3-(methylthio)propionaldehyde

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Short description of key information:
Data on fertility are not available.

Effects on developmental toxicity

Description of key information

Developmental toxicity (similar to OECD 414), rat

NOAEC (systemic maternal toxicity)= 251.0 mg/m3 air, corresponding to 58.3 ppm

NOAEC (developmental toxicity) = 550.1 mg/m3 air, corresponding to 127.8 ppm

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1997-05-12 to 1997-08-18

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

non GLP-study

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Investatigation of maternal and/or developmental toxicity of the test item in the pregnant rat.
- Short description of test conditions: The study was designed as range-finder. The test item was administered via whole body inhalation 6 h/day during Days 6-15 of gestation. Groups of 6 females were exposed to test item concentrations of 1, 5, 25 and 100 ppm, coresponding to 4.3, 21.5, 107.6 and 430.5 mg/m3 air.
- Parameters analysed / observed: clinical signs, mortality, body weights, food consumption and post-mortem investigations including gravid uterine weights and corpora lutea/uterine content implantation data, fetal weights, fetal sex and fetal gross external examinations.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: CD (Sprague-Dawley derived)

Remarks:

Albino, outbred, VAF/Plus

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, New York, USA
- Age at mating: 64 - 85 days
- Weight at study initiation: 208 - 239 g (mean: 226 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 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23
- Humidity (%): 48 - 80
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 31 Jul 1997 To: 18 Aug 1997

Route of administration:

inhalation: vapour

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:

All females were mated on receipt.

Duration of treatment / exposure:

6 h

Frequency of treatment:

6 h/day on Days 6-15 of gestation

Duration of test:

Gestation Days 6 - 20

Dose / conc.:

1 ppm (nominal)

Remarks:

corresponding to 0.0043 mg/L air or 4.3 mg/m3 air (corresponding to an analytical concentration of 1.29 ± 0.34 ppm, 0.0056 mg/L air or 5.6 mg/m3 air)

Dose / conc.:

5 ppm (nominal)

Remarks:

corresponding to 0.0215 mg/L air or 21.5 mg/m3 air (corresponding to an analytical concentration of 4.14 ± 0.61 ppm, 0.0178 mg/L air or 17.8 mg/m3 air)

Dose / conc.:

25 ppm (nominal)

Remarks:

corresponding to 0.108mg/L air or 107.6 mg/m3 air (corresponding to an analytical concentration of 25.5 ± 5.7 ppm, 0.11 mg/L air or 109.8 mg/m3 air)

Dose / conc.:

100 ppm (nominal)

Remarks:

corresponding to 0.431 mg/L air or 430.5 mg/m3 air (corresponding to an analytical concentration of 114 ± 25 ppm, 0.491 mg/L air or 490.7 mg/m3 air)

No. of animals per sex per dose:

6

Control animals:

yes, concurrent vehicle

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- 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: On Days 4, daily on study Days 6 - 15 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: No
- Skeletal examinations: No
- Head examinations: No

Statistics:

Means and standard deviations were calculated for maternal body weight, weight change, food consumption, uterine implantation data and fetal weight data but no additional statistical evaluations were performed due to the small group sizes.

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"

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No clinical findings were seen during the detailed physical examinations of animals in the 1, 5 and 25 ppm treated groups throughout the gestation period. In the 100 ppm group, several females were noted with yellow staining of the skin/fur on the ventral surface or ano-genital area. This finding was first seen late into the treatment period on days 14 and/or 15 of gestation and it continued to be seen throughout the remainder of gestation to day 20. Other findings seen in the 100 ppm group included the presence of a red exudate, chromodacryorrhea and alopecia. The only finding seen in the control group was yellow staining of the skin/fur in the ano-genital area. This was seen in one animal on day 11 of gestation.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Mean body weights and mean body weight gain data during gestation were similar between the control group and the groups treated with MMP at exposure levels of 1, 5 and 25 ppm. No adverse effect of treatment on gestation body weight data was indicated at these exposure levels. In the 100 ppm group, mean body weights during gestation were similar to or slightly higher than control but mean weight gain was slightly lower than control for Days 6-9 of gestation (6 vs. 9 grams for control) and over the entire Day 6-16 treatment period (49 vs. 54 grams for control). The effect was considered treatment-related but non-adverse. For all other intervals during gestation, body weight gain data for the 100 ppm group were considered similar to control data. Mean body weight gains over Days 6-20 of gestation using the actual and corrected Day 20 gestation weights were similar between the control and all treated groups.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Mean food consumption data during gestation were similar between the control group and the groups treated at exposure levels of 1, 5 and 25 ppm. In the 100 ppm dose group, a slight reduction in food consumption was seen over Days 6-9 of gestation and this was most apparent when food consumption was expressed relative to body weight (grams feed consumed/kg body weight/day). The effect was considered toxicologically not relevant, as the difference was of small magnitude and statistically not significant. For the remainder of gestation, food consumption data for the 100 ppm group were considered comparable to control data and unaffected by treatment.

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:

effects observed, non-treatment-related

Description (incidence and severity):

An enlarged spleen was seen in one female in the 5 ppm group but in the absence of similar findings in females from the 25 and 100 ppm groups, this was not considered treatment-related.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

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

Key result

Dose descriptor:

NOAEC

Remarks:

systemic

Effect level:

100 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effect observed

Remarks on result:

other: corresponding to 0.431 mg/L air or 430.5 mg/m3 air

Key result

Dose descriptor:

NOAEC

Remarks:

fertility

Effect level:

100 ppm (nominal)

Based on:

test mat.

Basis for effect level:

other: no adverse effect observed

Remarks on result:

other: corresponding to 0.431 mg/L air or 430.5 mg/m3 air

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Mean fetal weights, distinguished by sex and for both sexes combined, were similar to control data in the 1, 5 and 25 ppm dose groups. At the 100 ppm exposure level, the mean weight of male fetuses was about 11% reduced when compared to control and the mean fetal weight of combined sexes was about 7% lower than control. The observation was considered treatment-related but not toxicologically relevant, due to the small magnitude in mean body weight gain reduction. The mean fetal weight of females was comparable to the control group.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

effects observed, non-treatment-related

Description (incidence and severity):

The mean percentages of male and female fetuses per litter were similar to control in the groups treated at exposure levels of 1, 5 and 25 ppm. In the 100 ppm group, there was a slight increase in male fetuses (61.8% vs. 53.5% in controls) but this was not considered to represent a treatment-related response.

Changes in litter size and weights:

not examined

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

External malformations comprised one fetus (from 83 fetuses in 7 litters) in the 1 ppm group with two additional pairs of limbs and a cranial defect and one edemaous fetus (from 75 fetuses in 6 litters) at 100 ppm. Generalized edema has not been seen in recent historical control data for this laboratory but was reported to have a low incidence of occurence in this strain. The findings were considered to be incidental.

Skeletal malformations:

not examined

Visceral malformations:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEC

Remarks:

developmental

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect observed

Remarks on result:

other: corresponding to 0.431 mg/L air or 430.5 mg/m3 air

Key result

Abnormalities:

no effects observed

Conclusions:

Based on the experimental findings, the test item did not induce maternal toxicity and had no adverse effect on fetal development. The NOAEC for systemic toxicity, the NOAEC for fertility and the NOAEC for developmental toxicity were 100 ppm, corresponding to 0.431 mg/L air or 430.5 mg/m3 air. No teratogenic effects were observed at any dose level.

Reference 2

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

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

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

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

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.

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"

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

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

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

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

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

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

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.

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

550.1 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 1) data.

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Two inhalation developmental toxicity studies are available investigating the test items potential for induction of prenatal developmental toxicity and teratogenic effects. 

In a key study conducted according to EPA OPPTS 870.3600, similar to OECD guideline 414 and compliant with GLP, the test item was administered as a vapour in the breathing air of the animals and applied via whole body inhalation (99-0190-DGR). Groups of 24 pregnant female CD rats were exposed for 6 h/day during gestation Days 6 – 16 at test item concentrations of 10, 60 and 125 ppm (nominal concentration), corresponding to 42.5, 251.0 and 550.1 mg/m³. A similar constituted group of females was treated with control air.

During exposure, all animals were observed for their appearance, activity and unusual findings. Afterwards, the animals were observed twice daily for mortality, general appearance and clinical signs of toxicity. Individual body weights were recorded prior to treatment and on Days 4, 6, 9, 12, 16, 18 and 20 of gestation. Food consumption was monitored for gestation Days 4-6, 6-9, 9-12, 12-16, 16-18, and 18-20. At study termination on gestation Day 20, the uteri and ovaries of each rat were dissected and examined for the following parameters: gravid uterus weight, number of corpora lutea, number of implantations, number of early and late resorptions and number of live and dead fetuses. The fetuses were further examined for external, visceral (half per litter) and skeletal abnormalities (half per litter). The measured analytical concentration was 9.87, 58.3 and 127.8 ppm.

During exposure, the most frequent clinical signs were lacrimation, labored breathing and closed eyes. The findings were observed predominantly in the 127.8 ppm group and considered treatment-related.

After exposure, yellow (urinary) staining and/or brown staining of the anogenital area and ventral surface was observed at all treatment levels. The incidence was dose-related and attributed to treatment. Findings were observed in a single low dose (9.87 ppm) animal, in 7/24 mid dose (58.3 ppm) animals and in all 24 high dose (127.8 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. The severity was generally slight to moderate in all groups. In addition, animals of the high dose group (127.8 ppm) had red/brown staining on the face and snout, which was considered to be treatment-related.

Dose related decreases in body weight gain were observed during the treatment period. At 9.87 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 58.3 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. In the high dose group (127.8 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 in the high dose group were considered treatment-related, as a clear dose-response relationship was evident.

Consistent with the body weight patterns, food consumption was decreased during gestation in test item-treated groups. 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 9.87 ppm group, at two intervals (Days 9-12 and 12-16) for the 58.3 ppm group and at all intervals (Days 6-9, 9-12, 12-16) during the treatment period for the 127.8 ppm group The findings in the high dose group were attributed to treatment and considered as toxicologically relevant.

There were no adverse effects on maternal developmental toxicity. Up to the highest dose level of 127.8 ppm, pregnancy rates, uterine and implantation data were not affected by treatment. The mean number of corpora lutea, uterine implants, live fetuses and resorption sites per female were comparable to those of control animals. In addition, pre- and post-implantation losses were not affected by treatment.

Examination of the fetuses revealed no adverse findings. Mean fetal weights and sex ratio were not affected by treatment and there were no external, skeletal or visceral malformations observed.

Under the conditions of the study, the no -observed-adverse effect concentration (NOAEC) was 127.8 ppm for maternal fertility as well as developmental toxicity, corresponding to 550.1 mg/m³air. The NOAEC for systemic maternal toxicity was 58.3 ppm, corresponding to 251.0 mg/m3 air.

The results were confirmed in a second developmental toxicity study (98-0292-DGR), in which the test item was administered via whole body inhalation at concentrations of 1, 5, 25 and 100 ppm (nominal concentration), corresponding to 5.6, 17.8, 109.8 and 490.7 mg/m³air. There were no adverse effects of toxicological relevance observed up to and including the highest dose level. The NOAEC was 100 ppm for fertility and developmental toxicity, corresponding to 490.7 mg/m³air.

Justification for classification or non-classification

The available data on developmental toxicity do not meet the criteria for classification according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

In addition, the available data on developmental toxicity do not meet the criteria for classification according to the criteria of the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations.