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Description of key information

The object of this study was to assess the the repeat oral dose toxicity and the potential neurotoxicity of the test substance, NBPT, to rats by dietary administration over a period of 13 weeks.
Treatment with NBPT for thirteen weeks at dietary inclusion levels of 0, 200, 1000 and 5000 ppm was associated with a range of effects.
At 5000 ppm, treatment was associated with some reactions that showed subsequent recovery (clinical signs, bodyweight gains, food utilisation, and responses on the functional observational battery) as well as some effects that continued throughout treatment (cumulative food consumption and haematology and biochemistry parameters). Organ weight and histopathological changes were also observed.
At 1000 ppm, there were limited effects on some biochemistry parameters and among females, an increased incidence of luminal dilatation of the uterus.
The no observed effect level (NOEL) was established in the males as being 200 ppm. However, it was not possible to demonstrate a NOEL among females as a slightly lower phosphorus level and a low incidence of luminal dilatation of the uterus was observed. The toxicological significance of these findings, if any, cannot be determined at this time.

Key value for chemical safety assessment

Additional information

Introduction.

The object of this study was to assess the the repeat oral dose toxicity and the potential neurotoxicity of the test substance, NBPT, to rats by dietary administration over a period of 13 weeks.

The neurotoxicity component was designed in accordance with EPA FIFRA Pesticide Assessment Guidelines, SubdivisionF, Addendum 10, Neurotoxicity, published March 1991, which is also applicable to neurotoxicity testing of industrial chemicals for TSCA. Otherwise, this study was designed in accordance with EPA TSCA Test Guidelines, 40 CFR Part 798 - Health Effects Testing Guidelines, September 27 1985, 798.2650, Oral Toxicity and Subsequent Revision, May 20 1987.

The treatment levels employed 0 (control), 200, 1000 and 5000 ppm were selected by the Sponsor based on a two week palatability/toxicity study performed in these laboratories (IMF/6).

The rat was the species of choice due to regulatory requirements and the Crl:CD BR strain was chosen due to availability of background data.

The route of exposure, dietary, was selected since the oral route is a potential route of human exposure to the test material.

Methods.

In this experiment, the toxicity of (N-(n-butyl) thiophosphoric triamide (NBPT), an organophosphorus compound and a urease inhibitor, was assessed in three groups of 15 male and 15 female Crl:CD BR rats which were given NBPT by dietary admixture at levels of 200, 1000 and 5000 ppm for 13 weeks. Dietary inclusion levels remained constant throughout the study. The overall achieved mean intakes in terms of mg/kg/day for main animals were 14.7, 74 and 377 for males and 17.4, 88 and 445 for females. A similar sized group was given untreated diet and acted as controls. Ten animals/sex/group were designated as Main group animals with the remaining five animals/sex/group designated as Satellite animals.

All animals were monitored for clinical signs, bodyweights and food consumption. Water consumption was measured during Week 12. The eyes of all control animals and animals treated at 5000 ppm were subjected to an ophthalmoscopic examination in Week 13. Laboratory investigations (haematology and clinical chemistry) were performed on all Main group animals in Weeks 5 and 13.

During the pre-dose period and Weeks 4, 8 and 13, 5 males and 5 females from the Main group and all the Satellite animals were screened for neurotoxicity (ie scored on a functional observational battery and were quantitatively assessed for locomotor activity). At Week 14 all the Satellite animals were killed using whole body perfusion and selected tissues of the nervous system were then examined histopathologically. At Week 14 all Main group animals were killed, a post mortem examination performed and organ weights were recorded for selected tissues. Histopathology was performed on indicated tissues.

Results.

Clinical signs and mortalities

One female treated at 5000 ppm was considered to be affected by treatment showing signs of unsteady gait, hunched posture and piloerection. These signs were exhibited during Weeks 3 to 10.

There were no mortalities associated with treatment.

Bodyweights

Cumulative gains were statistically significantly lower than controls among males and females treated at 5000 ppm from the commencement of treatment to Week 4. There was a suggestion among males at 5000 ppm of a slight reduction in weight gains during Weeks 8 to 12.

Food consumption

Cumulative intakes (Weeks 1 to 12) among males treated at 5000 ppm were statistically significantly lower than controls.

Efficiency of food utilisation

During the first 3 weeks of treatment, food utilisation was clearly impaired among males and females treated at 5000 ppm.

Water conswnption

There was no effect of treatment.

Neurotoxicity screening

There were transitory changes in behaviour during Week 4 which were characterised by decreased grip strength for all animals treated at 5000 ppm and a low incidence of hunched posture in females at 5000 ppm. With continuing exposure, these changes disappeared.

Ophthalmoscopic examination

There was no effect of treatment.

Haematology

During Week 5, white blood cell counts were statistically significantly lower among males treated at 5000 ppm due to increased lymphocyte counts.

Among females treated at 5000 ppm, platelet counts were statistically significantly increased at Week 5 and Week 13.

Biochemistry

Statistically significant differences were observed in the following parameters at 5000 ppm:

  • GPT decreased among males in Week 5 and among females in Weeks 5 and 13; GOT decreased among males in Weeks 5 and 13, and among females in Week 5; AP decreased among males in Week 13 and among females in Week 5; phosphorus levels decreased among males in Weeks 5 and 13 and among females in Week 13;

At 1000 ppm the following parameters were statistically significantly different:

  • GOT decreased among males in Week 5; AP decreased among males in Week 13; phosphorus levels decreased among females in Week 13;

At 200 ppm the following parameters were statistically significantly different:

  • Phosphorus levels decreased among females in Week 13;

Organ weights

Liver weights when adjusted for bodyweights were statistically significantly increased among males treated at 5000 ppm when compared with controls. Uterus weights of females treated at 1000 or 5000 ppm were statistically significantly increased compared with controls.

Macroscopic pathology

An increased incidence of fluid distension of the uterus was observed among females treated at 200, 1000 or 5000 ppm compared with controls.

Histopathology

Among males, a statistically significantly increased incidence of minimal centrilobular hepatocyte hypertrophy was observed in male rats 5000 ppm. Among female rats, at 5000 ppm, an increase in the incidence of foci of mineralisation in the kidney was observed. There was also a treatment related increase in the incidence of luminal dilatation of the uterus for females treated at all dosages of NBPT.

Neuropathology provided no evidence of neurotoxicity.

Conclusion

Treatment with NBPT for thirteen weeks at dietary inclusion levels of 0, 200, 1000 and 5000 ppm was associated with a range of effects.

At 5000 ppm, treatment was associated with some reactions that showed subsequent recovery (clinical signs, bodyweight gains, food utilisation, and responses on the functional observational battery) as well as some effects that continued throughout treatment (cumulative food consumption and haematology and biochemistry parameters). Organ weight and histopathological changes were also observed.

At 1000 ppm, there were limited effects on some biochemistry parameters and among females, an increased incidence of luminal dilatation of the uterus.

The no observed effect level (NOEL) was established in the males as being 200 ppm. However, it was not possible to demonstrate a NOEL among females as a slightly lower phosphorus level and a low incidence of luminal dilatation of the uterus was observed. The toxicological significance of these findings, if any, cannot be determined at this time.

Justification for classification or non-classification

Treatment with NBPT for thirteen weeks at dietary inclusion levels of 0, 200, 1000 and 5000 ppm was associated with a range of effects.

At 5000 ppm, treatment was associated with some reactions that showed subsequent recovery (clinical signs, bodyweight gains, food utilisation, and responses on the functional observational battery) as well as some effects that continued throughout treatment (cumulative food consumption and haematology and biochemistry parameters). Organ weight and histopathological changes were also observed.

At 1000 ppm, there were limited effects on some biochemistry parameters and among females, an increased incidence of luminal dilatation of the uterus.

The no observed effect level (NOEL) was established in the males as being 200 ppm. However, it was not possible to demonstrate a NOEL among females as a slightly lower phosphorus level and a low incidence of luminal dilatation of the uterus was observed. The toxicological significance of these findings, if any, cannot be determined at this time.