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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1993-01-07 to 1193-05-21
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study - original study report available

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Dipropylene Glycol Monoethyl Ether
- Substance type: Glycol ether
- Physical state: Colourless liquid
- Analytical purity: 90.15%
- Lot/batch No.: EDP
- Storage condition of test material: Room temperature in opaque plastic container and brown glass bottle
- Other:

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd, Manston, UK
- Age at study initiation: (P) 6-7 wks
- Weight at study initiation: (P) Males:183-186 g; Females: 148-151 g
- Housing:
- Diet : Pelleted rat and mouse diet ad libitum.
- Water : Tap water via bottle ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 40-75
- Air changes (per hr): >=15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1993-01-07 To: 1993-05-21

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

- Concentration in vehicle: Adjusted to achieve dosages of 0, 50, 225 or 1000 mg/kg in a 4 ml gavage dose
- Amount of vehicle (if gavage): 4 ml
Vehicle: Distilled water.


Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 21 days
- Proof of pregnancy: copulation plug and sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
- After successful mating each pregnant female was caged individually and males returned to holding cage.
- Any other deviations from standard protocol:
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of test material formulation were taken weekly for analysis for achieved concentration using gas chromatography by an external standard technique.
Duration of treatment / exposure:
Parental animals treated for 74 days and during breeding; dams through gestation and lactation.
Frequency of treatment:
Once daily.
Details on study schedule:
- Age at mating of the mated animals in the study: [17-18] weeks
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
225 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
32
Details on study design:
- Dose selection rationale: Based on acute toxicity
Positive control:
No positive control

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Immediately before and 1 hour after dosing.

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly; days 1, 4, 7, 14, 21 post coitum and post partum

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption by cage, schedule as for body weight.
Estrous cyclicity (parental animals):
By vaginal smear following ejection of copulation plug.
Sperm parameters (parental animals):
Not studied
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in [F1] offspring: clinical signs, number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, body weight and weight gain, physical or behavioural abnormalities, physical development (detachment of pinna, tooth eruption, eye-opening); reflexological assessment (surface righting, mid-air righting, startle and pupil).

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.
Postmortem examinations (parental animals):
DECEDENTS
Examine macroscopically internally and externally for abnormalities; abnormal tissues fixed for later study.
SACRIFICE
- Male and maternal animals: All surviving animals following successful weaning of offspring

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

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed (w), respectively.
Ovaries (w), uterus (w), cervix, vagina, testes (w), epididymides (w), seminal vesicles (w), prostate, coagulating gland, pituitary gland (w), kidneys (w) and significant abnormalities.
Postmortem examinations (offspring):
SACRIFICE
- 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.

Statistics:
Mating, pregnancy and parturition indices - Fisher Exact Probability Test.
Offspring viability Indices - Chi-squared analysis
Reproductive indices:
Pre-coital interval
Mating index
Pregnancy index
Gestation length
Gestation and Parturition index
Offspring viability indices:
Live Birth and Viability Indices (lactation data)
Sex ratio

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Up to half of animals in high dose group exhibited pre-dose salivation intermittently from week 5 until end of study. This observation is not regarded as adverse. No other treatment related observations.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Single death in high dose group attributed to mal-dosing. Three sacrifices made in mid and low dose group due to issues not related to treatment. One death also seen in control group.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Some statistical differences seen in the high dose group during weeks 4 and 6 was not attributed to treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
At 1000 and 225 mg/kg bw/day male rats showed a significant increase in the incidence and severity of basophilic renal tubules in the kidneys which is not unexpected and is not a reproductive effect.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
no effects observed
Description (incidence and severity):
No effects on fertility, gestation or parturition. An apparent slight decrease in offspring viability in the high dose group was attributed to a larger group mean litter size at birth resulting in increased offspring deaths in the first four days, ie artefactual and not a genuine observation.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

No adverse effects noted at any dosage.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEL
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: all other end points including reproductive toxicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Critical effects observed:
yes
Lowest effective dose / conc.:
225 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
Reflexological assessment

Details on results (F1)

No adverse effects

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

At 1000 mg/kg bw/day the only reactions of adults was pre-dose salivation which was intermittent and thought to be reflex response to test material that is either slightly irritant of 'foul' tasting. Also at the highest dosage there was an apparent decrease in offspring viability from birth to Day 4 post-partum due to larger group mean litter size at birth resulting in an increased number of deaths over the first 4 days of lactation. This was not considered an effect attributable to treatment. At 1000 and 225 mg/kg bw/day there was an increase in the incidence and severity of basophilic renal tubules of male rats only; this was not unexpected as a manifestation of known 'male rat hydrocarbon nephropathy' (Alden CL (1986). A review of unique male rat hydrocarbon nephropathy. Toxicologic Pathology Vol 14, No 1, pp 109 -111). This was not, however a reproductive toxicity.

At 50 mg/kg bw/day there were no significant treatment-related findings in either sex.

Summary of live birth and viability indices

Group

Live birth index (%)

Viability index %

1

2

3

4

5

1

96.7

06.8

99.1

99.3

100

95.2

2

95.3

98.8

99.0

100

100

97.6

3

96.6

97.7

99.5

98.7

100

95.9

4

91.5

96.0

99.1

99.1

100

94.3

 

Mean litter sizes during lactation

Group

Mean # born

Days post partum

1

4

7

14

21

1

15.8

15.2

14.8

14.6

14.5

14.5

2

15.4

14.7

14.5

14.3

14.3

14.3

3

15.1

14.6

14.2

14.1

14

14

4

16.7

15.3

14.7

14.6

14.5

14.5

Applicant's summary and conclusion

Conclusions:
The NOAEL (all reproductive measures) was 1000 mg/kg/day.
The NOAEL (male toxicity) was 50 mg/kg bw/day
Executive summary:

In a single generation OECD415 guideline study, Dipropylene Glycol Monoethyl Ether is not reprotoxic in the rat at dosages greater than those demonstrably toxic in male rats . The NOAEL (all reproductive measures) and in females was 1000 mg/g bw/day. The toxic NOAEL in males (only) was 50 mg/kg bw/day, a dosage that evokes male unique hydrocarbon nephropathy at a dose of 225mg/kg and above.