received 1000 or 2000 ppm OPD in drinking water exhibited smaller decreases in the amount of water consumed and transiently decreased rates of mean body weight gain. Rats that received 400 ppm OPD in drinking water immediately prior to administration of 1000 ppm OPD did not exhibit a reduction in the rate of body weight gain, but did exhibit decreased water consumption. Weight changes and decreased water consumption were also observed after rats that had received 1000 or 2000 ppm OPD were given 2000 or 4000 ppm OPD. The results suggest that concentrations of 1000 - 4000 ppm OPD in drinking water are not palatable to rats and, that during a longer term study, the administration to rats of drinking water containing ≥1000 ppm OPD may result in body weight or other clinical changes that are not related to the toxicity of OPD.