Pent-3-enenitrile

Endpoint summary

Description of key information

The oral NOAEL is 50 mg/kg bw/day.

Inhal NOAEL could not be determined (test not reliable).

Dermal NOAEL was not investigated.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2019-2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Version / remarks:

2018

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)

Version / remarks:

1998

Deviations:

no

GLP compliance:

yes

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Wistar Han

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chemical analyses of formulations were conducted in Week 1, 6 and 13 to assess accuracy
and homogeneity. Analytical method: UPLC.

Duration of treatment / exposure:

90 days

Frequency of treatment:

Daily, according to the most recent individual animal weights.

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

15 mg/kg bw/day (nominal)

Remarks:

Mean accuracy for formulation in Week 1 was just below the target concentration (i.e. 89% of target 90-110%), and therefore an adjustment of the preparation procedure was made from Week 3 onwards. This resulted in mean accuracies that were in agreement with target concentrations in Weeks 6 and 13 for Group 3. Test formulations prepared were considered homogeneous on all occasions.

Dose / conc.:

5 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

The following parameters and end points were evaluated in this study: clinical signs,
functional observation tests, body weights, food consumption, ophthalmology, clinical
pathology parameters (hematology, coagulation, clinical chemistry, and thyroid hormone),
gross necropsy findings, organ weights, and histopathologic examinations.

Sacrifice and pathology:

clinical pathology parameters (hematology, coagulation, clinical chemistry, and thyroid hormone),
gross necropsy findings, organ weights, and histopathologic examinations

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

At 50 mg/kg/day, hunched posture and erected fur were noted in several females between
Days 11 and 93. Moreover, thin appearance and abdominal distension were observed in one
female (No. 74) from Day 11 onwards.
Salivation seen after dosing among all test item dosed animals in a dose-related increased
incidence was not considered toxicologically relevant, taking into account the nature and
minor severity of the effect and its time of occurrence (i.e. after dosing). This sign was
considered to be a physiological response related to taste of the test item and/or vehicle rather
than a sign of systemic toxicity.
No findings were noted during the arena observations in this study.
Any other clinical signs noted during the Dosing Period occurred within the range of
background findings to be expected for rats of this age and strain which are housed and
treated under the conditions in this study and did not show any apparent dose-related trend. At
the incidence observed, these were considered to be unrelated to treatment with the test item

Mortality:

mortality observed, non-treatment-related

Description (incidence):

At 50 mg/kg/day, one female was killed in extremis on Day 32. After inspection, the cause of death was considered unrelated to the test item.
One male at 5 mg/kg/day was found dead on Day 74. Cause of death was unclear after inspection, but considered not to be related to the test item.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights and body weight gain of treated females and males at 5 and 15 mg/kg/day were
considered to have been unaffected by treatment with test item.
At 50 mg/kg/day, in males, body weights were slightly lower compared to controls from
Day 29 onwards and mean body weight was 8% lower than controls on Day 91. Overall
bodyweight gain for males and females was 88% of controls.
Any other statistically significant changes in body weight gain were considered to be
unrelated to treatment with test item since no trend was apparent regarding dose and duration
of treatment.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

No ophthalmology findings were noted that were considered to be related to treatment with
test item.
The nature and incidence of ophthalmology findings noted during the Pretreatment Period and
in Week 13 was similar among the groups, and occurred within the range considered normal
for rats of this age and strain. These findings were therefore considered to be unrelated to
treatment with the test item.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Haematological parameters of treated rats were considered not to have been affected by
treatment with test item at 5 and 15 mg/kg/day.
At 50 mg/kg/day, an increased reticulocyte count was observed in males (1.28x) compared to
controls. Moreover, a decreased red blood cell count was observed in females (0.95x)
compared to controls

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No toxicologically relevant changes were noted in clinical biochemistry parameters at 5 and
15 mg/kg/day.
At 50 mg/kg/day, increased total protein and albumin levels were observed in males (1.04 and
1.08x of controls, respectively).
Any other statistically significant changes in clinical biochemistry parameters were
considered to be unrelated to treatment with test item as these occurred in the absence of a
dose-related trend or as the opposite effect would be expected in case of organ toxicity.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

see Clinical Signs

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There were test item-related alterations in liver weights in both males and females at
50 mg/kg/day. Liver weights (relative to bodyweight) were statistically significantly increased in males and females treated at 50 mg/kg/day compared to the control animals.
There were no other test item-related organ weight changes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no test item-related gross observations.
All the recorded macroscopic findings were within the range of background gross
observations encountered in rats of this age and strain.

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test item-related microscopic findings after treatment with 3-Pentenenitrile were noted in the
liver of males and females, in the spleen of males and in the adrenal gland of females.
In the liver, an increased incidence of centrilobular hepatocellular hypertrophy was observed
in males treated at 15 and 50 mg/kg/day (minimal) and in females treated at 50 mg/kg/day
(minimal).
In the spleen, an increased severity of hematopoiesis and pigment was observed in males
treated at 15 and 50 mg/kg/day.
The remainder of the recorded microscopic findings were within the range of background
pathology encountered in rats of this age and strain. There was no test item-related alteration
in the prevalence, severity, or histologic character of those incidental tissue alterations.

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, treatment-related

Description (incidence and severity):

THYROID HORMONES
Total thyroxine (T4) levels were statistically significantly decreased in males at 15 and 50
mg/kg/day (0.81x and 0.75x of controls, respectively).
T4 levels in males at 5 mg/kg/day and females at all dose levels were comparable to controls.
Serum levels of thyroid stimulating hormone (TSH) and Triiodothyronine (T3) were
considered unaffected by treatment with the test item up to 50 mg/kg/day.

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

ophthalmological examination

organ weights and organ / body weight ratios

urinalysis

other: Thyroid hormone

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

50 mg/kg bw/day (nominal)

System:

integumentary

Organ:

liver

Conclusions:

In conclusion, administration of 3-Pentenenitrile by once daily oral gavage was well tolerated
in rats at levels of 50 mg/kg/day. Non-adverse alterations were observed in the in liver of
males starting at 15 mg/kg/day and in females at 50 mg/kg (minimal hepatocellular
hypertrophy) and in spleen of males starting at 15 mg/kg/day (increased hematopoiesis and
pigment). Based on these results, the no-observed-adverse-effect level (NOAEL) was
considered to be 50 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Experimental exposure time per week (hours/week):

168

Species:

rat

Quality of whole database:

Guideline study with no deviations