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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2022
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2022
Report date:
2022

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
2018
Deviations:
no
Remarks:
No deviations ocurred that impacted the integrity or results of the study.
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
MTDID 948
IUPAC Name:
MTDID 948
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report): MTDID 948
- Substance type: Mono-constituent
- Physical state: Liquid
- Analytical purity: 94.4%
- Purity test date: 16 April, 2014
- Lot/batch No.: 20014, Unit 027
- Expiration date of the lot/batch: 11 August, 2016
- Storage condition of test material: Ambient temperature
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: 3M Company, Batch 8082262
- Purity, including information on contaminants, isomers, etc.: 99.29%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
The test article was administered as a vapor.


Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 12-14 weeks
- Weight at study initiation: 225-310 g
- Fasting period before study: None
- Housing: Group housed (2–3 animals of the same gestation day and dose group together)
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 ad libitum
- Water (e.g. ad libitum):Municipal tap water, treated by reverse osmosis and utraviolet irradiation, ad libitum
- Acclimation period: None reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 100 L whole body exposure chamber. One exposure chamber was dedicated to each group for the duration of the study
- Method of holding animals in test chamber: Cage battery
- Source and rate of air:
- Method of conditioning air:
- Temperature, humidity, pressure in air chamber: Temperature and relative humidity of the exposure atmospheres were monitored using a display (Model No. HMT120, Vaisala; Helsinki, Finland) supplied with a Vaisala probe (Model No. HMP110).
- Air flow rate: The chambers were operated under dynamic conditions and at a slight negative pressure with at least 10 air changes per hour. Pressure was verified using a Dwyer magnehelic (Model No. 605-1C or 605-1, Dwyer Instruments, Inc.; Michigan City, IN). Airflow rates through each chamber was determined based on the requirements for test substance generation and dilution airflows, while additionally providing a sufficient volume of air for the number of animals that were exposed and for exposure atmosphere sampling.
- Air change rate: Chamber ventilation rate (CVR) was monitored using a sharp edge orifice meter and Dwyer Magnehelic® Indicating Transmitter pressure gauge (Model No. 605-2C or 605-2). Each gauge was calibrated for conversion from pressure to airflow in standard liters per minute (SLPM) through the use of a Fox Gas mass flowmeter transmitter (Model FT2A, Fox Thermal Instruments; Marina, CA).
- Treatment of exhaust air: Not reported

TEST ATMOSPHERE
- Brief description of analytical method used: The approximate animal breathing zone of the exposure atmospheres were sampled and analyzed a minimum of 6 times/exposure using a gas chromatograph (GC). The GC was equipped with an external Valco multi-position valve (Model E16, Valco Instruments Co., Inc., Houston, TX) that permitted sequential sampling that was under the control of Chromeleon data acquisition software (Version 7.2, ThermoFisher Scientific, Waltham, MA)
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The approximate animal breathing zone of the exposure atmospheres were sampled and analyzed a minimum of 6 times/exposure using a gas chromatograph (GC). The GC was equipped with an external Valco multi-position valve (Model E16, Valco Instruments Co., Inc., Houston, TX) that permitted sequential sampling that was under the control of Chromeleon data acquisition software (Version 7.2, ThermoFisher Scientific, Waltham, MA)
Details on mating procedure:
Time-mated females were utilized for this study
Duration of treatment / exposure:
Animals were exposed to filtered air or the test substance via whole-body inhalation for 6 hours/day during Gestation Days 6–20.
Frequency of treatment:
Daily
Duration of test:
Gestation Days 6–20.
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm (analytical)
Remarks:
Control
Dose / conc.:
151 ppm (analytical)
Remarks:
150 ppm target
Dose / conc.:
401 ppm (analytical)
Remarks:
400 ppm target
Dose / conc.:
549 ppm (analytical)
Remarks:
550 ppm target
No. of animals per sex per dose:
22 females per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: T he dose levels were selected based on results of a dose range-finding prenatal toxicity study in rats. In the range-finding study, time-mated female rats were exposed to the test substance at concentrations of 150, 450, and 700 ppm from Gestation Days 6 through 20, inclusively. Lower maternal body weight gain and correspondingly lower food consumption were observed at 700 ppm. This resulted in lower (15.9%) terminal body weights compared to the control group on Gestation Day 21. Lower mean fetal weights (-13.8%, combined sexes) were also observed at 700 ppm compared to the control group. At 450 ppm, slightly lower (8.7%) mean fetal weights were observed compared to the control group. There were no remarkable changes noted at 150 ppm. Based on these data, 150, 400, and 550 ppm were selected
for the exposure levels in the current definitive study.
- Rationale for animal assignment: Random
- Fasting period before blood sampling for (rat) dam thyroid hormones: None reported
- Time of day for (rat) dam blood sampling: None reported:

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice dailya (morning and afternoon), beginning upon arrival through termination.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestation days 5, 6, 9, 12, 15, 18 and 21

BODY WEIGHT: Yes
- Time schedule for examinations: Gestation Days 0 (by supplier), 5, 6, 9, 12, 15, 18, and 21

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Checked on Gestation Days 5, 6, 9, 12, 15, 18, and 21. Quantitatively measured. Measured on a per cage basis. Normalized to the number of animals/cage, and reported in g/animal/day. Food spillage within the cage was not accounted for due to use of bedding.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 21
- Organs examined: All surviving females were euthanized and subjected to a gross necropsy. The cranial, thoracic, abdominal, and pelvic cavities were opened and the contents examined. The uterus of each dam was excised and its adnexa trimmed. Corpora lutea were also counted and recorded. Gravid uterine weights were obtained and recorded. The uterus of each dam was opened and the number of viable and nonviable fetuses, early and late resorptions, and total number of implantation sites were recorded, and the placentae were examined. The individual uterine distribution was documented using the following procedure: all implantation sites, including early and late resorptions, were numbered in consecutive fashion beginning with the left distal uterine horn, noting the position of the cervix and continuing from the proximal to the distal right uterine horn. For all animals, the thyroid gland and liver were excised, weighed (thyroid only; post-fixation), and preserved in 10% neutral buffered formalin. Macroscopic lesions were also collected and preserved in 10% neutral buffered formalin for possible future histopathologic examination. Representative sections of corresponding organs from a sufficient number of controls were retained for comparison, if possible.

OTHER:
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
Blood sampling:
- Plasma: No
- Serum: Yes
- Volume collected : 1.0 mL
:
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes:, all per litter
- Anogenital distance of all live rodent pups: Yes
Statistics:
Levene’s test was used to assess the homogeneity of group variances.The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal-Wallis test was found to be significant, then pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively.
Indices:
The following indices were recorded: Pre-Implantation loss, Post-Implantation loss, Sex Ratio, Litter % of fetuses with abnormalities
Historical control data:
The laboratory maintains historical control data for statistical analysis.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No test substance-related clinical observations were noted at the daily examinations prior to exposures at any dose level. Observations noted in the test substance-treated groups occurred
infrequently, at similar frequencies in the control group, and/or in a manner that was not dose-related. No clinical observations were noted following exposures at any dose level.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
All females in the control, 150, 400, and 550 ppm groups survived to the scheduled necropsy on Gestation Day 21. All females were gravid.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the 550 ppm group, a statistically significantly lower mean body weight gain was noted following the initiation of exposure (Gestation Days 6–9) compared to the control group. Mean body weight gains in this group were slightly lower (not statistically significant) than the control group during Gestation Days 9–21. As a result, mean body weight gain in the 550 ppm group was statistically significantly lower than the control group when the entire exposure period (Gestation Days 6-21) was evaluated and the mean absolute body weight in this group was 4.6% lower (not statistically significant) on Gestation Day 21. The mean adjusted body weight and adjusted body weight gain in this group were also slightly lower (not statistically significant) than the control group. These aforementioned effects at 550 ppm were considered test substance-related, but nonadverse due to the low magnitude of the change. Mean gravid uterine weight at 550 ppm was slightly lower (not statistically significant) compared to the control group, however the value with within the range of the Charles River historical control data (version 2020.01) and was considered related to the slightly lower fetal weights in this group, and therefore was not considered test substance-related.

Mean maternal body weights, body weight gains, adjusted body weights, adjusted body weight gains, and gravid uterine weights in the 150 and 400 ppm groups were unaffected by test substance administration. Differences from the control group were slight and not statistically significant.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Lower mean food consumption was noted in the 550 ppm group throughout the study compared to the control group; differences were statistically significant from Gestation Days 9–21 and when the entire exposure period (Gestation Days 6–21) was evaluated. This corresponded with the lower mean body weight gains noted in this group and was considered test substance-related, but nonadverse due to the low magnitude of change.

Mean maternal food consumption in the 150 and 400 ppm groups unaffected by test substance exposure. Any statistically significant differences from the control group were transient and did not impact mean absolute body weights, and therefore were not considered test substance-related.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
no effects observed
Description (incidence and severity):
There were no test substance-related effects on thyroid hormone values at any exposure level on Gestation Day 21. Differences from the control group were slight and not statistically significant.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No test substance-related organ weight changes were noted.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test substance-related gross findings were noted. The gross findings observed were considered incidental, of the nature commonly observed in this strain and age of rat, and/or were of similar incidence in control and treated animals and, therefore, were considered unrelated to test substance exposure.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No test substance-related microscopic findings were noted. The microscopic findings observed were considered incidental, of the nature commonly observed in this strain and age of rat, and/or were of similar incidence and severity in control and treated animals and, therefore, were considered unrelated test substance exposure.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No test substance-related microscopic findings were noted. The microscopic findings observed were considered incidental, of the nature commonly observed in this strain and age of rat, and/or were of similar incidence and severity in control and treated animals and, therefore, were considered unrelated test substance exposure.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No test substance-related changes in the number of abortions were observed in any of the exposure groups.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No test substance-related changes in pre- and post-implantation loss were observed in any of the exposure groups.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
No test substance-related changes in total litter loss by resorption were observed in any of the exposure groups.
Early or late resorptions:
no effects observed
Description (incidence and severity):
No test substance-related changes in early or late resorptions were observed in any of the exposure groups.
Dead fetuses:
no effects observed
Description (incidence and severity):
No test substance-related changes in the number of dead fetuses were observed in any exposure groups.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No changes in pregnancy duration were noted.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
No changes in the number of pregnant rats were observed in groups exposed to the test article.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
575 ppm (analytical)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
In the 550 ppm group, lower mean body weight gains with correspondingly lower food consumption were noted throughout the study and when the entire exposure period (Gestation Days 6–21) was evaluated compared to the control group. As a result, mean absolute body weight in this group was slightly lower (4.6%) than the control group on Gestation Day 21. Slightly lower mean adjusted body weight and adjusted body weight gain at 550 ppm were also noted compared to the control group. These effects were considered test substance-related, but nonadverse due to the low magnitude of the change. Mean gravid uterine weight at 550 ppm was also slightly lower than the control group, however this was attributed to the slightly lower mean fetal weights in this group and was not considered test substance-related. Mean maternal body weights, body weight gains, food consumption, adjusted body weights, adjusted body weight gains, and gravid uterine weights in the 150 and 400 ppm groups were similar to the control group.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
The number of live offspring in the treated groups was similar to controls.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was unaffected by treatment.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No changes in litter size and weight were observed in the treated groups.
Anogenital distance of all rodent fetuses:
no effects observed
Description (incidence and severity):
Anogenital distance was unaffected by treatment.
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Survival rates were unaffected by treatment.
External malformations:
no effects observed
Description (incidence and severity):
No external malformations were observed in treated or control groups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No treatment-related skeletal malformations were observed.
Visceral malformations:
no effects observed
Description (incidence and severity):
No treatment-related visceral malformations were observed.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
549 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the absence of adverse effects, an exposure dose level of 549 ppm (analytical) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and prenatal development when the test article was administered via whole-body exposures for 6 hours/day during Gestation Days 6–20 to time-mated Crl:CD(SD) rats.
Executive summary:

The developmental toxicity potential of the test article was evaluated in rats. The study was conducted according to OECD 414 in compliance with OECD GLP. Animals were exposed to filtered air or the test substance via whole-body inhalation for 6 hours/day during Gestation Days 6–20. Rats were exposed to 0 (control), 150, 400, or 550 ppm test article. The following parameters and end points were evaluated in this study: mortality, clinical signs, body weights, body weight gains, gravid uterine weights, food consumption, thyroid hormone levels, organ weights, macroscopic and microscopic examinations, intrauterine growth and survival, fetal anogenital distances, and fetal morphology. Mean analyzed exposure concentrations, over the entire exposure period (Gestation Days 6–20), in the 0, 150, 400, and 550 ppm groups were 0, 151, 401, and 549 ppm, respectively. All animals survived to the scheduled necropsy on Gestation Day 21. There were no test substance-related clinical observations noted at the daily examinations prior to or following exposures at any exposure level. In the 550 ppm group, lower mean body weight gains with correspondingly lower food consumption were noted throughout the study and when the entire exposure period (Gestation Days 6–21) was evaluated compared to the control group. As a result, mean absolute body weight in this group was slightly lower (4.6%) than the control group on Gestation Day 21. Slightly lower mean adjusted body weight and adjusted body weight gain at 550 ppm were also noted compared to the control group. These effects were considered test substance-related, but non-adverse due to the low magnitude of the change. Mean gravid uterine weight at 550 ppm was also slightly lower than the control group, however this was attributed to the slightly lower mean fetal weights in this group and was not considered test substance-related. Mean maternal body weights, body weight gains, food consumption, adjusted body weights, adjusted body weight gains, and gravid uterine weights in the 150 and 400 ppm groups were similar to the control group. There were no test substance-related effects on thyroid hormone values at any exposure level. There were no test substance-related effects on organ weight, macroscopic findings, or microscopic changes to maternal thyroid glands. Intrauterine growth and survival and anogenital distances (absolute and normalized) at all exposure levels were unaffected by test substance administration. At 550 ppm, mean fetal body weights were up to 6.02% lower when compared to the control group, but were attributed to biological variability and not considered test substance-related. No test substance-related malformations or developmental variations were observed in fetuses in this study. Based on the absence of adverse effects, an exposure dose level of 549 ppm (analytical) was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and prenatal development when the test article was administered via whole-body exposures for 6 hours/day during Gestation Days 6–20 to time-mated Crl:CD(SD) rats.