3-dimethylaminopropan-1-ol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproduction toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE) is a structural analogue of dimethylaminopropanol and was used as read-across (CAS 108-01-0). To assess possible effects on fertility after exposure to dimethylpropanolamine the subchronic inhalative study with DMAE [Klone et al., 1987] was used (see also IUCLID chapter 7.5.2) in combination with the results of a modified developmental toxicity screening test (OECD 414, amended; OECD 421-postnatal part).
Repeated dose toxicity (vapour inhalation): Dimethylethanolamine: Acute, 2-week and 13-week Inhalation Toxicity Studies in Rats. Comparable to the OECD guideline 413 with concentrations tested of 8, 24 and 76 ppm (equivalent to 36, 108 and 325 mg/m³). The NOEC for local effects was 108 mg/m³ and the NOAEC for systemic effects was found to be greater than 325 mg/m³ (highest dose tested). [Klonne et al., 1987]
Modified developmental toxicity screening test: Dimethylethanolamine: The Modified Developmental Toxicity Screening Study in Wistar Rats with N,N-Dimethylaminoethanol. Comparable to the OECD Guideline 414 with dosages tested of 300 and 600 mg/kg bw. A NOAEL was not derivable. [BASF, 2008]

Link to relevant study records

Reference

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

not reported, published 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD TG 413

GLP compliance:

no

Limit test:

no

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: approx. 9 weeks old.
- Weight at study initiation: 180 g for males and 130 g females
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum): Purina Certified Rodent Chow 5002, Ralston Purina Co., St. Louis, MO ad libitum except during exposures
- Water (e.g. ad libitum): yes, except during exposures
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4320-liter stainless-steel and glass chambers
- Method of holding animals in test chamber: not reported
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: DMEA vapor was generated by metering the liquid into a heated, spiral-grooved evaporator with a countercurrent airstream, similar in design to the one used by Carpenter et al. (1975).
- Temperature, humidity, pressure in air chamber: 25°C and 46%,
- Air flow rate: 800-1000 liters/min
- Air change rate: not reported
- Method of particle size determination: not reported
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: The CC column was a 5 ft X 1/4 in stainless-steel column packed with 20% SP-2100 on 80/ 100 mesh Supelcoport (Supelco, BeIlefonte, PA), maintained at 200°C.
- Samples taken from breathing zone: yes

VEHICLE (if applicable) no

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations of DMEA were analyzed at approximately 40-min intervals with a Perkin-Elmer 3920B gas chromatograph (CC) equipped with a flame ionization detector. Chamber atmosphere samples were automatically injected into the GC with the use of a Perkin-Elmer environmental sampler.

Duration of treatment / exposure:

13 wk

Frequency of treatment:

6h/d, 5d/wk

Remarks:

Doses / Concentrations:
8, 24, 76 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

20

Control animals:

yes

Details on study design:

10 male rats were assigned to the control, middle and high concentration groups for possible ultrastructural evaluation of nerve tissue (not performed since no behavioral abnormalities or light microscopic lesions of nerve tissue were observed).

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): randomized
- Rationale for selecting satellite groups: to investigate recovery of effects of treatment
- Post-exposure recovery period in satellite groups: 5 week

One-half of all rats per sex per group were sacrificed after at least 2 days of exposure during the 14th week of the study; the remaining rats were sacrificed after 5 complete weeks of recovery.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked in table [No.3] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: were measured during the 16-hr urine collection period.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: were measured during the 16-hr urine collection period.


OPHTHALMOSCOPIC EXAMINATION: Yes, (evaluation of the eye with a light source and
magnifying lens)
- Time schedule for examinations: not reported
- Dose groups that were examined: not reported

HAEMATOLOGY: Yes
- Time schedule for collection of blood: made the morning following the last DMEA exposure day (except for recovery animals).
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: No
- How many animals: not reported
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: made the morning following the last DMEA exposure day (except for recovery animals).
- Animals fasted: No
- How many animals: not reported
- Parameters checked in table [No.2] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine:during a 16-hr period prior to sacrifice from rats held in polycarbonate metabolism cages
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters examined: Semiquantitative measurements on urine: included pH, protein, bilirubin, urobilinogen, glucose, ketones, and blood. In addition, osmolality determinations (Cryomatic osmometer, Advanced Instruments, Inc., Needham Heights, MA) and microscopic evaluations of the urine sediment were performed.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: not reported
- Dose groups that were examined: not reported
- Battery of functions tested: sensory activity / grip strength / motor activity / other: see Table 3

OTHER: Organ weight determinations, gross pathologic examination, and blood and urine sample collections were made the morning following
the last DMEA exposure day (except for recovery animals).

Postmortem examinations (parental animals):

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 4). Additional histopathologic examinations were performed on rats from the control and high exposure groups, with nasal turbinates also being evaluated for the middle exposure group rats.

Organ weights: brain, kidney, liver, lungs, testes, and adrenals.

Statistics:

Results of quantitative continuous variables were intercompared among the DMEA concentration levels and the control group by Bartlett’s homogeneity of variance (Sokal and Rohlf, 1969), analysis of variance (ANOVA), and Duncan’s multiple range test (Snedecor and Cochran, 1967). Duncan’s test was used when a significant F value from an ANOVA was observed. For heterogeneous group variances, the groups were compared by ANOVA for unequal variances (Brown and Forsythe, 1974) and either Student’s t test or Cochran’s t test (Snedecor and Cochran, 1967) was used. Corrected Bonferroni probabilities were used for t test comparisons (Miller, 1966). The fiducial limit of 0.05 (two-tailed) was used as the critical level of significance for all comparisons. For the calculation of the LC50, the method of Finney (1964) was used.

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

returned to control during the recovery period

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

returned to control during the recovery period

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

nasal lesions

CLINICAL SIGNS AND MORTALITY
No animals died during the study.

BODY WEIGHT AND WEIGHT GAIN

The body weight gains for both sexes of the 76 ppm group were statistically significantlly lower than control values for most of the latter half of the 13 week exposure regimen (Table 5). The body weight gain valuesfor the 76 ppm group returned to control values during the recovery period. There were no exposure-related alterations of body weight gain for rats exposed to 8 or 24 ppm of DMEA.

OPHTHALMOSCOPIC EXAMINATION
Corneal opacity occurred in the 24 and 76ppm groups at the end of the daily exposure, beginning approximately 2-3 weeks after initiation of exposures. The opacity regressed during the night-time nonexposure hours. There was also a moderate incidence (approximately 25%) of audible respiration in rats of the 76 ppm group.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no exposure related effects on the neurobehavioral, food and water consumption, hematologic, serum chemistry, or urinalysis evaluations, on organ weights, or on the gross appearance of organs. Exposure related nasal lesions were observed histologically at the termination of exposures in both sexes of the 76 ppm group, but were generally not observed in rats of the 24 ppm group. The lesions were limited to the anterior nasal cavity and included squamous metaplasia, microcysts (cystic intraepithelial glands) mucous cell hyperplasia of the respiratory epithelium, mild rhinitis, and atrosoluphy of the dorsal olfactory epithelium. The incidence and severity of these lesions were decreased at the end of the recovery period, indicating some degree of repair. Additionally, 4/10 males had laryngitis and two of these rats also had tracheitis. No similar lesions were found in female rats. Vacuolization of the corneal epithelium was observed in 3/10 female rats of the 76 ppm group at the termination of exposures but not at the end of the recovery period.

Dose descriptor:

NOEC

Effect level:

24 ppm (analytical)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Reproductive effects observed:

not specified

TABLE 5

Body Weight Gain for F-344 Rats Exposed to DMEA Vapor for 13 Weeks and Maintained for a 5-Week Recovery Period^a
Interval (weeks)	Mean exposure concentration (ppm)
	0	8	24	76
	Males
8^b	108 ± 12.2	112 ± 8.6	113 ± 11.1	102 ± 8.0*
14^c	154 ± 11.5	157 ± 9.9	157 ± 10.2	147 ± 10.6*
19^d	167 ± 16.7	166 ± 7.1	172 ± 13.2	169 ± 9.2
	Females
8	54 ± 4.7	53 ± 5.9	51 ± 5.0	49 ± 6.8**
14	73 ± 5.4	70 ± 5.8	70 ± 6.3	64 ± 6.6**
19	76 ± 6.8	73 ± 7.7	71 ± 5.1	71 ± 4.0
^aValues represent mean ± SD. ^bWeek 8 was the first week that a consistent statistically significant depression in body weight gain was observed for both sexes of the 76 ppm group. ^cFinal weight gain value obtained after two or three exposures during Week 14. ^dEnd of 5-week postexposure recovery period. * p<0.05 from controls. ** p <0.01 from controls.

TABLE 6
Incidence of Selected Nasal Tissue Histopathologic Lesions in F-344 Rats Exposed to DMEA Vapor for 2 or 13 Weeks and Sacrificed the Day after the Final Exposure
	2-week study^a						13-week study^b
	Males			Females			Males			Females
DMEA concentration (ppm):	0	98	288	0	98	288	0	24	76	0	24	76
Total No. examined	10	10	7	10	10	10	10	10	10	10	10	10
Unremarkable	10	1	0	9^c	5	0	9^d	8	0	9^d	8	1
Rhinitis	0	5	6	0	5	7	0	2	0	0	2	7
Squamous metaplasia	0	8	7	0	2	10	0	0	9	0	0	4
Epithelial erosion	0	1	4	0	0	0	0	0	0	0	0	0
Mucosal ulceration	0	4	6	0	2	8	0	0	0	0	0	0
Degeneration of olfactory mucosa/epithelium	0	0	1	0	0	9	0	0	0	0	0	0
Degeneration of respiratory epithelium	0	0	0	0	0	4	0	0	8	0	0	7
Atrophy of olfactory epithelium	0	0	0	0	0	0	0	0	10	0	0	3
Microcysts in respiratory epithelium	0	0	0	0	0	0	0	0	10	0	0	3
^aAll animals of the 586 ppm group died on study and were not histologically evaluated. Incidence values in the table also do not include those four male rats of the 288 ppm group which died on study. ^bRats of the 8 ppm group were not histologically evaluated as only minimal rhinitis was observed in 2 rats/sex of the 24 ppm group. ^cOne control had a hemorrhage in the nasolacrimal duct. ^dOne control had minimal mineralization of the olfactory epithelium

Conclusions:

DMAE acts primarily as an ocular and upper respiratory tract irritant. 24 ppm is the NOEC for local and 76 ppm for systemic effects.

Executive summary:

In the 13-week sub-chronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks. The principal exposure-related changes were transient corneal opacity in the 24 and 76 ppm groups; decreased body weight gain for the 76 ppm group; and histopathologic lesions of the respiratory and olfactory epithelium of the anterior nasal cavity of the 76 ppm group and of the eye of several 76 ppm group females. Rats maintained for a 5-week recovery period only exhibited histological lesions of the nasal tissue, with the lesions being decreased in incidence and severity. The body weight gain values for the 76 ppm group returned to control values during the recovery period, why this effect was not considered advers. DMEA acts primarily as an ocular and upper respiratory tract irritant and toxicant at vapor concentrations of 76 ppm, while 24 ppm or less produced no biologically significant local toxicity in rats. Thus, 24 ppm was considered to be the no-observable-effect concentration (NOEC) for local effects and the NOAEC for systemic effects was greater than 76 ppm.

To conclude, despite local effect on the respiratory system, no histopathological changes in the testes were observed after repeated exposure to DMAE in a 90-day inhalation study in rats.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

325 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Justification for selection of Effect on fertility via inhalation route: NOAEC was calculated using the following equation: c [mg/m3] = (c [ppm] x molecular weight) : 24.1 with molecular weight = 103.16 g/mol (dimethylaminopropanol)

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproduction toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used as read-across.

 

There is sufficient information on effects of DMAE on reproductive performance and fertility available from repeated dose toxicity and developmental studies (refer to IUCLID chapter 7.5.2 or 7.8.1).

REACH allows the assessment of the reproductive toxicity of a given chemical with the help of findings from studies with repeated administration. This is in line with the idea that the information requirements under REACH are regarded as the evaluation of endpoints which does not necessarily require data from specific studies. Because of a high correlation, histopathology data and organ weights from repeated dose studies may be used to assess male fertility (Mangelsdorf, 2003). These parameters, taken from 90-day studies, were in fact shown to be more sensitive than fertility parameters that were measured during multi-generation studies. It could also be shown that exposure for four weeks suffices for an assessment of male fertility, although 90-day studies have been regarded as superior in the past because they cover a complete cycle of spermatogenesis (Mangelsdorf, 2003). If such a 28-day study shows neither relevantly elevated testis or ovary weights nor histopathological alterations in those organs, the weight of the evidence is that effects on reproduction are also not expected (BAuA Forschungsbericht Fb 984, 2003). A comparison of more than one hundred 90-day studies with two-generation studies that used the same test substance additionally showed that the NOAELs differed by less than the variation limit of studies, i.e. a factor of two (Janer, 2007). Therefore, the information gained from a reproduction toxicity screening study according to OECD 421/422 can be regarded as minimal if a 90-day study has been performed.

 

References

- BAuA (2003). Extrapolation from results of animal studies to humans for the endpoint male fertility.Forschungsbericht Fb 984.

- Janer G, Piersma, AH, Vermeire T, Slob W (2007).A retrospective analysis of the added value of the rat two-generation reproductive toxicity study versus the rat subchronic toxicity study. Reproductive Toxicol 24: 103-113.

- Mangelsdorf I, Buschmann J, Orthen B (2003). Some aspects relating to the evaluation of the effects of chemicals on male fertility. Reg Toxicol Pharmacol 37: 356-369.

 

In the 13-week sub-chronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks (Klonne et al., 1987). No animals died during the study. The body weight gains for both sexes of the 76 ppm group were significantly lower than control values for most of the latter half of the 13-week exposure time. The body weight gain values for the 76 ppm group returned to control values during the recovery period. There were no exposure-related body weight gain effects for rats exposed to 8 or 24 ppm of DMEA. There were no exposure-related effects on the neurobehavioral, food and water consumption, hematologic, serum chemistry, or urinalysis evaluations, on organ weights, or on the gross appearance of organs. Exposure-related nasal lesions were observed histologically at the termination of exposures in both sexes of the 76 ppm group, but were generally not observed in rats of the 24 ppm group. The lesions were limited to the anterior nasal cavity and included squamous metaplasia, microcysts and mucous cell hyperplasia of the respiratory epithelium, mild rhinitis and atrophy of the dorsal olfactory epithelium. The incidence and severity of these lesions were decreased at the end of the recovery period, indicating some degree of repair. Additionally, 4/10 males had laryngitis and two of these rats also had tracheitis. No similar lesions were found in female rats. Vacuolization of the corneal epithelium was observed in 3/10 female rats of the 76 ppm group at the termination of exposures but not at the end of the recovery period. Corneal opacity occurred in the 24 and 76 ppm groups at the end of the daily exposure, beginning approximately 2-3 weeks after initiation of exposures. The opacity regressed during the night-time nonexposure hours. There was also a moderate incidence (approximately 25%) of audible respiration in rats of the 76 ppm group.

Thus, 24 ppm was considered to be the no-observable-effect concentration (NOEC) for local effects and the NOAEC for systemic effects was greater than 76 ppm. To conclude, despite local effect on the respiratory system, no histopathological changes in the testes were observed after repeated exposure to DMAE in a 90-day inhalation study in rats.

 

In the Modified Developmental Toxicity Screening Study in Wistar rats with DMAE (BASF, 2008), the test material was administered to time-pregnant female rats orally by gavage from gestation day (GD) 6 through GD 19 (prenatal study part) or GD 6 through postnatal day (PND) 3 (postnatal study part) at dose levels 300 and 600 mg/kg bw/day. In the prenatal part of study, the clinical signs by dams included salivation, respiratory sounds, statistically significant reduced food consumption as well as reduced mean body weight and body weight change. One animal was found dead and another was sacrificed moribund on GD 14. Gross pathology revealed increased liver weight compared to the control group (100%) and post-implantation loss compared to the control group and the historical control data (11.8% vs. 5.2% in control). In 8 out of 10 animals, stomach erosion/ulcera were observed. No substance related findings were observed in fetuses. Viability of pups was affected more severe (see below). In the postnatal part of study, 7 animals out of 8 delivered their pups. Live birth index was 91% (control 100%). The stomach erosion/ulcera were also the common observation. In the 300 mg/kg bw dose group, post implantation losses and increased resorption occured in the range of strong ulcera in the stomach. No test substance-related findings in fetuses and pups were observed.

Effects on developmental toxicity

Description of key information

No developmental toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE) is a structural analogue of dimethylaminopropanol and was used as read-across (CAS 108-01-0).
Modified developmental toxicity screening test: Dimethylethanolamine: The Modified Developmental Toxicity Screening Study in Wistar Rats with N,N-Dimethylaminoethanol. Comparable to the OECD Guideline 414 with dosages tested of 300 and 600 mg/kg bw. A NOAEL was not derivable. [BASF, 2008]
Developmental Toxicity Study (vapour inhalation): Developmental Toxicity Study in Fischer 344 Rats by Whole-body Exposure to N,N-Dimethylethanolamine Vapor. Comparable to the OECD Guideline 414 with concentrations tested of 10, 30 and 100 ppm. The NOAEC was at or above 100 ppm for embryofetal toxicity and teratogenicity. [Leung et al., 1996] 

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not reported, published in 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no data on GLP or OECD compliance. Acceptable, well ducumented publication which meets basic scientific principles.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Fischer 344

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley, Inc., Indianapolis, IN.
- Age at study initiation: 67-79 days old on arrival
- Weight at study initiation: not reported
- Fasting period before study: no
- Housing: in stainless-steel wire-meshcages
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not reported
- Humidity (%): not reported
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light):12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Liquid DMEA was metered from a piston pump into a heated glass maintained at the lowest temperature to vaporize the liquid. The resultant vapor
was carried into the exposure chamber by a countercurrent flow of conditioned air through the evaporator. Exposure was conducted in 4320-litre stainless-steel and glass chambers at an airflow of 1000 L/min.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber atmosphere was analyzed for DMEA concentrations once every 32 min during each 6-h exposure, using a Perkin-Elmer 3920B gas chromatograph equipped with a flame ionization detector. Nominal concentrations were calculated daily based on the amount of DMEA used and the chamber tube air flow during the exposure period.

Details on mating procedure:

- Impregnation procedure:[cohoused]
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: not reported

- Further matings after two unsuccessful attempts: [no]
- Verification of same strain and source of both sexes: [yes / no (explain)]
- Proof of pregnancy: [vaginal plug] referred to as [day 0] of pregnancy
- Any other deviations from standard protocol:

Duration of treatment / exposure:

6 h per day

Frequency of treatment:

each day

Duration of test:

on gestational days 6-15

Remarks:

Doses / Concentrations:
0, 10, 30 and 100 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

In a range-finding study, eight plug-positive females each were assigned to four DMEA-exposed groups (target DMEA concentrations
8, 25, 75 and l00ppm) and an air-exposed control group.
In the definitive study, 25 plug-positive females each were assigned to three DMEA-exposed groups and a control group.

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: Based on the results of the range-finding study.
The highest exposure concentration in the range-finding study, I00 ppm, was retained in the definitive study since it produced maternal toxicity (reduced body weights and weight gain, and clinical signs) and possible embryotoxicity (increased preimplantation loss) but no apparent fetotoxicity. The middle exposure concentration of 30ppm chosen for the definitive study was slightly above the 25 ppm in the range-finding study which produced maternal toxicity (transient weight gain depression and clinical signs limited to the eyes) and possible embryotoxicity (reduced implantations,
increased preimplantation loss and reduced number of viable fetuses per litter). The lowest exposure concentration, I0 ppm, was chosen as essentially the same as the 8 ppm in the range-finding study which produced no effects on maternal weights and only transient ocular changes and no evidence of embryofetal toxicity.
- Rationale for animal assignment (if not random):randomized

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes - Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: daily
BODY WEIGHT: Yes - Time schedule for examinations:Maternal body weights were measured on gd 0, 6, 12, 15, 18 and 21.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: The gravid uterus, ovaries (including corpora lutea), cervix, vagina and peritoneal and thoracic cavities were examined grossly. Ovarian corpora lutea of pregnancy were counted. Maternal liver and uterine weights were measured.

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: Uteri were examined externally for signs of hemorrhage. All live and dead fetuses were recorded

Fetal examinations:

- External examinations: Yes: [all per litter] including cleft palate
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter]

Statistics:

The unit of comparison was the pregnant female or the litler. Continuous quantitative data were compared between the DMEA-exposed groups and air-exposed control group by the use of Levene's test for equal variances 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 unequal variances," followed by the separate variance t-test when necessary. Non-parametric data obtained following laparohysterectomy were statistically treated using the Kruskal- Wallis test followed by the Mann-Whitney U test when appropriate. Incidence data were compared using Fisher's exact test. For all statistical tests, the fiducial limit of 0.05 (two-tailed) was used as the criterion for significance.

Indices:

listed in the table 4 in "Remarks on results"

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Table 2 (in "Remarks on results") shows the pregnancy and litter data of all plug-positive females on study. There were no maternal deaths or abortions. Pregnancy rate ranged from 88 to 96% and all pregnant females had one or more live fetuses at scheduled sacrifice, except one dam at 100 ppm, which had a totally resorbed litter. Reduced body weight and reduced body weight gain were observed at 100 ppm. Body weight reduced on gd 12 and 15 (during the exposure period) and on gd 15 and 21 (postexposure period). Body weight gain was reduced for all intervals except gd 6- 9 (pre-exposure) and gd 15-2 1 (post-exposure). There were no effects on body weight or body weight gain for the 10 or 30ppm groups. Clinical examination showed that dams at 100 ppm only exhibited perinasal fur discoloration, presumably from chromodacryorrhea. At 30 and l00ppm there were darkened (maroon), cloudy and hazy eyes, slight corneal vascularization and pupils dilated and fixed. Cloudy and hazy eyes were observed only during the exposure period. Darkened eyes were also observed at 10ppm during the exposure period. There were no statistically significant differences in gravid uterine weight and absolute or relative liver weights between the DMEA-exposed groups and the controls.

Dose descriptor:

NOAEL

Effect level:

10 ppm (nominal)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The present developmental toxicity evaluation revealed no treatment-related embryotoxicity at any exposure concentration employed. No consistent pattern of fetotoxicity was observed. Fetal body weights were elevated at l00ppm relative to those in controls (Table 3), and only one skeletal district, the cervical centra, exhibited evidence of reduced ossification at 100 ppm (Table 4), an exposure concentration which also produced maternal toxicity. This finding is the only one which could be consistent with indicating possible minimal fetotoxicity; however, there were no other indications of fetotoxicity, such as reduced fetal body weight. No other skeletal districts, of the number identified as sensitive indicators of delayed development in rat fetuses,” exhibited a delay in ossification. No increases in malformations were observed at any concentration of DMEA employed, including those which produced maternal toxicity.

Dose descriptor:

NOAEL

Effect level:

>= 100 ppm (nominal)

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Abnormalities:

not specified

Developmental effects observed:

not specified

Table 2. Pregnancy and litter data for Fischer 344 rats exposed whole body toN,N-dimethylethanolamine vapor
Exposure concentration (ppm)	0	10	30	100
Number in study	25	25	25	25
Number of early delivery	1	0	0	0
Number aborted	0	0	0	0
Number (%) pregnant at scheduled	22	23	22	24
sacrifice	(91.7)	(92.0)	(88.0)	(96.0)
Number of litters examined	22	23	22	23^a
^aOne dam carried a totally resorbed litter.

Table 3. Gestational parameters and fetal body weights in Fischer 344 rats exposed whole body toN,N-dimethylethanolamine vapor*
Exposure conc. (ppm)	0	10	30	100
Number of dams	22	23	22	24
Corpora lutea/dam	11.4 ± 1.2	11.1 ± 1.2^b	11.3 ± 1.1	11.8 ± 1.2
Total implants/litter	9.6 ± 1.7	7.9 ± 3.0	8.6 ± 3.3	8.5 ± 3.0
Preimplantation loss (%)	15.5 ± 14.6	26.9 ± 25.4^b	25.9 ± 26.8	28.1 ± 24.3
Viable implants/litter	9.5 ± 1.7	7.6 ± 3.1*	8.5 ± 3.4	8.0 ± 3.3
Non-viable implants/litter	0.0 ± 0.2	0.3 ± 0.6	0.1 ± 0.4	0.5 ± 1.5
Early resorptions	0.0 ± 0.0	0.2 ± 0.5	0.0 ± 0.2	0.4 ± 1.4
Late resorptions	0.0 ± 0.2	0.1 ± 0.3	0.1 ± 0.3	0.0 ± 0.0
Dead fetuses	0.0 ± 0.0	0.0 ± 0.2	0.0 ± 0.0	0.0 ± 0.2
Live fetuses/litter (%/litter)	99.5 ± 2.4	95.6 ± 9.0*	97.9 ± 6.1	94.4 ± 20.6
Sex ratio (% males)	56.0 ± 16.0	60.0 ± 21.0	41.6 ± 18.4*	49.0 ± 16.9^c
Live litter size	9.5 ± 1.7	7.6 ± 3.1*	8.5 ± 3.4	8.4 ± 2.9^c
Fetal body weight/litter (g)
All fetuses	4.47 ± 0.15	4.56 ± 0.26	4.53 ± 0.24	4.66 ± 0.27^c
Male fetuses	4.63 ± 0.16	4.67 ± 0.24	4.61 ± 0.26^d	4.82 ± 0.26*^c
Female fetuses	4.28 ± 0.13	4.38 ± 0.26^e	4.43 ± 0.26	4.52 ± 0.30**^c
^aValues presented as mean ± standard deviations; *p < 0.05 and **p < 0.01 versus control. ^bn = 22 because the corpora lutea count from one dam was inadvertently not recorded. ^cn = 23 because one dam carried a totally resorbed litter. ^dn = 20 because two litters consisted of only female fetuses. ^en = 22 because one litter consisted of only male fetuses.

Table 4. Skeletal variations in the fetuses of Fischer 344 rats exposed whole body toN,N-dimethylethanolamine vapor
	Fetuses				Litters
Exposure concentration (ppm)	0	10	30	100	0	10	30	100
Number examined skeletally	102	82	89	91	22	23	20	23
Cervical centrum 6 poorly ossified	43	46	48	33	22	21	18	15**
Cervical centra 1, 2, 3 and/or 4 split	3	2	6	13	3	2	5	12*
Thoracic centrum 1 bilobed	8	14	15	11	6	14*	12	10
Thoracic centrum 9 bilobed	14	5	6	6	12	5*	6	6
Some proximal phalanges (forelimb) unossified	7	0	5	5	6	0*	5	5
Sternebra 5 bilobed	16	10	6	14	12	5*	5	11
*p < 0.05 and **p < 0.01 versus control.

Conclusions:

In summary, whole-body exposure to DMEA vapor of timed-pregnant Fischer 344 rats during organogenesis at 0, 10, 30 or l00 ppm resulted in maternal toxicity at 30 and 100 ppm (with transient minor ocular changes at 10ppm). There was no evidence of embryonic or fetal toxicity, including teratogenicity, at any exposure concentration employed. Therefore, the no-observed-adverse-effect level is around 10 ppm for maternal toxicity and ≥ 100 ppm for embryofetal toxicity and teratogenicity in this study.

Executive summary:

Timed-pregnant Fischer 344 rats were exposed whole body to NJV-dimethylethanolamine vapor for 6 h per day on gestational days 6-15 at mean (fSD) analytically measured concentrations of 10.4 2 0.86, 29.8 f 2.14 and 100 2 4.9 ppm. Dams were sacrificed on gestational day 21. There was no maternal mortality in any exposed groups. Maternal toxicity observed in the 100 ppm group included reduced body weight during and after exposures, reduced weight gain during exposure and ocular changes (darkened, cloudy and hazy eyes, slight corneal vascularization and fixed, dilated pupils). Ocular effects were also noted in the other two exposure groups; the effects were quite marked at 30ppm but only minimal and transient at 10 ppm. There were no effects of treatment on any gestational parameters, including pre- and postimplantation loss or sex ratio. Fetal body weights per litter were statistically significantly increased at 100 ppm relative to controls. There were no increases in the incidences of total malformations by category (external, visceral or skeletal) or individually. The incidence of six skeletal variations out of 120 noted differed in exposed groups relative to that of control. Four of these variations were decreases in incidence; only one fetal variation, the split (bipartite) cervical centrum, was elevated at 100 ppm relative to controls. In the absence of any other indications of delayed ossification or fetal body weights, the observed fetal variation does not suggest a consistent pattern of fetal toxicity. Hence, the no-observed-adverse-effect level is around 10 ppm for maternal toxicity and at or above 100 ppm for embryofetal toxicity and teratogenicity.

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

428 mg/m³

Quality of whole database:

Justification for selection of Effect on developmental toxicity: via inhalation route: NOAEC was calculated using the following equation: c [mg/m3] = (c [ppm] x molecular weight) : 24.1 with molecular weight = 103.16 g/mol (dimethylaminopropanol)

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproduction toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used as read-across.

 

In the Modified Developmental Toxicity Screening Study in Wistar rats with DMAE, the test material was administered to time-pregnant female rats orally by gavage from gestation day (GD) 6 through GD 19 (prenatal study part) or GD 6 through postnatal day (PND) 3 (postnatal study part) at dose levels 300 and 600 mg/kg bw/day. In the prenatal part of study, no test substance-related findings were observed in fetuses at the both dose levels. In the high dose group (600 mg/kg bw), viabilty of pups was affected severe (viability index 43% compared to 100% in control). Six out of 64 pups were stillborn. From the 58 liveborn pups, 24 died ahead of scedule. Nine pups were cannibalized. No pups were alive in 4 out of 7 litters. Body weight was significantly reduced compared to the control group (set to100%), i.e, on PND 1 (76%) and on PND 4 (71%) and body weight change (57% between PND 1 -4). Twelve runts were born (no runts in the control). Pups in the 300 mg/kg bw dose group were not affected. [BASF, 2008]

 

Leung et al. exposed pregnant rats to vapours of DMAE at 1, 10, 30 and 100 ppm. There was no evidence of embryonic or fetal toxicity, including teratogenicity, at any exposure concentration employed (including that which produced maternal toxicity).

There were no statistically significant increases in the incidences of individual malformations, malformations by category (external, visceral including craniofacial and skeletal) or total malformations at any exposure concentration relative to controls. 

The incidence of litters with one or more fetuses having variations did not differ for any individual external or visceral variations, or for total external, visceral or skeletal variations, or for total variations. The incidences of six skeletal variations out of 120 evaluated were statistically significantly different in DMEA-exposed groups relative to that of controls. Four of these variations were decreased in incidence; only one fetal variation, the split (bipartite) cervical centrum, was elevated at 100 ppm relative to controls (an exposure concentration which also produced maternal toxicity). In the absence of any other indications of delayed ossification or fetal body weights, the observed fetal variation does not suggest a consistent pattern of fetal toxicity. Inconsistent pattern of skeletal variations reported were poorly ossified cervical centrum, bilobed thoracic centrum, bilobed sternebrae, unossified proximal phalanges of the forelimb, and increased incidences of split cervical centra, and bilobed thoracic centrum.

Fetal body weights per litter were statistically significantly increased at 100 ppm relative to controls. There were no other indications of fetotoxicity such as reduced fetal body weight.

 

The no-observed-adverse-effect concentration was at or above 100 ppm for embryofetal toxicity and teratogenicity.

Justification for classification or non-classification

Based on the available data, the test substance does not need to be classified for reproduction toxicity according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.