Diallyl isophthalate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 April to 07 May 2003

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

ANALOGUE APPROACH JUSTIFICATION
Please refer to attached document.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2004

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Diallyl phthalate

EC Number:

205-016-3

EC Name:

Diallyl phthalate

Cas Number:

131-17-9

Molecular formula:

C14H14O4

IUPAC Name:

1,2-Benzenedicarboxylic acid, di-2-propenyl ester

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Sprague-Dawley Crl:CD (SD) IGS BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Commercial laboratory animal supplier.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males: 308 - 366g; Females: 196 - 234g;
- Fasting period before study: No
- Housing: Polypropylene cages with stell grid floors and tops, suspended over paper-lined polypropylene trays.
- Diet: Rodent pellets ad libitum
- Water: ad libitum
- Acclimation period: no data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2°C
- Humidity (%): 55 ± 15%
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): once

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: No data
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required):
- Purity:

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation:
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 / day 1 no data of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The standard and sample solutions were analysed by HPLC using the following conditions;
HPLC; Agilent technologies 1050 or 1100, incorporating autosampler and workstation
Column; Prodigy ODS (250 x 4.6 mm id)
Mobile phase; acetonitrile:water (75:25 v/v)
Flow-rate; 1.0 ml/min
UV detector wavelength; 223 nm
Injection volume; 25 µl
Retention time; ~5.6 min

Duration of treatment / exposure:

14 days pre coitus

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

16.7 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

50 mg/kg bw/day (nominal)

Doses / concentrations 4

Dose / conc.:

150 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily in the week and once daily during weekends and public holidays.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily, immediately before dosing, immediately after dosing and one hour after dosing for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: During maturation and mating weighed weekly. Following mating weighed weekly until termination. Parental females showing evidence of mating weighed on days 0, 7, 14 and 20 post coitum. Parental generation females with a live litter were weighed on days 1 and 4 post partum.

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

No data

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities,

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities;

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals killed on day 5 post partum
- Maternal animals: All surviving animals killed on day 5 post partum

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
All main organs were prepared for microscopic examination and weighed

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
All main tissues were prepared for microscopic examination and weighed, respectively.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

All animals showed increased salivation immediately post dose at 150 mg/kg/day

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

At 150 mg/kg/day there were 3 mortalities

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At 150 mg/kg/day there was a slight reduction in bodyweight gain.

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

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

Target system / organ toxicity (P0)

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):

no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Details on results (F1)

There were no treatment related effects on litter sizes at birth or on subsequent offspring survival throughout lactation. There were no effects on offspring growth or development. There were no effects on offspring reflexological responses and no effects on the intra-litter sex ratios.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects seen clinically or histopathologically.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

The F1 generation displayed no treatment-related effects on growth or development. No macroscopic abnormalities were seen at terminal necropsy.

The P0 parent showed dose-related effects to their livers; periportal hepatocyte necrosis, enlargement and basophilia, bile duct proliferation and periportal fibrosis.