pymetrozine (ISO); (E)-4,5-dihydro-6-methyl-4-(3-pyridylmethyleneamino)-1,2,4-triazin-3(2H)-one

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity, other

Remarks:

Developmental neurotoxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

5 Nov 2002 to12 Sep 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.6300 (Developmental Neurotoxicity Study)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

6-methyl-4-[(E)-[(pyridin-3-yl)methylidene]amino]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one

EC Number:

602-927-1

Cas Number:

123312-89-0

Molecular formula:

C10H11N5O

IUPAC Name:

6-methyl-4-[(E)-[(pyridin-3-yl)methylidene]amino]-2,3,4,5-tetrahydro-1,2,4-triazin-3-one

Results and discussion

Effect levels

1

Dose descriptor:

NOEL

Remarks:

Maternal toxicity

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Dose descriptor:

NOEL

Remarks:

Developmental neurotoxicity

Effect level:

500 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

neuropathology

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Maternal toxicity observed at 2500 ppm was more severe than anticipated. Marked effects on body weight, body weight gain and food consumption were seen during gestation and early lactation. Of the first 15 dams fed 2500 ppm, two were killed at the time of parturition due to adverse clinical signs (hunched posture, piloerection and subdued behaviour) and body weight loss. One of the second set of 15 females was killed due to parturition difficulties. In addition, there was high neonatal mortality with 4 out of 13 dams with whole litter losses and 31% live born pups either dead or missing by day 5 post-partum. This dose level was, therefore, considered to be too high based on maternal toxicity and high pup mortality, which would result in an insufficient number of pups to allow a meaningful evaluation of developmental neurotoxicity. Therefore, the group was terminated on 20 December 2002. At a subsequent meeting with the members of the Health Effects Division of the EPA, the Agency scientists agreed that the loss of this top dose level should not preclude a meaningful evaluation of the developmental neurotoxicity potential of the technical test material.

There were no adverse clinical signs or treatment-related effects in the functional observation battery on days 10 and 17 of gestation and days 2 and 9 of lactation for dams fed 500 or 100 ppm.

At 500 ppm, parent females had lower growth during late gestation (approximately 10% lower body weight than control), together with lower food consumption (7% lower than control) during week 3 of gestation. Body weightpost-partumwas similar to controls, although food consumption was lower between days 1 and 5.

There were 5 whole litter losses at 500 ppm. Although day 1 litter size, total litter weight and pup body weights for days 1-5 were unaffected, day 5 (pre-cull) litter size and total litter weight and the proportion of pups surviving during days 1-5 (pre-cull) were all slightly lower than control. There was an increase in the number of pups/litters with pups 'missing presumed dead' compared with control. The percentage of live born pups dead or missing by day 5 post-partum (31.8%) was the same as that seen at 2500 ppm.

Maternal body weight and food consumption during the dosing period was unaffected at 100 ppm. There was no effect on reproductive performance, litter size, survival, total litter weight or pup body weight to day 5 (pre-cull) at 100 ppm.

There were no effects of maternal treatment with technical test material at 100 or 500 ppm on body weight, developmental landmarks, functional observation battery, locomotor activity, learning and memory, auditory startle, haematology, brain weight, brain morphometry and histopathology of the nervous system of the selected F1 animals.

At 2500 ppm, there was clear evidence of maternal toxicity as characterised by effects on Body weight and food consumption during both gestation and lactation, and high neonatal pup mortality, leading to insufficient pups available for a meaningful assessment of developmental neurotoxicity potential. Therefore, this dose level was terminated. Maternal treatment with 500 ppm technical test substance showed some evidence of maternal toxicity characterised by lower growth and food consumption during late gestation, together with neonatal mortality, including five whole litter losses and increased numbers of pups and litters with pups either 'missing presumed dead' or dead. Also observed were slight reductions, relative to controls, in day 5 (pre-cull) litter size and total litter weight and the proportion of pups surviving during days 1-5 (pre-cull). However, there were no effects on any of the observations that detect gross neurologic and behavioural abnormalities.

Applicant's summary and conclusion

Conclusions:

At 500 ppm, there were no effects on any of the observations that detect gross neurologic and behavioural abnormalities, therefore, 500 ppm is considered to be the no observed effect level for developmental neurotoxicity in F1 animals. The dose level 100 ppm is the no observed effect level for maternal toxicity.

Executive summary:

The purpose of this study was to determine the potential for developmental neurotoxicity in the assessment and evaluation of the toxic characteristics the technical test material in rats. The potential functional and morphological hazards to the nervous system that may arise in the offspring when the test substance is administered orally, via diet, to the parent female during gestation and lactation, were investigated.This study was conducted according to US EPA 870.6300, Developmental Neurotoxicity Study. Groups of 30, time-mated, female Alpk:APfSD (Wistar-derived) rats were given diets containing 0, 100, 500 or 2500 ppm technical test material from day 7 of gestation through day 22 post-partum. The day of sperm positive vaginal smear was designated day 1 of gestation. Pups were allocated to the F1 phase of the study on post-partum day 5, separated from the dam on day 29 and allowed to grow to adulthood. Evaluations included observations to detect gross neurological and behavioural abnormalities, effects on motor activity, response to auditory startle, assessment of learning and memory, neuropathological evaluation, including brain morphometry and brain weights and haematology.

Maternal toxicity observed at 2500 ppm was more severe than anticipated. Marked effects on body weight, body weight gain and food consumption were seen during gestation and early lactation. Of the first 15 dams fed 2500 ppm, two were killed at the time of parturition due to adverse clinical signs (hunched posture, piloerection and subdued behaviour) and body weight loss. One of the second set of 15 females was killed due to parturition difficulties. In addition, there was high neonatal mortality with 4 out of 13 dams with whole litter losses and 31% live born pups either dead or missing by day 5 post-partum .This dose level was, therefore, considered to be too high based on maternal toxicity and high pup mortality, which would result in an insufficient number of pups to allow a meaningful evaluation of developmental neurotoxicity. Therefore, the group was terminated on 20 December 2002. At a subsequent meeting with the members of the Health Effects Division of the EPA, the Agency scientists agreed that the loss of this top dose level should not preclude a meaningful evaluation of the developmental neurotoxicity potential of the technical test material.

There were no adverse clinical signs or treatment-related effects in the functional observation battery on days 10 and 17 of gestation and days 2 and 9 of lactation for dams fed 500 or 100 ppm.

At 500 ppm, parent females had lower growth during late gestation (approximately 10% lower body weight than control), together with lower food consumption (7% lower than control) during week 3 of gestation. Body weight post-partum was similar to controls, although food consumption was lower between days 1 and 5.

There were 5 whole litter losses at 500 ppm. Although day 1 litter size, total litter weight and pup body weights for days 1-5 were unaffected, day 5 (pre-cull) litter size and total litter weight and the proportion of pups surviving during days 1-5 (pre-cull) were all slightly lower than control. There was an increase in the number of pups/litters with pups 'missing presumed dead' compared with control. The percentage of live born pups dead or missing by day 5 post-partum (31.8%) was the same as that seen at 2500 ppm.

Maternal body weight and food consumption during the dosing period was unaffected at 100 ppm. There was no effect on reproductive performance, litter size, survival, total litter weight or pup body weight to day 5 (pre-cull) at 100 ppm.

There were no effects of maternal treatment with technical test material at 100 or 500 ppm on body weight, developmental landmarks, functional observation battery, locomotor activity, learning and memory, auditory startle, haematology, brain weight, brain morphometry and histopathology of the nervous system of the selected F1 animals.

At 2500 ppm, there was clear evidence of maternal toxicity as characterised by effects on Body weight and food consumption during both gestation and lactation, and high neonatal pup mortality, leading to insufficient pups available for a meaningful assessment of developmental neurotoxicity potential. Therefore, this dose level was terminated. Maternal treatment with 500 ppm technical test substance showed some evidence of maternal toxicity characterised by lower growth and food consumption during late gestation, together with neonatal mortality, including five whole litter losses and increased numbers of pups and litters with pups either 'missing presumed dead' or dead. Also observed were slight reductions, relative to controls, in day 5 (pre-cull) litter size and total litter weight and the proportion of pups surviving during days 1-5 (pre-cull). However, there were no effects on any of the observations that detect gross neurologic and behavioural abnormalities, therefore, 500 ppm is considered to be the no observed effect level for developmental neurotoxicity in F1 animals.The dose level 100 ppm is the no observed effect level for maternal toxicity.