Sodium 2-hexyloxyethanolate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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 OECD Guideline 414 with acceptable restrictions (partly limited documentation, inhalation of test substance instead of oral application)

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Evaluation of the developmental toxicity of ethylene glycol monohexylether vapor in Fisher 344 rats and New Zealand white rabbits.

Author:

Tyl, RW et al.

Year:

1989

Bibliographic source:

Fundam. Appl. Toxicol. 12: 269-280

Reference 2

Reference Type:

publication

Title:

Developmental toxicity evaluation of inhaled ethylene glycol monohexy ether (EGHE) in rats and rabbits

Author:

Tyl, RW et al.

Year:

1987

Bibliographic source:

Teratology 35: 53A-54A, Abstract No. P43

Reference 3

Reference Type:

secondary source

Title:

Unnamed

Year:

2005

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

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: 99%
- Stability under test conditions: no compositional changes during the study as analyzed by gas chromatography

Test animals

Species:

rat

Strain:

Fischer 344

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc. (Kingston, NY)
- Age at arrival: males 69 days, females 62 days
- Gestational body weight at study initiation: mean 163.9 - 164.7
- Housing: stainless-steel cages
- Diet: Certified Ground Rodent Chow (Ralston Purina Co., St. Louis, MO) ad libitum except during exposures
- Water: ad libitum except during exposures
- Acclimation period: 2 weeks

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

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320-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, mixed with the vapour, and was then carried into the exposure chamber
- Air flow rate: approx 1000 L/min
- Air change rate: 14 per hour

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 every 30 min during each 6-h exposure period

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 10-ft x 1/8 in. (i.d.) stainless-steel column packed with 20% SP-2100 on 80/100 mesh Supelcoport (Supelco, Bellefonte, PA)
- Daily nominal concentrations were also calculated for each chamber based on the amount of test material delivered and the chamber air flow during the exposure period

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: until vaginal plug was found (checked twice daily)
- Verification of same strain and source of both sexes: yes, COBS CDF (F-344)/CrlBR
- Proof of pregnancy: vaginal plug referred to as day 0 of gestation

Duration of treatment / exposure:

gestation days 6 - 15

Frequency of treatment:

daily, 6 h/day

Duration of test:

until gestation day 21

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
126, 249 and 480 mg/m³ (20.8, 41.1 and 79.2 ppm)
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
158, 238 and 558 mg/m³ (26.1, 39.2 and 92.0 ppm)
Basis:
nominal conc.

No. of animals per sex per dose:

22 pregnant females in 0-mg/m³ (control) group
20 pregnant females in 126-mg/m³ group
21 pregnant females in 249-mg/m³ group
22 pregnant females in 480-mg/m³ group

Control animals:

yes, concurrent no treatment

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily (gestation days 0-21)

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15 and 21

FOOD CONSUMPTION: Yes
- Food consumption was measured for the intervals gestation days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21

WATER CONSUMPTION: Yes
- Water consumption was measured for the intervals gestation days 0-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: blood, pelvic, abdominal and thoracic viscera, liver

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, approx. half per litter
- Head examinations: Yes, half per litter

Statistics:

The unit of comparison was the pregnant female or the litter (Weil CS, Food Cosmet. Toxicol. 8:177-182, 1970). Results of quantitative continuous variables were intercompared for the three exposure groups and the control group by use of Levene's test for equal variances (Levene H, In: Contributions to Probability and Statistics, pp. 278-292, 1960), analysis of variance (ANOVA), and t tests with Bonferroni probabilities. The t tests were used when the F value from the ANOVA was significant. When Levene's test indicated homogeneous variances, and the ANOVA was significant, the pooled t test was used. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unusual variances (Brown MD and Forsythe AB, Technometrics 16:129-132, 1974) followed, when necessary, by the separate variance t test. Nonparametric data were statistically treated using the Kruskal-Wallsi test (Sokal RR and Rohlf FJ, Teratology 9:A37, 1969) when appropriate. Incidence data were compared using Fisher's exact test (Sokal RR and Rohlf FJ, Teratology 9:A37, 1969). For all statistical tests, the fiducial limit of 0.05 (two-tailed) was used as the criterion for significance.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Details on maternal toxic effects:
No dams died or aborted, but one dam in the 126-mg/m³ group and one in the 249-mg/m³ group delivered early. There was a significant decrease in body weight in the 480-mg/m³ groupon gestation day (gd) 12 and gd 15. Weight gain was reduced markedly for gd 6-9 and gd 6-15 at 480 mg/m³ and slightly for these periods at 249 mg/m³. Weight gain was also reduced in the 480-mg/m³ group for the interval 6-12. Excess lacrimation was seen throughout the exposure period at 480 mg/m³. Maternal food consumption was reduced in the 480-mg/m³ group for the intervals gd 6-9, gd 9-12, gd 12-15 (exposure period), and increased for postexposure gd 18-21, while maternal water consumption was increased in this group for intervals gd 12-15 and gd 15-18. There were no treatment-related effects on erythrocyte parameters and total and differential leukocyte counts. At necropsy there was no treatment-related gross pathology. There were no effects on gravid uterine weight, body weight at sacrifice (absolute or corrected), gestational body weight change (corrected), or absolute or relative liver weight.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

126 mg/m³ air (analytical)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No treatment-related effects on gestational parameters (including corpora lutea, implantations or losses, sex ratio, or fetal body weight) were found. There were no increases in the incidence of individual malformations, malformations by category (external, visceral, or skeletal), or total malformations. There were no significant changes in the incidence of any external variations. Of 15 visceral variations observed, the incidence of fetal atelectasis was increased in the 126-mg/m³ group but not in the 249-mg/m³ or 480-mg/m³ groups. Of 96 skeletal variations, only two exhibited incidences that differed significantly from the controls (split cervical centrum 1 was reduced in the 249-mg/m³ group; bilobed thoracic centrum 9 was reduced in the 480-mg/m³ group). The incidence of fetal variations by category or of total variations did not differ among groups.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

>= 480 mg/m³ air (analytical)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Body weights and body weight changes for control and EGHE vapour-exposed Fischer 344 rats during gestation:

Gestational time	Vapour concentration (mg/m³)
	0 (N=22)	126 (N=20)	249 (N=21)	480 (N=22)
Gestational body weight (g) [mean+/-SD]
Day 0	164.3+/-4.65	163.9+/-4.54	164.3+/-5.04	164.7+/-4.85
Day 6	179.5+/-4.70	178.3+/-5.48	180.2+/-6.53	180.0+/-5.13
Day 9	183.0+/-4.88	180.6+/-5.88	181.7+/-6.83	179.4+/-4.78
Day 12	192.1+/-4.86	189.1+/-6.65	190.9+/-5.96	187.0+/-5.33*
Day 15	202.6+/-5.58	198.4+/-7.89	200.0+/-6.90	196.0+/-5.81**
Day 21	243.1+/-13.81	242.5+/-16.19	244.8+/-13.92	238.2+/-12.86
Gestational body weight change (g) [mean+/-SD]
Days 0-6 (preexposure)	15.2+/-2.95	14.4+/-3.34	15.9+/-3.05	15.3+/-2.82
Days 6-15 (exposure period)	23.2+/-3.24	20.1+/-5.38	19.8+/-3.37*	16.1+/-4.23***
Days 15-21 (postexposure)	40.5+/-10.33	44.1+/-11.80	44.8+/-9.62	42.2+/-9.73
Days 0-21 (gestation)	78.8+/-12.59	78.6+/-14.90	80.5+/-11.59	73.5+/-13.03
Days 6-9	3.5+/-2.26	2.3+/-2.84	1.5+/-2.46*	-0.6+/-1.59***
Days 9-12	9.1+/-2.38	8.5+/-2.55	9.2+/-1.74	7.5+/-2.03
Days 12-15	10.6+/-2.26	9.3+/-4.41	9.1+/-2.01	9.1+/-2.24

* P<0.05, ** P<0.01, *** P<0.001 (compared to controls).

Applicant's summary and conclusion

Conclusions:

The NOAEL of the test substance regarding maternal toxicity is 126 mg/m³ (20.8 ppm). The NOAEL of the test substance regarding teratogenicity is >= 480 mg/m³ (79.2 ppm).

Executive summary:

The study is comparable to OECD Guideline 414 with acceptable restrictions (partly limited documentation, inhalation of test substance instead of oral application).

Timed pregnant Fischer 344 rats (20 -22 per group were exposed to vapours of the test substance at 126, 2 49 mg/m³ (20.8, 41.1 and 79.2 ppm) on days 6 -15 of gestation. The rats were sacrificed at gestation day 21. Maternal toxicity, as shown by transient decrease in gestational body weight gain, was observed at 249 and 480 mg/m³ only during the exposure period. There were no treatment-related effects with respect to haematology, necropsy, gestational parameters, malformations, or variations. It was concluded that exposure to vapour of the test substance resulted in maternal toxicity, but there is no evidence for developmental toxicity or teratogenicity of the test substance.

Conclusion: The NOAEL of the test substance regarding maternal toxicity is 126 mg/m³ (20.8 ppm). The NOAEL of the test substance regarding teratogenicity is >= 480 mg/m³ (79.2 ppm).