p-vinylphenol

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

Range finding study

Type of information:

experimental study

Adequacy of study:

key study

Study period:

21 September to 11 December 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

Range finding study

Deviations:

no

GLP compliance:

no

Remarks:

Study was a range finding study and was not conducted to full GLP requirements.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

p-vinylphenol

EC Number:

220-103-6

EC Name:

p-vinylphenol

Cas Number:

2628-17-3

Molecular formula:

C8H8O

IUPAC Name:

p-vinylphenol

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
Maruzen Petrochemical Co.Ltd./ Bx 7831WJD
- Expiration date of the lot/batch:
- Purity test date:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
Opaque airtight container at -30°C to -10°C
- Stability under test conditions:
Stable
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid:

FORM AS APPLIED IN THE TEST (if different from that of starting material)

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable)

OTHER SPECIFICS:

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
Commercial laboratory animal supplier.
- Females: nulliparous and non-pregnant: yes
- Age at study initiation:
7 weeks
- Weight at study initiation:

- Fasting period before study:
- Housing:
Barrier-system animal rooms
- Diet:
autoclaved pelleted diet ad libitum.
- Water:. ad libitum
- Acclimation period: 6 days


DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
21 - 25°C
- Humidity (%):
40 - 70%
- Air changes (per hr):
10-15
- Photoperiod: 12hrs dark / 12hrs light

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: gum arabic

Details on exposure:

The animals were orally treated by gavage for 14 days daily with a syringe connected to a catheter at dosing volumes of 5 ml/Kg based on body weight

Details on mating procedure:

None, toxic effect meant mating would not take place

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

The animals were orally treated by gavage for 14 days daily with a syringe connected to a catheter at dosing volumes of 5 ml/Kg based on body weight

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Control

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Remarks:

low dose

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Doses / concentrations 4

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Doses / concentrations 5

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

3

Control animals:

yes

yes, concurrent no treatment

Examinations

Parental animals: Observations and examinations:

Daily before and after dosing

Postmortem examinations (parental animals):

In males, salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 1000 mg/kg.bw group on day 1.
Salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 500 mg/kg.bw group on day 1.
Salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 200 mg/kg.bw group on day 1.
Decreased spontaneous locomotion and decreased respiratory rate were observed in one of the 50mg/kg group from day 2 to day 4.

In females, prone position, lateral position, colonic convulsion, decreased spontaneous locomotion, incomplete eyelid opening were observed and all animals died in the 1000 mg/kg group on day 1.
Salivation, lateral position,colonic convulsion, decreased spontaneous locomotion, incomplete eyelid opening were observed and all animals died in the 500 mg/kg group.
Decreased spontaneous locomotion, lacrimation, incomplete eyelid opening, decreased respiratory rate, sub-normal temperature were observed in the 200 mg/kg group on day 1.One animal in the 200 mg/kg group hada shuffling gate from day 2 and salivation, anorexia, decreased stool volume were observed on day 3 and this animal was euthanised on day 3. No abnormalities were observed in the 50 mg/kg group.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In males, salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 1000 mg/kg.bw group on day 1.
Salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 500 mg/kg.bw group on day 1.
Salivation, prone position, colonic convulsions, decrease spontaneous locomotion, lacriamtion, incomplete eyelid opening were observed and all animals were dead in the 200 mg/kg.bw group on day 1.
Decreased spontaneous locomotion and decreased respiratory rate were observed in one of the 50mg/kg group from day 2 to day 4.

In females, prone position, lateral position, colonic convulsion, decreased spontaneous locomotion, incomplete eyelid opening were observed and all animals died in the 1000 mg/kg group on day 1.
Salivation, lateral position,colonic convulsion, decreased spontaneous locomotion, incomplete eyelid opening were observed and all animals died in the 500 mg/kg group.
Decreased spontaneous locomotion, lacrimation, incomplete eyelid opening, decreased respiratory rate, sub-normal temperature were observed in the 200 mg/kg group on day 1.One animal in the 200 mg/kg group hada shuffling gate from day 2 and salivation, anorexia, decreased stool volume were observed on day 3 and this animal was euthanised on day 3. No abnormalities were observed in the 50 mg/kg group.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Mortality occured at 500 and 1000 mg/kg doses.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

For males decreased body weigh was observed in the 200 mg/kg group. No affect was observed on the 50mg/kg group.

In feamales, decreased body weigths were observed in 200 and 50 mg/kg groups.

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:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

Target system / organ toxicity (P0)

1

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 mg/kg bw/day (actual dose received)

System:

central nervous system

Organ:

spinal cord

Treatment related:

yes

Dose response relationship:

not specified

Relevant for humans:

yes

2

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 mg/kg bw/day (actual dose received)

System:

gastrointestinal tract

Organ:

colon

duodenum

ileum

intestine

jejunum

oesophagus

oral cavity

rectum

stomach

tongue

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

3

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 mg/kg bw/day (actual dose received)

System:

nervous system

Organ:

forebrain

neurons

spinal cord

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

4

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

50 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

bladder

kidney

ureter

urethra

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

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:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Effect levels (P1)

Key result

Dose descriptor:

NOAEL

Effect level:

> 0 mg/kg bw/day (actual dose received)

Based on:

test mat. (total fraction)

Sex:

male/female

Basis for effect level:

clinical signs

mortality

gross pathology

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Results: F1 generation

General toxicity (F1)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

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:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

other: Not tested

Effect level:

> 0 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Results: F2 generation

General toxicity (F2)

Clinical signs:

not examined

Mortality / viability:

not examined

Body weight and weight changes:

not examined

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:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not examined

Effect levels (F2)

Key result

Dose descriptor:

NOAEL

Generation:

other: not tested

Effect level:

> 0 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

mortality

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Overall reproductive toxicity

Key result

Reproductive effects observed:

yes

Lowest effective dose / conc.:

50 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to other toxic effects:

reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects

Dose response relationship:

yes

Relevant for humans:

yes

Any other information on results incl. tables

Male animals were not capable of reproduction at the low dose of 50mg/kg/bw

Applicant's summary and conclusion

Conclusions:

The toxic changes in this fourteen day study are similar to those of phenol (EC 203-632-7 CAS 108-95-2), corrosive and chemical burns at contact site, transient CNS stimulation followed by CNS depression, coma, seizures, diarrhea, methemoglobinemia, etc. Reference should be made to Agency for Toxic Substances and Disease Registry (USA) Medical Management Guidelines for Phenol mmg115 2017.

Due to the toxic effects coninuation of the study will only lead to unecessary suffering of more animals