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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Experiment using the rapidly formed hydrolysis product of the target chemical conducted according to a protocol comparable to guideline OECD TG 414; publication meets generally accepted standards and is reported in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicology evaluation of 1-pentanol, 1-hexanol, and 2-ethyl-1-hexanol administered by inhalation to rats
Author:
BK Nelson, WS Brightwell, A Khan, EF Krieg, AM Hoberman
Year:
1989
Bibliographic source:
Journal of the American College of Toxicology, Vol 8, Number 2, 405-410

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
15 female test animals (instead of 25)
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI, U.S.A.
- Age at study initiation: No data
- Weight at study initiation: 200-300 g at beginning of pregnancy
- Fasting period before study: No
- Housing: singly, in stainless steel mesh wire cages during gestation and exposure
- Diet: Ad libitum (during exposure-free periods)
- Water: Ad libitum (during exposure-free periods)
- Acclimation period: 1-2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24±2
- Humidity (%): 50±10
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Remarks:
Constant flow of test item mixed with a defined volume of heated air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hinners-type 0.5 m³ exposure chamber
- Method of holding animals in test chamber: In cages
- Source and rate of air: Compressed ambient air
- Method of conditioning air: Heating
- Temperature and humidity in air chamber: 77±2 F° (i.e. 25°C), 50±15 %
- Air flow rate: 0.5 m³/min
- Air change rate: 60/h

TEST ATMOSPHERE
- Brief description of analytical method used: Hourly by infrared analyzer, twice a week by GC of charcoal tubes from the exposure chamber
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- A Miran 1A infrared analyzer was constantly used for hourly measurement.
- Additionally the Exposure concentrations were
verified weekly by a secondary analysis. Charcoal tube samples were drawn 2 days/week and analyzed by gas chromatography, with partial verification by samples spiked with known concentrations
Details on mating procedure:
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0
Duration of treatment / exposure:
Gestation days 1-19
Frequency of treatment:
7 h every day
Duration of test:
19 days (dams were sacrificed on day 20)
Doses / concentrations
Remarks:
Doses / Concentrations:
850 mg/m³ air
Basis:
analytical conc.
No. of animals per sex per dose:
15 (only females included)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Probably in expectation of absence of effects, the experimental equipment was used to provide the highest achievable concentration while keeping the mixing chamber temperature below 80 °F (ca. 27 °C)>

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Daily for the first week and weekly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, calculated on a weekly basis

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus, ovaries
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Examinations included:
- Gravid uterus weight: Not reported
- 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 animals per litter
- Soft tissue examinations: Yes, half of the animals per litter
- Skeletal examinations: Yes, half of the animals per litter
- Head examinations: No
Statistics:
Multivariate analysis of variance (MANOVA) and analysis of variance (ANOVA)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects. Remark: Overall feed consumption was approximatley 10-15% lower than in control animals.

Details on maternal toxic effects:
Although the weight gain appeared to be lower these difference did not reach statistical significance.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Remarks:
Discriminating level = sole test concentration, 7 h/day, gd 1-19
Effect level:
>= 850 mg/m³ air
Based on:
test mat.
Remarks:
2-Ethylhexan-1-ol
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Remarks:
Discriminating level
Effect level:
>= 160 ppm
Based on:
test mat.
Remarks:
2-Ethylhexan-1-ol
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Remarks:
Discriminating level
Effect level:
>= 1 148 mg/m³ air
Based on:
other: conversion to target chemical 2-Ethylhexyl Nitrate
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEC
Remarks:
Discriminating level
Effect level:
>= 6.5 other: mmol/m³
Based on:
other: molar concentration of source and target chemical
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Remarks:
Discriminating dose
Effect level:
>= 193 other: mg/kg bw/day (inhalation-to-oral extrapolation)
Based on:
other: conversion to target chemical 2-Ethylhexyl Nitrate
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Remarks:
Discriminating dose
Effect level:
>= 1.1 other: mmol/kg bw/day (inhalation-to-oral extrapolation)
Based on:
other: conversion to target chemical 2-Ethylhexyl Nitrate
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No indication of malformations induced after exposure of pregnant rats were found.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEC
Effect level:
850 mg/m³ air
Based on:
test mat.
Basis for effect level:
other: No toxicity to highest dose tested
Dose descriptor:
NOAEC
Effect level:
6.5 other: mmol/m3
Based on:
test mat.
Basis for effect level:
other: conversion to molar concentration to conver to 2-EHN concentration
Dose descriptor:
NOAEC
Effect level:
1 148 mg/m³ air
Based on:
act. ingr.
Basis for effect level:
other: conversion from molar concentration to 2-EHN concentration in mg/m3

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Summary of data (Litter mean ± standard deviation)

Data

Test item 2-EH

Control

Mean maternal weight [g]

Day 0

283 ± 18

243 ± 25

Day 7

286 ± 17

262 ± 24

Day 14

310 ± 17

291 ± 26

Day 20

371 ± 20

354 ± 32

Overall gain

88

111

Mean feed consumption [g]

Week 1

97 ± 17

108 ± 14

Week 2

107 ± 12

124 ± 12

Week 3

113 ± 11

118 ± 10

Overall mean

106 ± 15 (a)

117 ± 13

Mean water intake [g]

Week 1

196 ± 32

204 ± 46

Week 2

203 ± 24

276 t 93

Week 3

248 ± 30

265 ± 123

Overall mean

216 ± 36

248 ± 96

Mean corpora lutea per litter

15 ± 2

14 ± 4

Mean resorptions per litter

0.3

0.4

Mean number females per litter

7 ± 2

8 ± 2

Mean number males per litter

7 ± 2

7 ± 2

Mean fetal weight [g]

 

 

Female

3.02 ± 0.20

3.19 ± 0.20

Male

3.18 ± 0.30

3.28 ± 0.27

(a) Significantly different from control

Applicant's summary and conclusion

Conclusions:
No maternal or foetal toxicity after inhalation exposure using the maximum vapour concentration of 850 mg/m³ air.
Executive summary:

The prenatal developmental toxicity of the test item 2-Ethylhexan-1-ol (CAS 104-76-7) via the inhalation route in the rat was measured in a GLP-compliant study using a “Prenatal Developmental Toxicity Study” compliant with OECD TG 414 (2001), with the sole deviation that the number of test animals was reduced (15 female test animals instead of 25). The validity criteria were met and the experiment can be considered relevant and adequate for the endpoint, however a reduced number of test animals were included. Nonetheless it is deemed conclusive and was rated „reliable with restrictions“, i.e. “Klimisch 2” according to the scale of Klimisch et al. (1997). In consideration of possible read-across from this study to metabolic precursors, additional uncertainties have to be taken into account. The rating of the study for use in such analogue or metabolite approach is lower compared to equally rated studies providing direct data from a target substance.

Fifteen sperm-positive female Sprague-Dawley rats were exposed to vapours of the test item through whole body exposure during gestation days 0 -19. Hinners type 0.5m³ exposure chambers to vapours of the test item at a concentration of 850 mg/m³ air was confirmed independently 2 methods; hourly by infrared analyzer and twice weekly by gas chromatography of charcoal tubes from the exposed chamber.

No maternal toxicity or developmental toxicity was noted in a rat inhalation study. The overall feed consumption was approximatley 10 -15% lower in treated animals compared to controls. Although the weight gain appeared to be lower in the treated animals, these differences did not reach statistical significance. The reproduction parameters were unchanged. No malformations were induced after exposure of the pregnant rats to the test substance. The incidences of resorptions, the number of fetuses per litter, the sex ratio, fetal weight, were not different to the control group and no external, skeletal or visceral malformations have been recorded.

In conclusion no substance-related adverse effects of the test item were observed at the highest vapour concentration achievable. Therefore the NOAEL (discriminating dose) was assigned to the highest test concentration. The NOAEL for maternal and developmental toxicity and teratogenicity in the rat is thus ≥ 850 mg/m³ air or ≥ 6.5 mmol/m³ as a basis for equimolar comparison in read-across approaches.

Reading-across to 2-Ethylhexyl nitrate (2 -EHN, CAS 27247-96-7) delivers on the same molar concentration an air level of ≥1148 mg/m³ air. Taking the significantly lower vapour pressure of the target chemical (only 27 versus 93 Pa of 2 -EH at 20 °C) into account, an equimolar exposure exceeding saturated vapour concentrations of the target chemical can be concluded to be non-toxic during developmental exposure.

  • Klimisch HJ, Andreae M, Tillmann U (1997). A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data. DOI 10.1006/rtph.1996.1076 PMID 9056496 Regul Toxicol Pharmacol 25:1-5.