Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: examination of reproductive organs from 91-day study
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is comparable to a guideline study with acceptable restrictions (partly limited documentation)

Data source

Reference
Reference Type:
publication
Title:
Acute, 9-day and 13-week inhalation studies of ethylene glycol monohexylether
Author:
Klonne, DR et al.
Year:
1987
Bibliographic source:
Fundam. Appl. Toxicol. 8, 198-206

Materials and methods

Principles of method if other than guideline:
Twenty rats/sex/group (8-10 weeks old) were exposed to air (control), or 20 (+/- 0.8), 41 (+/- 1.5), or 71 (+/- 5.0) ppm test material for 6 hours/day, 5 days/week for 13 weeks. Ten rats/sex/group were euthanized during the 14th week and the remaining rats were euthanized at the end of a 4-week recovery period. Standard hematological and clinical chemistry endpoints were measured. Animals were examined for gross pathology, organ weights were obtained (kidney, liver, lungs, testes, spleen, brain, thymus), and selected organs from control and high-dose animals (adrenals, brain,
epididymis, gastrocnemius muscle, heart, cervical lymph nodes, parathyroids, pituitary, sciatic nerve, thyroid, urinary bladder, lungs, larynx, trachea, nasal turbinates, gonads (types not stated), liver, thymus, spleen, kidneys, and all gross lesions) were examined histologically.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hexyloxyethanol
EC Number:
203-951-1
EC Name:
2-hexyloxyethanol
Cas Number:
112-25-4
Molecular formula:
C8H18O2
IUPAC Name:
2-(hexyloxy)ethanol
Constituent 2
Reference substance name:
Hexylglycol (EGHE)
IUPAC Name:
Hexylglycol (EGHE)
Details on test material:
- Analytical purity: at least 98%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY)
- Age at study initiation: 8-10 weeks
- Diet: Purina Certified Rodent Chow 5002 (Ralston Purina Co., St. Louis, MO) ad libitum, except during exposures
- Water: ad libitum, except during exposures

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber: 4400-liter stainless-steel and glass chambers
- Vapour generation: Vapour was generated by metering the liquid test material into a heated, spiral-grooved evaporator. A countercurrent air stream entered the bottom of the evaporator, ixed with the vapour, and was the carried into the exposure chamber
- Temperature / humidity in air chamber: 25°C / 43%
- Air flow rate: 750-1000 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: Perkin-Elmer 3920B gas chromatograph equipped with a flame ionization detector
- Samples taken from breathing zone: yes, approx. once per hour
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Perkin-Elmer 3920B gas chromatograph (GC) equipped with a flame ionization detector
- GC column was a 6-ft x 1/4 in. glass column packed with 20% SP-2100 on 80/100 mesh Supelcoport (Supelco, Bellefonte, PA) support material, maintained at 200°C
- Vapour standards were prepared in Tedlar bags for calibration of GC
- A saturated vapour and the Antoine equation were additionally used to validate the bag mix calibration
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
121, 249 and 431 mg/m³ (20, 41 and 71 ppm)
Basis:
analytical conc.
No. of animals per sex per dose:
20 animals per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- 10 rats/sex/dose were sacrificed after at least 2 d of exposure during the 14th study week
- 10 rats/sex/dose were sacrificed at the end of a 4-week recovery period
- control animals were treated as the vapour-exposed rats, except they were exposed to air only

Examinations

Parental animals: Observations and examinations:
CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OTHER: ophthalmoscopic examination (prior to exposure and at sacrifice), haematology (at sacrifice), clinical chemistry (at sacrifice), urinalysis (during a 16-h period prior to sacrifice)
Statistics:
Results of quantitative continuous variables were analyzed for homogeneity of variance using Bartlett's test. Homogenous data were analyzed using analysis of variance (ANOVA) and means were compared using Duncan's multiple range test. Heterogeneous data were analyzed using ANOVA for unequal variances (Brown and Forsythe, Technometrics 16:129-132, 1974) and means were compared using the Student t-test or the Cochran t-test. Corrected Bonferroni probabilities were used for t-test comparisons. The limit of 0.05 (two-tailed) was used as the critical level of significance for all comparisons.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 71 ppm
Sex:
male/female
Basis for effect level:
other: weight and histopathology of reproductive organs

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The NOAEL for reproductive effects was > = 71 ppm. There was no effect of treatment on weights or histology of reproductive organs. The NOAEL for systemic effects was 41 ppm. Rats exposed to 71 ppm exhibited changes in weights of the liver and kidney and alterations in some clinical chemistry values.

Applicant's summary and conclusion

Conclusions:
The NOAEL for reproductive effects was > = 71 ppm.
Executive summary:

The study is reliable with restrictions (partly limited documentation).

Twenty rats/sex/group (8-10 weeks old) were exposed to air (control), or 20 (+/- 0.8), 41 (+/- 1.5), or 71 (+/- 5.0) ppm test material for 6 hours/day, 5 days/week for 13 weeks. Ten rats/sex/group were sacrificed during the 14th week and the remaining rats were sacrificed at the end of a 4-week recovery period. Standard haematological and clinical chemistry endpoints were measured. Animals were examined for gross pathology, organ weights were obtained (kidney, liver, lungs, testes, spleen, brain, thymus), and selected organs from control and high-dose animals (adrenals, brain, epididymis, gastrocnemius muscle, heart, cervical lymph nodes, parathyroids, pituitary, sciatic nerve, thyroid, urinary bladder, lungs, larynx, trachea, nasal turbinates, gonads (types not stated), liver, thymus, spleen, kidneys, and all gross lesions) were examined histologically.

The NOAEL for reproductive effects was > = 71 ppm. There was no effect of treatment on weights or histology of reproductive organs. The NOAEL for systemic effects was 41 ppm. Rats exposed to 71 ppm exhibited changes in weights of the liver and kidney and alterations in some clinical chemistry values.