5,7-dichloro-4-(4-fluorophenoxy)quinoline;quinoxyfen (ISO)

Neurotoxicity

Description of key information

Acute Neurotox Study Rat Gavage NOAEL: >2000 mg/kg; not neurotoxic. OECD 424; Reliability = 1

90-Day Study Rat Diet Systemic NOAEL: 20 mg/kg, Neurotox NOEL: 80 mg/kg (highest dose tested); not neurotoxic. EPA 83-1; Reliability = 1

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

neurotoxicity: chronic oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OPP 83-1 (Chronic Toxicity)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Substance ID: TSN 100097
- Name of substance: XDE-795
- Purity: 97.4%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

12 months for neurotoxicity study

Frequency of treatment:

daily

Dose / conc.:

5 mg/kg bw/day

Dose / conc.:

20 mg/kg bw/day

Dose / conc.:

80 mg/kg bw/day

No. of animals per sex per dose:

10 for neurotoxicity study

Control animals:

yes

Details on study design:

The study was conducted concurrently with the first year portion of a two-year chronic toxicity/oncogenicity study in Fischer 344 rats. The neurotoxicity and concurrent chronic toxicity studies with the test substance were carried out at dose levels of 0, 5, 20 and 80 mg/kg/day of test substance via the diet of the rats. Ten male and ten female Fischer 344 rats per dose level were assigned to the neurotoxicity study. The neurotoxicity subset of rats were evaluated pre-exposure, and at months 3, 6, 9 and 12 by a functional observational battery (FOB), forelimb and hindlimb grip performance, landing foot splay, and an automated test of motor activity. After completion of 12 months of exposure, neuropathologic examination of perfusion fixed central and peripheral nervous tissues was conducted on 5 rats/sex from the control and high-dose groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Repeated-Measure analysis of monthly body weight data revealed that the test substance did not significantly alter pre-existent differences in body weights over time. Body weight summary histograms and descriptive statistics show a slight decrease in body weights in the high-dose group compared to controls. This decrease persisted from month 3 to month 12 and was more apparent in females. This decrease attained toxicological significance when body weights were evaluated as body weight gains.

Compared to controls, the body weight gain was 10.2% less in the high-dose (80 mg/kg/day) females at month 3 and was 11% less in the same group at month 12. This decreased gain attained toxicological significance going by EPA guidance for toxicity considerations for subchronic and chronic studies (10% change in weight gain). The high-dose females gained lesser at the 6-month (~8% less than controls) and 9-month (~9% less than controls) time points also. The high-dose males had slightly lower body weight gains than controls (never exceeding 4%) although not enough to be considered significant.

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

Hand-held and Open field Observations: The distribution of FOB observations (non-ranked and ranked) suggested a low incidence of random differences; there were no patterns of effects that suggested treatment-related differences. The FOB composite scores provided an overall summary of the magnitude or intensity of ranked observations. Only a few composite scores were sufficiently disparate between groups as to merit further attention, but did not suggest an effect of treatment. Ranked FOB observations were evaluated statistically, treatment vs. control, by the test of proportions. There potentially were 360 pairwise comparisons, only two of which were significant. Like composite scores, the statistical findings reflected a random pattern of differences between sexes and dose groups. The lack of any kind of dose response relationship supports an absence of treatment-related effects.
Hindlimb and forelimb grip performance and landing foot splay: There were no treatment related differences at any test period in either males or females. There were no sex differences at any test period in how males and females responded to treatment.
Hand-held clinical evaluation: There were no treatment related differences at any test period in either males or females seen in the clinical evaluations. Some perineal soiling was seen in high-dose females. However, whenever the soiling occurred (generally, occurred at different times for different rats) it never lasted more than a few days in any of 4 rats that were diagnosed with perineal soiling.
Motor activity: The overall treatment-by-month interaction was not significant (p = 0.491),i.e., total motor activity counts of males and females were not affected by treatment at any test period. The treatment-by-month-by-sex interaction was not significant (p = 0.761), i.e., motor activity was not significantly different in males and females as a consequence of treatment at any test period. The treatment-by-month-by-epoch interaction was not significant (p = 0.343), i.e., the count distribution across epochs did not change as a consequence of treatment at any test period. Thus, there was no evidence of a treatment effect on habituation.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Only mild treatment-related effects were noted. Liver weights of high-dose males and females were increased, and kidney weights of high-dose male rats were increased. There were no treatment-related histopathologic findings in the liver or kidneys at one year of exposure. After two years of exposure, high-dose male rats had an increased incidence of chronic progressive glomerulonephropathy.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no gross pathologic observations attributable to dosage with the test substance in the animals from the chronic neurotoxicity study. All gross pathologic observations were interpreted to be spontaneous findings, unassociated with dietary administration of the test substance.

Neuropathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no histopathologic observations attributable to dosage with test substance in the animals from the chronic neurotoxicity study. All histopathologic observations were interpreted to be spontaneous findings, unassociated with dietary administration of the test substance.

Key result

Dose descriptor:

NOEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOEL

Effect level:

80 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no treatment related neurotoxicological effects were observed

Remarks on result:

other: highest dose tested

Conclusions:

Neurotoxicological NOEL: 20 mg/kg/day for female rats (based on body weight gain findings) and 80 mg/kg/day for male rats

Executive summary:

This one-year chronic neurotoxicity study was conducted according to EPA-FIFRA Guideline No. 83-1. The study was conducted concurrently with the first year portion of a two-year chronic toxicity/oncogenicity study in Fischer 344 rats.

The neurotoxicity and concurrent chronic toxicity studies with the test substance were carried out at dose levels of 0, 5, 20 and 80 mg/kg/day of test substance via the diet of the rats. Ten male and ten female Fischer 344 rats per dose level were assigned to the neurotoxicity study. The neurotoxicity subset of rats were evaluated pre-exposure, and at months 3, 6, 9 and 12 by a functional observational battery (FOB), forelimb and hindlimb grip performance, landing foot splay, and an automated test of motor activity. After completion of 12 months of exposure, neuropathologic examination of perfusion fixed central and peripheral nervous tissues was conducted on 5 rats/sex from the control and high-dose groups.

Rats in the chronic neurotoxicity study showed treatment-related effects at the 3-month time point (80 mg/kg/day group females) and at the end of 12 months of treatment on body weight gains (80 mg/kg/day group females). All other neurotoxicological parameters showed no treatment-related effects. The neurotoxicological NOEL was greater than 20 mg/kg day for female rats (based on body weight gain findings) and 80 mg/kg/day for male rats.

Only mild treatment-related effects were noted in the concurrent one-year portion of the 2-year toxicity study. Liver weights of high-dose males and females were increased, and kidney weights of high-dose male rats were increased. There were no treatment-related histopathologic findings in the liver or kidneys at one year of exposure. After two years of exposure, high-dose male rats had an increased incidence of chronic progressive glomerulonephropathy.

Reference 2

Endpoint:

neurotoxicity: acute oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 424 (Neurotoxicity Study in Rodents)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.6200 (Neurotoxicity Screening Battery)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Substance ID: TSN 100097
- Name of substance: XDE-795
- Lot number: DECO-97-152-1
- Purity: 97.4%

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 0.5% w/v solution of methyl cellulose in Milli-Q water

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

Single dose

Frequency of treatment:

Single dose

Dose / conc.:

200 mg/kg bw (total dose)

Dose / conc.:

632 mg/kg bw (total dose)

Dose / conc.:

2 000 mg/kg bw (total dose)

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

Body weights were taken and a functional observational battery and test for motor activity were both conducted during the week of pre-exposure, and on the day of dosing (i.e., Day 1), Day 8 and Day 15. Functional observational battery included hand-held and open-field observations as well as measurements of rectal temperature, grip performance and landing foot splay. Clinical observations were conducted on Days 2, 3 and 4. Five rats/sex/dose level were perfused for neurohistopathology on Day 16.

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Ophthalmological findings:

no effects observed

Behaviour (functional findings):

effects observed, non-treatment-related

Description (incidence and severity):

Hand-held and Open field Observations: Only 4 average rank values were 0.5 greater or lesser than control average ranks. These occurred at low-dose and at mid-dose and were randomly distributed among time periods (three at pre-exposure and one at Day 8) and among observations (resistance to removal and level of activity). These data showed no pattern indicating a treatment-related effect. Between average ranks and z-scores, all findings were at pre-exposure except for one significant finding that occurred on Day 8 - the middle dose males had a higher level of activity than control males. To summarize, there were no FOB observations related to treatment.

Grip performance: No treatment-related effects were seen in hindlimb or forelimb grip performance at any time during the study. Sexes did not react differently to treatment at any time.

Landing foot splay: No treatment-related effects were seen in landing foot splay at any time during the study. Sexes did not react differently to treatment at any time.

Rectal temperature: No treatment-related effects were seen in rectal temperature at any time during the study. Rectal temperature data analysis resulted in a significant interaction of Treatment by Day (p = 0.0494). Mean rectal temperatures, overall, did not differ much from each other. Sexes did not react differently to treatment at any time. Stepdown analysis was performed to follow up on the significant Treatment x Day interaction. The only significant contrast was control vs low dose at p = 0.0133. The significance seen was deemed to be unrelated to treatment.

Motor activity: No treatment-related effects were seen in motor activity at any time during the study. Sexes did not react differently to treatment at any time. The test substance did not affect the distribution of motor activity counts at any time point, i.e., no change in habituation occurred due to test substance treatment.

Gross pathological findings:

no effects observed

Neuropathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no treatment-related histopathologic observations in the central or peripheral nervous systems of rats administered quinoxyfen. All histopathologic observations were interpreted to be spontaneous findings, unassociated with oral administration of the test substance.

Key result

Dose descriptor:

NOEL

Effect level:

> 2 000 mg/kg bw (total dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No neurotoxicological effects

Remarks on result:

other: highest dose tested

Conclusions:

Rat NOEL (male/female): >2000 mg/kg bw (highest dose tested)

Executive summary:

The study was conducted following OECD guideline 424 and US EPA guideline 870.6200. Ten male and ten female Fischer 344 rats per group were dosed by oral gavage with 0, 200, 632 or 2000 mg/kg bw to evaluate the potential for acute neurotoxicity. Body weights were taken and a functional observational battery and test for motor activity were both conducted during the week of pre-exposure, and on the day of dosing (i.e., Day 1), Day 8 and Day 15. Functional observational battery included hand-held and open-field observations as well as measurements of rectal temperature, grip performance and landing foot splay. Clinical observations were conducted on Days 2, 3 and 4. Five rats/sex/dose level were perfused for neurohistopathology on Day 16.

There were no treatment-related effects seen on body weights, clinical observations, functional observations and measurements, motor activity or neuropathology at any time. Based on the absence of neurotoxicological effects, the neurotoxicological no-observed-effect level (NOEL) for Fischer 344 rats of either sex was greater than the highest dose of test substance tested (i.e., greater than 2000 mg/kg) under the exposure conditions of this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Ten male and ten female Fischer 344 rats per group were dosed by oral gavage with 0, 200, 632 or 2000 mg/kg bw to evaluate the potential for acute neurotoxicity. Body weights were taken and a functional observational battery and test for motor activity were both conducted during the week of pre-exposure, and on the day of dosing (i.e., Day 1), Day 8 and Day 15. Functional observational battery included hand-held and open-field observations as well as measurements of rectal temperature, grip performance and landing foot splay. Clinical observations were conducted on Days 2, 3 and 4. Five rats/sex/dose level were perfused for neurohistopathology on Day 16. There were no treatment-related effects seen on body weights, clinical observations, functional observations and measurements, motor activity or neuropathology at any time. Based on the absence of neurotoxicological effects, the neurotoxicological no-observed-effect level (NOEL) for Fischer 344 rats of either sex was greater than the highest dose of test substance tested (i.e., greater than 2000 mg/kg) under the exposure conditions of this study.

The neurotoxicity and concurrent chronic toxicity studies with the test substance were carried out at dose levels of 0, 5, 20 and 80 mg/kg/day of test substance via the diet of the rats. Ten male and ten female Fischer 344 rats per dose level were assigned to the neurotoxicity study. The neurotoxicity subset of rats were evaluated pre-exposure, and at months 3, 6, 9 and 12 by a functional observational battery (FOB), forelimb and hindlimb grip performance, landing foot splay, and an automated test of motor activity. After completion of 12 months of exposure, neuropathologic examination of perfusion fixed central and peripheral nervous tissues was conducted on 5 rats/sex from the control and high-dose groups. Rats in the chronic neurotoxicity study showed treatment-related effects at the 3-month time point (80 mg/kg/day group females) and at the end of 12 months of treatment on body weight gains (80 mg/kg/day group females). All other neurotoxicological parameters showed no treatment-related effects. The neurotoxicological NOEL was greater than 20 mg/kg day for female rats (based on body weight gain findings) and 80 mg/kg/day for male rats.

Justification for classification or non-classification

The test substance was negative for neurotoxicity in an acute and a 90-day rat neurotoxicity study. Therefore, the substance does not need to be classified for neurotoxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.