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EC number: 459-520-5 | CAS number: 132182-92-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 2016
- Deviations:
- no
- Remarks:
- No deviations ocurred that negatively impacted the integrity of the study.
- GLP compliance:
- yes
- Justification for study design:
- Per OECD 421.
Test material
- Reference substance name:
- Novec 7300
- IUPAC Name:
- Novec 7300
- Details on test material:
- - Name of test material (as cited in study report): Novec 7300
- Physical state: Colorless, clear liquid
- Analytical purity: 99.85%
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Lot 20176
- Expiration date of the lot/batch: 22 January, 2021
- Purity test date: 22 January, 2019
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Kept in a controlled temperature area set to maintain 18°C to 24°C
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The Crl:CD(SD) rat is recognized as appropriate for reproduction studies. Charles River Ashland has reproductive historical control data in this species from the same strain and source. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 11 weeks old
- Weight at study initiation: 206-420 grams
- Fasting period before study: None
- Housing: On arrival, animals were group housed (up to 3 animals of the same sex) until cohabitation. During cohabitation, animals were paired for mating in the home cage of the male. Following the breeding period, animals were individually housed. Animals were housed in solid-bottom cages containing appropriate bedding equipped with an automatic watering valve throughout the study.
- Diet (e.g. ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet 5002 (meal) was provided ad libitum throughout the study, except during inhalation exposure procedures
- Water (e.g. ad libitum): Municipal tap water after treatment by reverse osmosis and ultraviolet irradiation was freely available to each animal via an automatic watering system, except during inhalation exposure procedures.
- Acclimation period: At least a week
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 04 March, 2019 To: 05 November, 2019
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: Exposures were conducted using approximately 1000-L stainless steel whole-body chambers. One exposure chamber was dedicated to each group for the duration of the study. All chambers were operated with a minimum of 12 air changes per hour (minimum of 200 liters per minute)
and at a slight negative pressure. Air supplied to the whole-body chamber was provided from the in-house compressed nitrogen source and a HEPA- and charcoal-filtered, temperature- and humidity-controlled supply air source. All exhaust passed through the facility exhaust system, which consists of redundant exhaust blowers preceded by activated-charcoal and HEPA-filtration units.
- Method of holding animals in test chamber: None- whole body
- Source and rate of air: 200 L/min. Air supplied to the whole-body chamber was provided from the in-house compressed nitrogen source and a HEPA- and charcoal-filtered, temperature- and humidity-controlled supply air source
- Method of conditioning air: Air supplied to the whole-body chamber was provided from the in-house compressed nitrogen source and a HEPA- and charcoal-filtered, temperature- and humidity-controlled supply air source
- System of generating particulates/aerosols: NA
- Air change rate: 12 changes/hour
- Treatment of exhaust air: All exhaust passed through the facility exhaust system, which consists of redundant exhaust blowers preceded by activated-charcoal and HEPA-filtration units.
TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed exposure concentrations were determined at approximately 60-minute intervals using a gas chromatograph (GC). Samples were collected from the approximate animal-breathing zone of the exposure chamber. An external multi-position valve permitted sequential sampling from the exposure room and each exposure chamber. Gas sampling injection onto the chromatography column occurred via an internal gas-sampling valve with a sample loop, the concentration was calculated based off the prime calibration curve and stored. The WINH system then acquired the calculated concentration data and displayed the concentration in ppm.
- Samples taken from breathing zone: Yes - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as Day 0 of pregnancy
- After 14 days of unsuccessful pairing the male was not replaced
- After successful mating each pregnant female was caged (how): Individually - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyzed exposure concentrations were determined at approximately 60-minute intervals using a gas chromatograph (GC). Samples were collected from the approximate animal-breathing zone of the exposure chamber. An external multi-position valve permitted sequential sampling from the exposure room and each exposure chamber. Gas sampling injection onto the chromatography column occurred via an internal gas-sampling valve with a sample loop, the concentration was calculated based off the prime calibration curve and stored. The WINH system then acquired the calculated concentration data and displayed the concentration in ppm.
- Duration of treatment / exposure:
- Animals were exposed to the test substance or humidified, filtered air (control), daily as a 6-hour, whole-body inhalation exposure. Males were exposed for 14 days prior to mating and continuing throughout mating for a minimum of 28 days. Females were exposed for 14 days prior to mating and continuing through Gestation Day 20; exposure was re-initiated on Lactation Day 5 and continued through 1 day prior to euthanasia (Lactation Day 12 for females that delivered or Postmating Day 25 for females that failed to deliver). All animals were exposed at approximately the same time each day.
- Frequency of treatment:
- Daily
- Details on study schedule:
- The following parameters and endpoints were evaluated in this study: clinical signs, body weight gains, food consumption, estrous cycles, reproductive performance, parturition, litter viability and survival, anogenital distance, areolae/nipple anlagen, thyroid hormones, gross necropsy findings, organ weights, and histopathological examinations. Male rats were sacrificed after 28 days of treatment on study day 28/29 and female rats were sacrificed on day 13 of lactation. At necropsy, the adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries with oviducts, pituitary gland, prostate gland, seminal vesicle (with coagulating gland and fluid), spleen, testes, thymus gland, and thyroids with parathyroids were collected and organ weights were obtained. Other tissues collected at necropsy and preserved include the brain, coagulating glands, kidneys, liver, mammary glands, ovaries and oviducts, pituitary gland, prostate gland, seminal vesicle, testes with epididymides and vas deferens, uterus with cervix and vagina, and all gross lesions. The previously identified tissues of all animals in the control and high-exposure groups underwent histopathological examination. Other tissues that were examined include the liver and kidney of male’s rats and gross lesions.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/L air
- Remarks:
- Control
- Dose / conc.:
- 72.25 mg/L air (analytical)
- Remarks:
- 5046 ppm
- Dose / conc.:
- 143.22 mg/L air (analytical)
- Remarks:
- 10,003 ppm
- Dose / conc.:
- 281.17 mg/L air (analytical)
- Remarks:
- 19,637 ppm
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Based on previous repeated dose inhalation studies conducted with the test substance.
- Rationale for animal assignment (if not random): Random - Positive control:
- NA
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Throughout the study, animals were observed for general health/mortality and moribundity twice daily, once in the morning and once in the afternoon. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were removed from the cage, and a detailed clinical observation was performed once daily throughout the study. During the exposure period, these observations were performed prior to exposure. On exposure days, clinical observations were also recorded 1–2 hours following the completion of exposure.
BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually weekly throughout the study and prior to the scheduled necropsy. Once evidence of mating was observed, female body weights were recorded on Gestation Days 0, 4, 7, 11, 14, 17, and 20 and on Lactation Days 1, 4, 7, 10, and 13.
FOOD CONSUMPTION: Food consumption was quantitatively measured weekly until cohabitation. Once evidence of mating was observed, female food consumption was recorded on Gestation Days 0, 4, 7, 11, 14, 17, and 20 and Lactation Days 1, 4, 7, 10, and 13. - Oestrous cyclicity (parental animals):
- For all females, vaginal lavages were performed daily for 14 days prior to randomization and continuing until evidence of mating was observed. The slides were microscopically examined to determine the stage of the estrous cycle. The average cycle length was calculated for complete estrous cycles (i.e., the total number of returns to metestrus [M] or diestrus [D] from estrus [E] or proestrus [P] for 14 consecutive days before cohabitation and until the detection of evidence of
mating). Estrous cycle length was determined by counting the number of days from the first M or D in a cycle to the first M or D in a subsequent cycle. The cycle during which evidence of mating was observed for a given animal was not included in the individual mean estrous cycle length calculation. Vaginal lavages were also performed on the day of necropsy to determine the stage of the estrous cycle. - Sperm parameters (parental animals):
- Parameters examined in P generations: seminal vesicle, testes with epididymides and vas deferens
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: Litters were observed for general health/mortality and moribundity twice daily, once in the morning and once in the afternoon. A daily record of litter size was maintained. Animals were not removed from cage during observation, unless necessary for identification or confirmation of possible findings.
The following parameters were evaluated: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups.
GROSS EXAMINATION OF DEAD PUPS:
Intact offspring that were found dead or euthanized for humane reasons during PND 0–4 were necropsied using a fresh dissection technique, which included examination of the heart and major vessels. Findings were recorded as developmental variations or malformations, as appropriate.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: None
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: None - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals on study Day 28/29
- Maternal animals: All surviving animals on lactation Day 13
GROSS NECROPSY:
Animals were subjected to a complete necropsy examination, which included examination of the external surface, all orifices, the cranial cavity, the external surface of the brain, and the thoracic, abdominal, and pelvic cavities, including viscera. The numbers of former implantation sites were recorded for females that delivered. The number of unaccounted-for sites was calculated for each female by subtracting the number of pups born from the number of former implantation sites observed. Uteri of females without macroscopic evidence of implantation were opened and placed in 10% ammonium sulfide solution for detection of early implantation loss.
HISTOPATHOLOGY / ORGAN WEIGHTS:
At necropsy, the adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries with oviducts, pituitary gland, prostate gland, seminal vesicle (with coagulating gland and fluid), spleen, testes, thymus gland, and thyroids with parathyroids were collected and organ weights were obtained. Other tissues collected at necropsy and preserved include the brain, coagulating glands, kidneys, liver, mammary glands, ovaries and oviducts, pituitary gland, prostate gland, seminal vesicle, testes with epididymides and vas deferens, uterus with cervix and vagina, and all gross lesions. The previously identified tissues of all animals in the control and high-exposure groups underwent histopathological examination. Other tissues that were examined include the liver and kidney of male’s rats and gross lesions. - Postmortem examinations (offspring):
- SACRIFICE
- Offspring were sacrificed on PND 13.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: On PND 13, 1 pup/sex/litter was subjected to a complete necropsy examination, with emphasis on developmental morphology and organs of the reproductive system. All other animals were
discarded without examination.
GROSS NECROPSY
On PND 13, 1 pup/sex/litter was subjected to a complete necropsy examination, with emphasis on developmental morphology and organs of the reproductive system. All other animals were discarded without examination.
HISTOPATHOLOGY / ORGAN WEIGTHS
At necropsy, the thyroid (with parathyroid, if present) were weighed from 1 pup/sex/litter. - Statistics:
- Each mean was presented with the standard deviation (S.D.) and the number of animals or cages (N) used to calculate the mean. Where applicable, the litter was used as the experimental unit. Statistical analyses were not conducted on F0 weekly female body weight data after 1 or more animals had entered the gestation phase. Due to the use of significant figures and the different rounding conventions inherent in the types of software used, the means and standard deviations
on the summary and individual tables may differ slightly. Therefore, the use of reported individual values to calculate subsequent parameters or means will, in some instances, yield minor variations from those listed in the report data tables. Data obtained from nongravid animals were excluded from statistical analyses.
All statistical tests were performed using WTDMS unless otherwise noted. Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group by sex. - Reproductive indices:
- Male mating index, female mating indes, maler fertility index, female fertility index, male copulation index, female conception index, estrous cycle length, pre-coital interval, gestation length
- Offspring viability indices:
- Number of pups born, live litter size, and sex ratio, postnatal survival
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No substance-related clinical observations were noted at any exposure level.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- All parental animals survived to the scheduled necropsy.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test substance-related effects were noted on parental body weight gains
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No test substance-related effects were noted on parental food consumption.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- Lower mean T4 values were noted in parental males at 5046, 10003, and 19637 ppm.
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance-related microscopic findings were noted in the liver of the 5000, 10,000, and 20000 ppm group males. Hepatocellular hypertrophy was characterized as a minimal to mild, diffuse (or rarely centrilobular) enlargement of hepatocytes. This change was not observed in the test
substance-exposed females. There were no other definitive test substance-related histologic changes. - Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No neoplastic lesions were observed.
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Estrous cycle length was not altered by treatment.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- No changes were noted in the seminal vesicle or testes with epididymides and vas deferens.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No test substance-related effects on reproductive performance were observed at any exposure level.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEC
- Effect level:
- 281.17 mg/L air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- organ weights and organ / body weight ratios
- gross pathology
- histopathology: non-neoplastic
- reproductive function (oestrous cycle)
- reproductive performance
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The general physical condition (defined as the occurrence and severity of clinical observations) of all F1 pups in this study was unaffected by test substance exposure.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Two (2), 5(4), 7(5), and 3(2) pups (litters) in the control, 5000, 10,000, and 20,000 ppm groups, respectively, were found dead or euthanized in extremis. One pup in the 10,000 ppm group was missing and presumed to have been cannibalized.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean male and female pup body weights and body weight changes during PND 1–4 in the 5000, 10,000, and 20,000 ppm were similar to the control group. Lower mean body weight gains were noted in male and female F1 pups at 5000, 10,000, and 20,000 ppm during PND 4–7; differences from the control group were generally statistically significant. As a result, mean absolute male and female pup body weights in these group were lower (up to 10.4%) than the control group during PND 7–13; differences were statistically significant for males at 5000 and 20,000 ppm on PND 13. However, the aforementioned effects were noted in a manner that was not concentration-related, and therefore were not considered test substance-related.
- Food consumption and compound intake (if feeding study):
- not examined
- 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:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on thyroid hormone values in the F1 males and females at any dosage level on PND 13. Differences from the control group were considered to be the result of normal biological variation and were not considered to be of toxicological significance.
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Description (incidence and severity):
- Screening study
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related effects on thyroid weights in the F1 males and females at any dosage level on PND 13. Differences from the control group were considered to be the result of normal biological variation and were not considered to be of toxicological significance.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Two (2), 5(4), 7(5), and 3(2) pups (litters) in the control, 5000, 10,000, and 20,000 ppm (nominal) groups, respectively, were found dead or euthanized in extremis. No internal findings that could be attributed to parental test substance exposure were noted at the necropsies of pups that were found dead or euthanized in extremis. Aside from the presence or absence of milk in the stomach, no other internal findings were noted.
No internal findings that could be attributed to parental test substance exposure were noted at the necropsy of pups euthanized on PND 13. A small thyroid was noted for 1 female (No. 1966-14) in the 20,000 ppm group and 1 male (No. 1934-01) and 1 female (No. 1960-12) in the control group. In the 10,000 ppm group, 1 female (No. 1952-08) was noted with dark red discoloration of the thyroid gland. These internal findings were noted in frequency and/or at similar frequencies in the control group. - Histopathological findings:
- not examined
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 281.17 mg/L air (analytical)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- viability
- clinical signs
- mortality
- body weight and weight gain
- clinical biochemistry
- gross pathology
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, there were no effects on F0 reproduction at any exposure concentration, and therefore an exposure level of 19637 ppm was the no-observed-adverse-effect concentration (NOAEC) for F0 reproductive toxicity of MTDID 665 when rats were exposed via whole body inhalation. A no-observed-effect-concentration (NOEC) for F0 male systemic toxicity could not be determined, and the NOEC for F0 female systemic toxicity was 281.17 mg/L (19637 ppm); the NOAEC for F0 male and female rats was considered to be 281.17 mg/L (19637 ppm). The NOAEC for F1 neonatal toxicity was 281.17 mg/L (19637 ppm) based on the absence of any adverse effects on postnatal development at any exposure level.
- Executive summary:
The objective of this study was to provide data on the potential effects of MTDID 665 on reproductive performance, pup development, and general toxicity of rats by inhalation exposure. The study was conducted according to OECD 421 in compliance with OECD GLP. MTDID 665 was administered daily to rats (N= 10/sex/exposure concentration) by inhalation whole body exposure (6 hours/day) at target concentrations of 0 (control), 5000, 10000, and 20,000 ppm. Actual exposure concentrations were 0 (control), 72.25, 143.22, and 281.17 mg/L (5046, 10003, and 19637 ppm), respectively. Males were exposed for 14 days prior to mating and continuing through mating for a minimum of 28 days. Females were exposed for 14 days prior to mating and continuing through Gestation day 20; exposure resumed on Lactation day 5 and continued through Lactation day 12. The following parameters and endpoints were evaluated in this study: clinical signs, body weight gains, food consumption, estrous cycles, reproductive performance, parturition, litter viability and survival, anogenital distance, areolae/nipple anlagen, thyroid hormones, gross necropsy findings, organ weights, and histopathological examinations. Male rats were sacrificed after 28 days of treatment on study day 28/29 and female rats were sacrificed on day 13 of lactation. At necropsy, the adrenal glands, brain, epididymides, heart, kidneys, liver, ovaries with oviducts, pituitary gland, prostate gland, seminal vesicle (with coagulating gland and fluid), spleen, testes, thymus gland, and thyroids with parathyroids were collected and organ weights were obtained. Other tissues collected at necropsy and preserved include the brain, coagulating glands, kidneys, liver, mammary glands, ovaries and oviducts, pituitary gland, prostate gland, seminal vesicle, testes with epididymides and vas deferens, uterus with cervix and vagina, and all gross lesions. The previously identified tissues of all animals in the control and high-exposure groups underwent histopathological examination. Other tissues that were examined include the liver and kidney of male’s rats and gross lesions. All F0 animals survived to the scheduled necropsy. No substance-related clinical observations were noted at any exposure level. No test substance-related effects were noted on F0 body weight gains, food consumption, estrous cyclicity, reproductive performance (mating, fertility, copulation, and conception), gestation length, or parturition. Test substance-related higher liver weights were identified in the 5046, 10003, and 19637 ppm group males, which correlated with hepatocellular hypertrophy observed in histopathological evaluation of the liver. Higher thyroid/parathyroid weights were identified in the 5046 and 10003 ppm group males, and 19637 ppm group males and females. Lower mean T4 values were noted in F0 males at 5046, 10003, and 19637 ppm. Higher thyroid/parathyroid weight (secondary to thyroid follicular hypertrophy) has been reported in associated with hepatocellular hypertrophy and lower total T4 concentrations and may represent an adaptive change secondary to treatment-induced hepatocellular enzyme induction with secondary thyroxine metabolism. The thyroid/parathyroid glands were not evaluated histologically in the current study; however, the decreased serum T4 in conjunction with the increased liver weights, hepatocellular hypertrophy, and increased thyroid/parathyroid weight demonstrate that this effect is a non-adverse adaptive finding. No test substance-related effects were noted on F1 postnatal survival, growth, clinical condition, anogenital distance, areolae/nipple anlagen, thyroid hormone levels, or gross necropsy. Under the conditions of this study, there were no effects on F0 reproduction at any exposure concentration, and therefore an exposure level of 19637 ppm was the no-observed-adverse-effect concentration (NOAEC) for F0 reproductive toxicity of MTDID 665 when rats were exposed via whole body inhalation. A no-observed-effect-concentration (NOEC) for F0 male systemic toxicity could not be determined, and the NOEC for F0 female systemic toxicity was 281.17 mg/L (19637 ppm); the NOAEC for F0 male and female rats was considered to be 281.17 mg/L (19637 ppm). The NOAEC for F1 neonatal toxicity was 281.17 mg/L (19637 ppm) based on the absence of any adverse effects on postnatal development at any exposure level.
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