Propanol, (2-ethoxymethylethoxy)-

Toxicity to reproduction

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

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Dipropylene Glycol Monoethyl Ether

IUPAC Name:

Dipropylene Glycol Monoethyl Ether

Constituent 2

Reference substance name:

Propanol, (2-methoxy-methylethoxy)-

IUPAC Name:

Propanol, (2-methoxy-methylethoxy)-

Constituent 3

Reference substance name:

-

EC Number:

405-820-6

EC Name:

-

Cas Number:

30025-38-8

Molecular formula:

C8H18O3

IUPAC Name:

reaction mass of 5-methyl-4,7-dioxa-2-nonanol and 6-methyl-4,7-dioxa-2-nonanol

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 or test system 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 / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

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.

Oestrous 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 generation)

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

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: oestrous 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)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

2

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.