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Toxicological information

Toxicity to reproduction

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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

Constituent 1
Chemical structure
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 / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
16.7 mg/kg bw/day (nominal)
Dose / conc.:
50 mg/kg bw/day (nominal)
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.