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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-10-06 to 1999-09-22
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3600 (Inhalation Developmental Toxicity Screen)
Version / remarks:
adopted 27 Sep 1985
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted 212 May 1981
Deviations:
yes
Remarks:
particle sizes not given, MMAD not determined
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(methylthio)propionaldehyde
EC Number:
221-882-5
EC Name:
3-(methylthio)propionaldehyde
Cas Number:
3268-49-3
Molecular formula:
C4H8OS
IUPAC Name:
3-(methylthio)propionaldehyde

Test animals

Species:
rat
Strain:
other: CD (Sprague-Dawley derived)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Kingston, New York, USA
- Age at study initiation: 64 - 72 days
- Weight at study initiation: 192 - 250 g (mean: 209.6 g)
- Housing: individually in suspended stainless steel wire mesh cages
- Diet: Certified Rodent Diet, No. 5002 (PMI Feeds, Inc., St. Louis, Missouri) ad libitum
- Water: facility water, provided to the animals via an automated watering system, ad libitum
- Acclimation period: at least 3 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21- 23
- Humidity (%): 32 - 72
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 Oct 1997 To: 07 Nov 1997

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
The test material was administered as a vapor in the breathing air of the animals.
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: All females were purchased timed pregnant.
Duration of treatment / exposure:
6 h
Frequency of treatment:
6 h/day during Day 6 - 16 of gestation
Duration of test:
Gestation Days 6 - 20
Doses / concentrationsopen allclose all
Dose / conc.:
10 ppm (nominal)
Remarks:
corresponding to 0.043 mg/L air or 43.0 mg/m3 air (corresponding to an analytical concentration of 9.87 ± 1.3 ppm, 0.0425 mg/L air or 42.5 mg/m3 air)
Dose / conc.:
65 ppm (nominal)
Remarks:
corresponding to 0.28 mg/L air or 279.8 mg/m3 air (corresponding to an analytical concentration of 58.3 ± 7.2 ppm, 0.251 mg/L air or 251.0 mg/m3 air)
Dose / conc.:
125 ppm (nominal)
Remarks:
corresponding to 0.538 mg/L air or 538.1 mg/m3 air (corresponding to an analytical concentration of 127.8 ± 18 ppm, 0.55 mg/L air or 550.1 mg/m3 air)
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were selected based on the results of a pilot inhalation developmental toxicity study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- In chamber observations: All animals were observed as a group at least once during each exposure for appearance, activity or other unusual findings.
- Cage side observations: All animals were observed at least twice daily for mortality, general appearance and signs of severe toxic or pharmacologic effects.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: during treatment interval pre- and postexposure on Days 4, daily on study Days 6 - 16 and on Day 20 of gestation.
- The observations included: general condition, skin and fur, eyes, nose, oral cavity, abdomen and external genitalia as well as evaluations of respiration. Unusual behavior was also recorded. During the treatment period, these examinations were performed both pre- and post-exposure.

BODY WEIGHT: Yes
- Time schedule for examinations: on Days 4, 6, 9, 12, 16, 18 and 20 of gestation. Day 0 gestation body weights were provided by the supplier

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was recorded for each female during the following intervals of gestation: Days 4-6, 6-9, 9-12, 12-16, 16-18, and 18-20.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
- Organs examined: uterus and ovaries
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
- Other: Number of live and dead fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
Means and standard deviations were calculated for continuous data (body weight, body weight change, food consumption, number of corpora lutea, uterine implantation data, implantation loss, number of male/female fetuses, percentage of fetuses per litter, fetal weight). All statistical tests were conducted at the 5% and 1%, two-sided risk levels. In addition, multiple group analysis was performed when more than one treated group was compared to control. Statistical evaluation of equality of means were made by the appropriate one way analysis of variance (ANOVA) technique, followed by a multiple comparison procedure, if needed. If ANOVA showed no difference, no additional comparisons were made. If ANOVA was significant, Dunnett's test was used to determine which data, if any, differed from the control. Incidence data (mortality and pregnancy rate, incidence of litters containing fetuses with malformations or variations) was performed when more than one group was compared to control. In this case, a Fisher Exact Test with Bonferonni correction was performed to identify differences between the groups.
Indices:
Pre-implantation loss = ((number of corpora lutea - number of implantations) / number of corpora lutea) x 100
Post-implantation loss = ((number of early and late resorptions and dead fetuses) / number of implantation sites) x 100
Historical control data:
Please refer to Table No. 1 under "Any other information on materials and methods incl. tables"

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
During exposure: In the 125 ppm group, the most frequently seen in-chamber observations were lacrimation, labored breathing and closed eyes. These findings were considered treatment-related. Other less frequently seen in-chamber observations in this group included mucoid nasal discharge, salivation, chromodacryorrhea and brown ano-genital staining. The latter observations were observed in a few animals only and not attributed to treatment. There were no remarkable observations at 10 and 65 ppm.
Post-exposure: Yellow (urinary) and/or brown staining of the anogenital area and ventral surface were observed at all treatment levels. The incidence was dose-related and attributed to treatment. Findings were observed in a single low dose (10 ppm) animal (on two occasions), in 7of 24 mid dose (65 ppm) animals and in all 24 high dose (125 ppm) animals. These findings were seen as early as Day 8 of gestation and continued to be seen in several animals to Day 20 of gestation. Severity was generally slight to moderate in all groups. In addition, animals of the high dose group (125 ppm) had red/brown stainings on the face and snout, which was considered to be treatment-related. For details please refer to Table 1 under “Any other information on results incl. tables”.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Dose related decreases in body weight gain were observed during the treatment period (please refer to Tables 2 and 3 under “Any other information on results incl. tables”). At 10 ppm, mean body weight gains over the treatment period (Days 6-16 of gestation) were only slightly lower than body weight gains of the controls (57 vs. 64 g) and the mean body weights at study termination was within 2% of the mean control weights. Mean body weight gain during Days 6-20 of gestation were slightly, but significantly lower than controls (40 vs. 52 g), which was attributed to heavier gravid uterine weight seen in this group when compared to control data.
At 65 ppm, mean body weight gain was significantly decreased during gestation Days 6-16 (55 vs. 64 g), and over the gestation period Day 6-20 (52 vs. 41 g) when compared to control animals. At study termination, the mean body weights for the group were 4% lower than the mean control weight.
At 125 ppm, mean body weight gains from gestation Days 6-9, gestation Days 6-16 and gestation Days 9-20 were significantly reduced when compared to control animals. At study termination, the mean body weight gain was 8% lower than the mean control weight. The findings were considered treatment-related, as a clear dose-response relationship was evident. Findings in the high dose group were considered to be of toxicological significance.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption patterns during gestation in the treated groups were consistent with body weight patterns. Dose-related decreases, relative to control values, occurred for food consumption measured either as total food intake (grams of food/day) or food intake adjusted for body weight (grams of food/kilogram of body weight/day). Statistically significant differences from concurrent control values occurred at a single interval (Days 12-16) for the 10 ppm group, at two intervals (Days 9-12 and 12-16) for the 65 ppm group and at all intervals (Days 6-9, 9-12, 12-16) during the treatment period for the 125 ppm group (please refer to Table 5 under “Any other information on results incl. tables”). The findings in the high dose group were attributed to treatment and considered as toxicologically relevant.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not examined

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
LOAEC
Remarks:
systemic
Effect level:
127.8 ppm (analytical)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
Remarks on result:
other: corresponding to 0.55 mg/L air or 550.1 mg/m3 air
Key result
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
58.3 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: no adverse effect observed
Remarks on result:
other: corresponding to 0.251 mg/L air or 251.0 mg/m3 air
Key result
Dose descriptor:
NOAEC
Remarks:
fertility
Effect level:
127.8 ppm (analytical)
Based on:
test mat.
Basis for effect level:
other: no adverse effect observed
Remarks on result:
other: corresponding to 0.55 mg/L air or 550.1 mg/m3 air

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Remarks:
developmental
Effect level:
127.8 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effect observed
Remarks on result:
other: corresponding to 0.55 mg/L air or 550.1 mg/m3 air

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Clinical findings post exposure (frequency/animals)

Group 1 2 3 4
Concentration (ppm) 0 10 65 125
General Appearance
Necrotic tip of tail 0/0 0/0 0/0 8/1
Dermal findings
Brown stains facial 0/0 0/0 0/0 5/1
Ano-genital stains 9/6 19/9 43/15 164/23
Red stains facial 0/0 5/3 15/9 51/16
Ocular findings
Chromodacryorrhea - unilateral 1/1 1/1 3/2 3/3
Chromodacryorrhea - bilateral 0/0 0/0 0/0 5/2
Lacrimation - unilateral 1/1 0/0 3/1 10/5
Lacrimation - bilateral 0/0 1/1 0/0 22/8
Oral/Buccal findings
Nasal discharge - clear 0/0 0/0 0/0 2/2
Excessive salivation 0/0 0/0 0/0 1/1

Table 2: Mean body weight dams

Group 1 2 3 4
Concentration (ppm) 0 10 65 125
Day
0 211 ± 12.5 212 ± 11.5 209 ± 12.2 210 ± 15.9
4 235 ± 13.5 235 ± 14.5 234 ± 12.5 234 ± 15.9
6 254 ± 16.2 254 ± 14.9 253 ± 14.1 250 ± 17.3
9 268 ± 17.6 266 ± 18.1 264 ± 13.9 250 ± 16.4**
12 289 ± 20.1 281 ± 21.3 279 ± 13.6 265 ± 17.1**
16 319 ± 22.9 311 ± 23.1 308 ± 15.3 290 ± 19.2**
18 349 ± 28.7 338 ± 25.8 334 ± 20.8 319 ± 23.0**
20 381 ± 31.0 373 ± 27.0 367 ± 25.1 349 ± 28.6**

** = p < 0.01

Table 3: Body weight gains

Group 1 2 3 4
Concentration (ppm) 0 10 65 125
Days 0-4 24 ± 4.4 23 ± 8.0 24 ± 5.3 23 ± 6.3
Days 0-6 19 ± 5.6 19 ± 6.7 19 ± 5.9 17 ± 4.9
Days 6-9 14 ± 4.5 13 ± 4.9 11 ± 4.1 0 ± 6.3 **
Days 9-12 20 ± 6.0 14 ± 8.8 15 ± 6.8 15 ± 5.5
Days 12-16 30 ± 10.2 30 ± 10.4 29 ± 9.1 25 ± 8.3
Days 6-16 64 ± 12.6 57 ± 10.4 55 ± 7.0* 40 ± 11.6**
Days 16-20 63 ± 12.5 62 ± 6.6 59 ± 12.7 59 ± 12.6

* = p< 0.05, ** = p< 0.01

Table 4: Net body weight change minus gravid uterine weight at termination  (terminal body weight minus day 6 body weight minus uterine weight)

Control 10 ppm 65 ppm 125 ppm
52 ± 12.7 40 ± 11.4* 41 ± 13.6* 28 ± 9.7**

* = p< 0.05, ** = p< 0.01

Table 5: Mean food consumption

Group 1 2 3 4
Concentration (ppm) 0 10 65 125
Food consumption data in g/animal/day
Days 4-6 23 ± 2.4 23 ± 2.4 23 ± 2.1 22 ± 2.2
Days 6-9 23 ± 2.8 22 ± 2.1 22 ± 1.8 16 ± 2.5**
Days 9-12 25 ± 2.8 23 ± 2.3 22 ± 2.6** 20 ± 2.2**
Days 12-16 26 ± 3.3 23 ± 2.4** 22 ± 2.3** 20 ± 2.6**
Days 16-18 30 ± 4.0 27 ± 4.4 26 ± 4.3 31 ± 16.3
Days 18-20 28 ± 2.9 27 ± 2.0 27 ± 2.6 26 ± 2.8*
Food consumption data in g/kg/day
Days 4-6 99± 8.4 97 ± 9.3 97 ± 7.5 94 ± 7.5
Days 6-9 90 ± 8.8 88 ± 5.4 87 ± 5.7 66 ± 11.0**
Days 9-12 92 ± 7.9 87 ± 6.1 84 ± 8.2** 79 ± 7.8**
Days 12-16 89 ± 8.3 81 ± 8.8* 79 ± 8.3** 75 ± 9.6**
Days 16-18 95 ± 8.2 86 ± 11.9 85 ± 12.8 105 ± 54.0
Days 18-20 81 ± 7.7 80 ± 6.7 81 ± 7.9 80 ± 8.8

Table 6: Fetal body weights

Control 10 ppm 65 ppm 125 ppm
males 4.1 ± 0.22 4.2 ± 0.25 4.4 ± 0.77 4.1 ± 0.40
females 4.0 ± 0.25 4.1 ± 0.20 4.2 ± 0.75 3.9 ± 0.43
litter 4.0 ± 0.21 4.2 ± 0.23 4.3 ± 0.74 4.0 ± 0.40


The concentrations of acrolein in the inhalation chambers for the 4 dose  groups were 0, below detection limit, 1.19 ppm and 2.34 ppm (2.8 and 5.5  mg/m3). Actual concentration of test substance was only between 30 and  50% of nominal, no explanation given by the authors.





Applicant's summary and conclusion

Conclusions:
Maternal toxicity was noted at 127.8 ppm (corresponding to 0.55 mg/L air or 550.1 mg/m3 air), thus a LOAEC for systemic toxicity was derived to be 127.8 ppm (corresponding to 0.55 mg/L air or 550.1 mg/m3 air). The NOAEC for systemic toxicity was 58.3 ppm, corresponding to 0.251 mg/L air or 251.0 mg/m3 air. As the test item showed no adverse effects on fetal development, the NOAEC developmental was derived to be 127.8 ppm (corresponding to 0.55 mg/L air or 550.1 mg/m3 air). No teratogenic effects were observed at any dose level.