Registration Dossier
Registration Dossier
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EC number: 700-903-6 | CAS number: 255830-15-0
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There are no reproductive toxicity test data available for ATMP-N-Oxide-xK, and therefore, read across data from a three generation study that was performed using ATMP-H (CAS 6419-19-8) in the rat have been used for this endpoint.
The key reproductive study is a multigenerational study for the
category member, ATMP-H, conducted prior to the adoption of OECD test
guidelines and pre-GLP. Male and female Long-Evans rats were
administered ATMP 60 days prior to mating (F0) and continuously
thereafter (F1, F2, F3) in the diet at fixed concentrations of 0, 300,
1000 and 3000 ppm for three consecutive generations. The NOAEL for
general toxicity and reproductive toxicity was greater than the highest
dose tested of 3000 ppm. The concentration of the test substance and
mean weekly food intake values were used to determine the approximate
doses received by the animals. The dose of 3000 ppm was approximately
equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day in
females (Biodynamics Inc., 1979a).
Link to relevant study records
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 29.10.1976 to 15.08.1978
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Three generation reproduction toxicity study with the following restrictions: no assessment of estrus cycle, sperm parameters, sexual milestones and no analytical confirmation of exposure levels.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Long-Evans
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Blue Spruce Farms, Altamont, New York.
- Age at study initiation: (P) 6-7 weeks
- Weight at study initiation: (P) males approximately 370 grams, females approximately 240 grams at mating
- Fasting period before study: No data
- Housing: Individually (except during mating and lactation) in elevated stainless steel wire mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 14 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
IN-LIFE DATES: From: 12.11.1976 To: 15.08.1978 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Weekly
- Mixing appropriate amounts with (Type of food): Purina Laboratory Chow (standard laboratory diet)
- Storage temperature of food: No data - Details on mating procedure:
- - M/F ratio per cage: 1/2 (See table 1)
- Length of cohabitation: Overnight for up to 15 days.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Remated (for F1b/F2b/F3b generation) following a 14 d rest period.
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged: individually in elevated stainless steel wire mesh cages.
- Any other deviations from standard protocol: None apparent. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Diet samples were taken from control and treated groups weekly. Samples were stored frozen and sent to the sponsor at regular intervals throughout the study. No further details.
- Duration of treatment / exposure:
- From 60 days prior to first mating of P generation then continuous over 3 generations . Duration of test in total was approximately 21 months.
- Frequency of treatment:
- Daily
- Details on study schedule:
- - F1 and F2 parental animals not mated until after a growth period (unspecified duration) following selection from the F1b and F2b litters.
- Selection of parents from F1 and F2 generation when pups were 7 days post weaning.
- Age at mating of the mated animals in the study: Not clear, but there was a 14 day rest period between matings. - Dose / conc.:
- 300 ppm (nominal)
- Remarks:
- nominal in diet
See table 3 for conversion to mg/kg bw/day - Dose / conc.:
- 1 000 ppm (nominal)
- Remarks:
- nominal in diet
See table 3 for conversion to mg/kg bw/day - Dose / conc.:
- 3 000 ppm (nominal)
- Remarks:
- nominal in diet
See table 3 for conversion to mg/kg bw/day - No. of animals per sex per dose:
- 12 male and 24 females (see Table 1)
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random - Positive control:
- None
- Parental animals: Observations and examinations:
- Examination conducted on F0, F1, F2 AND F3 (all adult generations)
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Gross examination occurred twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly during growth and rest periods of all animals. As well as pregnant females (F0, F1b, F2b) on GD 0, 6, 15 and 20 and lactating females (F0, F1) on LD 0, 4, 14 and 21.
FOOD CONSUMPTION AND COMPOUND INTAKE: Weekly for males and non-pregnant females.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
WATER CONSUMPTION AND COMPOUND INTAKE: No
OPHTHALMOSCOPIC EXAMINATION: F0 parents after weaning of F1b litter. - Oestrous cyclicity (parental animals):
- Not investigated.
- Sperm parameters (parental animals):
- Not investigated.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, to 10 pups/sex/litter as nearly as possible; excess pups were killed and discarded.
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, physical or behavioral abnormalities. See Tables 4, 5 and 6 for pup survival data.
GROSS EXAMINATION OF DEAD PUPS:
yes, sex determined and stomach checked for presence of milk. Cause of death was not determined. - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals after completion of pup selection for the F0 and F1 generations, and after weaning of last litters for the F2 generation.
- Maternal animals: All surviving animals after completion of pup selection for the F0 and F1 generations, and after weaning of last litters for the F2 generation. Additionally, non-pregnant dams from first mating.
- Dead and moribund animals examined as death occurred.
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
- Dams uterine contents examined for the presence of implantation sites and/or scars.
HISTOPATHOLOGY / ORGAN WEIGHTS: None scheduled for adults. Only grossly abnormal tissues were examined. - Postmortem examinations (offspring):
- SACRIFICE
- The F1a/F2a/F3a offspring not selected as parental animals were sacrificed at 21 days of age.
- F1b and F2b progeny (non-parental): sacrificed after pup selection for next generation.
- F3b sacrificed at weaning.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGTHS
The tissues indicated in Table 2 were prepared for microscopic examination from 10 pups/sex/group of the F3b generation. In addition, any grossly abnormal tissues were examined. - Statistics:
- Offspring body weights, off-spring numbers (LD 0 LD 4): F-test and Student's T-test.
Offspring survival, litter deaths, litters weaned, mortality, mating rates, pregnancy rates, fertility rates: Chi square.
Body weights, body weight change, food intake: Dunnett's test. - Reproductive indices:
- Mating indices (%), pregnancy rates (%) and fertility (%). No details given.
- Offspring viability indices:
- No details given.
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- F0: One mid dose male was sacrificed in a moribund state during mating for F1b litter ("severely tilted head"). One high dose female was sacrificed post-weaning of F1b litter with "extremely distended abdomen". There was no dose response and the deaths were considered sporadic, therefore not related to treatment. Physical observations were comparable between all groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There was no effect in either sex on mean body weight or body weight gain during growth or rest periods. There were no effects on maternal body weight or body weight change during gestation or lactation periods.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The ophthalmoscopic examination revealed four rats (one control female, two mid dose males and one high dose male) with ocular abnormalities. However, these were not considered to be treatment related.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- Gestation length, mean number of live and dead pups at birth and percentage of live pups at birth were comparable between groups.
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F0
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Critical effects observed:
- no
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Red and swollen ears on the tagged ear were noted in F1 and F2 adults. Physical observations were comparable between all groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- F1: One mid dose male died during mating. One high dose female died during post-weaning interval, prior to sacrifice. One control male and one high dose female sacrificed with "severely tilted heads" (male sacrificed wk 4, female in rest period between matings). There was no dose response and the deaths were considered sporadic and therefore, not related to treatment.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Immunological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- A high number of dead pups within a single mid dose litter lead to a significant decrease in the survival index at birth in the mid dose group for F1b.
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F1 / P1
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F2 / P2
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Physical observations comparable were between all groups.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- F2: One low dose female died during week 3 of the growth period. One mid dose male died during week 8 of the growth period. One mid dose female died on GD 21 for the F3b litter. One high dose male died during the mating interval to produce the second litter. There was no dose response and the deaths were considered sporadic and therefore, not related to treatment.
- Body weight and weight changes:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- No adverse effect was concluded. There was no effect on mating indices (%), pregnancy rates (%) or fertility (%).
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F1
- Generation:
- F1
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- Significant decrease (P<0.01) in survival index at birth in the second mid dose litter (F1 for F2b). This was not considered indicative of a treatment-related effect by the study authors since comparable changes this was not replicated in other phases of the study, nor was any dose/response relationship present. Survival at birth was significantly increased (P<0.01) for the high dose F3b litter. Some statistically significant differences were apparent in postnatal survival indices between control and treated groups, however these were not considered adverse by the authors since no trend was present. These differences generally reflected a statistically significant enhancement in survival relative to the controls (9 instances), while decreased survival was relatively infrequent (2 instances). The percentages of litters with offspring deaths and litters weaned were comparable between control and treated groups.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Scattered red foci was present in the lung from some F2b offspring from the mid and high dose groups. This was not present in controls and the low dose group. The effects were considered as not treatment-related by the authors due to the absence of this in the other generations. All other necropsy observations were similar for the control and the treated litters. Evaluation of selected tissues from 10 control weanlings and 10 high dose weanlings from the F3b generation revealed no abnormalities. Changes present in the lung were consistent with minimal to mild interstital pneumonia. The microscopic appearance of the gonads was unremarkable and consistent with sexually immature rats.
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- The sex ratio was not affected by treatment.
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F2
- Generation:
- F2
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- F3
- Generation:
- other: F3
- Effect level:
- >= 3 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Conclusions:
- The key reproductive study is a multigenerational study for the category member, ATMP-H, conducted prior to the adoption of OECD test guidelines and pre-GLP. Male and female Long-Evans rats were administered ATMP 60 days prior to mating (F0) and continuously thereafter (F1, F2, F3) in the diet at fixed concentrations of 0, 300, 1000 and 3000 ppm for three consecutive generations. The NOAEL for general toxicity and reproductive toxicity was greater than the highest dose tested of 3000 ppm. The concentration of the test substance and mean weekly food intake values were used to determine the approximate doses received by the animals. The dose of 3000 ppm was approximately equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day in females (Biodynamics Inc., 1979a).
Reference
Table 3 - Test substance intake based on food intake (weekly mean data) measurements .
| Males (mg/kg bw/day) | Males (mg/kg bw/day) | Males (mg/kg bw/day) | Females (mg/kg bw/day) | Females (mg/kg bw/day) | Females (mg/kg bw/day) | |
| Group (ppm) | II (300) | III (1000) | IV (3000) | II (300) | III (1000) | IV (3000) |
| F0 growth | 33.4 | 111.6 | 342.3 | 37.3 | 117.1 | 362.5 |
| F0 rest | 18.4 | 60.7 | 182.9 | 24.3 | 75.7 | 247.2 |
| F1 growth | 26.3 | 89.6 | 270.2 | 28.1 | 98.4 | 290.2 |
| F1 rest | 14.4 | 41.7 | 141.0 | 20.1 | 67.3 | 201.1 |
| F2 growth | 29.6 | 95.4 | 296.6 | 34.3 | 112.6 | 337.8 |
| F2 rest | 17.6 | 58.3 | 171.9 | 25.0 | 81.4 | 243.9 |
Table 4 - Summary of offspring
survival for the F1 generation.
| Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | Postnatal survival (%) | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) |
| 0 -4a | 4 -14b | 14 -21 | |||||||
| F0 to F1a | |||||||||
| I (0) | 22.5 | 98.8 | 9.1 | 92.0 | 94.3 | 100 | 57.1 | 95.2 | 0.87 |
| II (300) | 22.4 | 98.2 | 8.6 | 97.3* | 90.5 | 100 | 65 | 100 | 0.87 |
| III (1000) | 22.5 | 98.1 | 7.6* | 96.2 | 85.4** | 100 | 47.6 | 95.2 | 0.88 |
| IV (3000) | 22.3 | 98.1 | 8.7 | 99.2** | 91.4 | 99 | 52.2 | 100 | 1.24 |
| F0 to F1b | |||||||||
| I (0) | 22.1 | 93.0 | 8.9 | 87.2 | 96.0 | 99.3 | 61.1 | 88.9 | 1.07 |
| II (300) | 22.1 | 96.0 | 8.7 | 91.7 | 91.3 | 99.4 | 83.3 | 100 | 1.12 |
| III (1000) | 22.1 | 97.2 | 9.3 | 94.8* | 93.7 | 100 | 56.3 | 100 | 0.84 |
| IV (3000) | 22.1 | 95.8 | 9.2 | 97.6** | 96.5 | 99.5 | 28.6 | 100 | 0.96 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at Day 0 of lactation are used in calculations.
Table 5 - Summary of offspring survival for the F2 generation.
| Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | Postnatal survival (%) | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) |
| 0 -4a | 4 -14b | 14 -21 | |||||||
| F1 to F2a | |||||||||
| I (0) | 22.2 | 99.5 | 9.2 | 96.2 | 93.5 | 100 | 33.3 | 94.4 | 1.09 |
| II (300) | 22.3 | 100 | 9.5 | 96.8 | 99.5** | 100 | 35.0 | 100 | 1.18 |
| III (1000) | 22.1 | 99.6 | 9.4 | 95.4 | 99.5** | 98.6 | 40.9 | 100 | 1.06 |
| IV (3000) | 22.3 | 97.4 | 9.1 | 97.3 | 100** | 100 | 30.4 | 100 | 0.92 |
| F1 to F2b | |||||||||
| I (0) | 22.4 | 99.3 | 8.8 | 78.5 | 100 | 100 | 35.7 | 85.7 | 0.89 |
| II (300) | 22.1 | 96.1 | 8.8 | 93.6** | 92.5 | 98.1 | 61.1 | 100 | 1.11 |
| III (1000) | 22.1 | 92.5** | 8.2 | 92.4** | 88.5** | 58.8 | 93.8 | 93.8 | 0.95 |
| IV (3000) | 22.5 | 99.1 | 9.0 | 96.6** | 97.8 | 98.9 | 50.0 | 100 | 0.94 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at Day 0 of lactation are used in calculations.
Table 6 - Summary of offspring survival for the F3 generation.
| Group (ppm) | Mean gestation length | % pups born alive | Mean no weaned/litter | Postnatal survival (%) | Postnatal survival (%) | Postnatal survival (%) | % litters with death (days 0 -21)c | % litters weanedc | Sex ratio (M/F) |
| 0 -4a | 4 -14b | 14 -21 | |||||||
| F2 to F3a | |||||||||
| I (0) | 22.3 | 97.9 | 7.8 | 89.5 | 94.3 | 99.4 | 54.5 | 95.5 | 0.91 |
| II (300) | 22.4 | 91.3 | 6.4 | 87.2 | 89.5 | 100 | 75.0 | 100 | 1.13 |
| III (1000) | 22.2 | 96.2 | 7.7 | 85.9 | 89 | 100 | 57.1 | 87.7 | 1.09 |
| IV (3000) | 22.2 | 98.6 | 8.8 | 96.7** | 91.9 | 99.4 | 66.7 | 94.7 | 1.11 |
| F2 to F3b | |||||||||
| I (0) | 22.2 | 92.9 | 9.1 | 89.5 | 97.4 | 98.6 | 50.0 | 88.9 | 1.00 |
| II (300) | 22.4 | 96.1 | 8.7 | 92.4 | 98.5 | 99.2 | 43.8 | 93.8 | 1.06 |
| III (1000) | 22.1 | 92.7 | 8.3 | 93.5 | 97.3 | 100 | 38.5 | 100 | 0.83 |
| IV (3000) | 22.2 | 98.5** | 9.2 | 89.9 | 98.7 | 100 | 52.9 | 94.1 | 1.45 |
Significantly different from control *p≤0.05; **p≤0.01
aComparison between days for postnatal offspring survival are calculated using Day 4 pre-cull data.
bComparison between days for postnatal offspring survival are calculated using Day 4 post-cull data.
cOnly those pups found alive at
Day 0 of lactation are used in calculations.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 275 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Klimisch score 2
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There are no reproductive toxicity test data available for ATMP-N-Oxide-5K, and therefore, read across data from a three generation study that was performed using ATMP-H (CAS 6419 -19 -8) in the rat were used to fulfil this endpoint.
The key reproductive study is a multigenerational study for the category member, ATMP-H, and is judged to be reliable with restrictions. Male and female Long-Evans rats were administered ATMP 60 days prior to mating (F0) and continuously thereafter (F1, F2, F3) in the diet at fixed concentrations of 0, 300, 1000 and 3000 ppm for three consecutive generations. The litters from F0, F1 and F2 matings were raised to maturity and also mated. Offspring from the first litter of each generation (F1a, F2a, F3a) were taken for necropsy on lactation Day 21. The parents were re-mated following a 14-day rest period and the offspring randomly selected at seven days post-weaning to continue as the F1b and F2b generation parents. Remaining F1b and F2b animals, as well as the F3a and F3b generation, were taken for necropsy. A gross internal examination was conducted on these animals. Randomly selected offspring from the F3a litters (10 pups/sex/group) were necropsied and selected tissues examined microscopically. Evaluations of adult mortality, mating, pregnancy, fertility, body weight data, food consumption data (growth and rest periods), litter survival, offspring viability at parturition, offspring weight and sex, and necropsy of adults and offspring, did not indicate any treatment-related adverse effects. The NOAEL for general toxicity and reproductive toxicity was greater than the highest dose tested, 3000 ppm. The concentration of the test substance and mean weekly food intake values were used to determine the approximate doses received by the animals. 3000 ppm was approximately equal to a dose of 275 mg/kg bw/day in males and 310 mg/kg bw/day in females (Biodynamics Inc., 1979a).
Effects on developmental toxicity
Description of key information
There are no developmental toxicity test data available for ATMP-N-Oxide-5K. Therefore, read across data from studies for ATMP-H (CAS 6419-19-8) in the rat and mouse respectively were used for this endpoint.
In a developmental toxicity study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H was administered by oral gavage to pregnant Charles River SD rats (24/dose) on gestation days 6-15. The doses tested were 100, 500 or 1000 mg/kg bw/day. The maternal NOAEL was concluded to be 500 mg/kg bw/day and the NOAEL for fetotoxicity and teratogenicity were concluded to be ≥1000 mg/kg bw/day respectively. This was based on females exposed to 1000 mg/kg bw/day gained less weight compared to the controls during the dosing period and was considered as treatment related. No other treatment-related effects were observed (BioDynamics Inc., 1979c).
In a developmental toxicity study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H was administered by oral gavage to pregnant CD-1 mice (35 mated females/dose) on gestation days 6 -15. The doses tested were 100, 500 and 1000 mg/kg bw/day. The NOAEL for maternal toxicity, foetal toxicity and teratogenicity was concluded to be ≥1000 mg/kg bw/day (Biodynamics Inc., 1980).
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data. Dates of treatment were 27.12.1978 to 19.01.1979
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Guideline:
- other: FDA "Guidelines for reproductive studies for evaluation of drugs for human use", segment II (teratological study)
- Deviations:
- not specified
- Remarks:
- Treatment on GD 6 - 15; no record of gravid uterine weight; number corpora lutea not recorded; no analytical confirmation of exposure levels.
- Principles of method if other than guideline:
- Study was used to assess the teratogenic and/or embryotoxic potential of the test substance.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Wilmington, Mass
- Age: 72 days at mating
- Weight at study initiation: 240 – 250 grams
- Fasting period before study: Not specified
- Housing: Individually housed in elevated stainless steel cage (however, not under the mating).
- Diet: Purina Certified Rodent Chow 5001, ad libitum
- Water: By automated water system, ad libitum
- Acclimation period: 28 November to 19 December 1978
ENVIRONMENTAL CONDITIONS
- Temperature (°C): monitored twice daily, no more details.
- Humidity (%): Not specified
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
IN-LIFE DATES: From: Not specified To: 19th of January 1979 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Distilled
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: The test substance was mixed with water and administered at 10 mg/kg bw/day. Dosing solutions were prepared fresh daily. Individual doses were adjusted based on the most recent body weight data.
DIET PREPARATION
- Rate of preparation of diet: Daily
- Storage temperature of food: Room temperature
VEHICLE
- Justification for use and choice of vehicle: N/a
- Concentration in vehicle: 22.4%
- Amount of vehicle: 10 mg/kg bw/day
- Lot/batch no.: Not specified
- Purity: Not specified - Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: Overnight
- Further matings after two unsuccessful attempts: No data
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- Gestation days 6 - 15
- Frequency of treatment:
- Daily as a single dose
- Duration of test:
- 21 days
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 24 mated females/dose
- Control animals:
- yes, concurrent vehicle
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations included gross signs
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestation day 0, 6, 10, 15, 20 and 21 (pre-necropsy)
BODY WEIGHT: Yes
- Time schedule for examinations: Gestation day 0, 6-15, 21
FOOD CONSUMPTION AND COMPOUND INTAKE:
WATER CONSUMPTION AND COMPOUND INTAKE: No
POST-MORTEM EXAMINATIONS: Yes, all females
- Sacrifice on gestation day 21 (all surviving dams) and day 21 post-mating (all surviving non-pregnant females). - Ovaries and uterine content:
- Examinations included:
- Number of corpora lutea: Yes
- Sites of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes, approximately 50% of foetuses subject to gross dissection
- Soft tissue examinations: Yes, approximately 50% of foetuses subject to gross dissection (followed by processing / staining (Alizarin red) for skeletal abnormalities/variations)
- Skeletal examinations: Yes, approximately 50% of foetuses subject to gross dissection
Type of skeletal malformations control: angulated ribs, cervical rib, wavy rib
- Head examinations: Not specified
Other: Approximately 1/2 of the foetuses were subject to Wilson serial sectioning for neural/visceral defects (10X or 20X magnification) after fixing in Bouin's solution. Additionally, approximately 1/2 of the foetuses were examined of skeletons anomalies and ossification variation after Alizarin red staining using the method of Crary but with the following modification: eviscerated foetuses were immediately placed into an aqueous potassium hydroxide solution followed by staining. Thereafter, stained foetuses were placed in Mall's solution to remove excess stain prior to clearing and storage in benzyl alcohol-glycerine solution. Internal sex determination occurred for both the groups. - Statistics:
- Chi squared, F-test and Student's T-test (absolute data) were used to compare between control and each test substance-treated group. T-tests modified using Cochran's approximation were used when variances differed significantly. Live foetuses, resorptions, implantations and corpora lutea were compared to control by using one-tailed T-test.
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- One female in the 100 mg/kg bw/day dose group was sacrificed in a moribund condition on gestation day 6 which was the first day of treatment. No other mortality occurred in any of the other dose groups or the control group.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- In the 1000 mg/kg bw/day dose group, lower weight gain compared to the control group was observed, although not statistically significant. No other significant differences in the mean body weight between the dose groups were observed.
- 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:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were observed.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a statistically significant increase in the implantation efficiency in the 100 mg/kg bw/day dose group. However, this was not considered to be treatment-related.
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The occurrence of ≥2 resorptions in each of the treated dose groups compared to the control group was higher. However, the values were within the historical control values and therefore, not considered as treatment-related.
- Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean number of resorption observed in the 100 and 1000 mg/kg bw/day dose groups were significantly greater than the control dose group. However, the values were within the historical control range and therefore not considered as treatment-related.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no dead foetuses in any groups.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There were no treatment-related changes in the pregnancy rate.
- Other effects:
- no effects observed
- Description (incidence and severity):
- A statistically significant decrease in the mean number of corpora lutea were observed in the 100 mg/kg bw/day dose group, however, this was not considered as treatment-related since it was not occurring in a dose-dependent manner.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day
- Basis for effect level:
- body weight and weight gain
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The mean foetal weights were comparable between the treated animals and the control dose group.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The mean numbers of live foetuses were comparable between control and the treated groups.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Sex: males/litter 6.9/7.0/6.6/6.0; females 7.4/6.9/7.0/6.9 (no significant effect) Sex ratio (m:f): 92.4%/102.0%/94.6%/87.3% (no significant effect)
- Changes in litter size and weights:
- not specified
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In the 1000 kg/kg bw/day dose group, 6 of 16 foetuses in one female had defects including flexed forepaws, shortened and thickened torso, abdominal distension and exaggerated forward flexure of the head. No other significant external malformations were observed. No other dose groups had any malformations.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- In the foetal skeletal examination, variations in the ossification occurred. These variations may represent delays in the ossification process or slight ossification irregularities. However, the varation were comparable between the treated groups and the control group.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The incidence of foetuses with soft tissue malformations was considered comparable between the control group and the treatment groups. The types of soft tissue malformations, e.g. distended renal pelvis and/or distended ureter are frequently observed in the specific rat strain used. A malrotation defect of the heart was observed in two foetuses in the 1000 mg/kg bw/day. Both of these foetuses had external malformations and were from the same litter as had observed external malformations. Incidences in the 500 and 1000 mg/kg bw/day were comparable to the control group. In the 100 mg/kg bw/day, the incidence of soft tissue malformations was higher than in the control group. However, this difference was not statistically significant and there was no dose relationship. Therefore, the observed effects were not considered as treatment-related.
- Other effects:
- no effects observed
- Description (incidence and severity):
- The mean crown-rump length for both sexes was significantly greater in the 500 mg/kg bw/day compared to the control group. This difference was not considered as biologically significant and therefore, not treatment related. No other differences were observed compared to the control group.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No teratogenic effects observed.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No fetotoxic effects observed.
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- In a developmental toxicity study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H was administered by oral gavage to pregnant Charles River SD rats (24/dose) on gestation days 6-15. The doses tested were 100, 500 or 1000 mg/kg bw/day. The maternal NOAEL was concluded to be 500 mg/kg bw/day and the NOAEL for fetotoxicity and teratogenicity were concluded to be ≥1000 mg/kg bw/day respectively. This was based on females exposed to 1000 mg/kg bw/day gained less weight compared to the controls during the dosing period and was considered as treatment related. No other treatment-related effects were observed.
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- No data. Treatment days were 09.04.1980 to 13.05.1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Guideline:
- other: FDA "Guidelines for reproductive studies for evaluation of drugs for human use", segment II (teratological study)
- Deviations:
- not specified
- Remarks:
- No analytical evaluation of exposure levels.
- Principles of method if other than guideline:
- The study was designed to evaluate the embryotoxic and/or teratogenic potential of the test substance. Dosing was on gestation days 6-15, no measurement of gravid uterine weights and corpora lutea were not counted.
- GLP compliance:
- no
- Limit test:
- no
- Species:
- mouse
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: Females 57 days (males stated to be sexually mature)
- Weight at study initiation: Females on gestation Day 0 were approximately 26 g.
- Fasting period before study: No data
- Housing: Individual in elevated stainless steel cages.
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: One month
ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data. Monitored twice daily.
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
IN-LIFE DATES: From: Day 6 of gestation: 09.04.1980 - 04.05.1980 To: Day 15 of gestation: 18.04.1980 - 13.05.1980. - Route of administration:
- oral: gavage
- Vehicle:
- other: Not clear, stated to be distilled water and corn oil in different parts of the report.
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of test substance were dissolved in distilled water and administered at a constant volume of 10 ml/kg bw/day. Dosing solutions were prepared fresh daily.
- Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- - Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: Overnight
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy. - Duration of treatment / exposure:
- GD 6 - 15
- Frequency of treatment:
- daily
- Duration of test:
- 18 days
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 500 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 35 mated females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: No data
- Rationale for animal assignment: Random - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes for mortality and gross signs of toxicological effects (no further details).
- Time schedule: Twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Gestation days 0, 6, 9, 12, 15 and 18.
BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 6, 9, 12, 15 and 18. Calculated body weight change for days 0-6, 6-15 and 15-18.
FOOD CONSUMPTION: No
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 18 (all surviving dams) and Day 18 post-mating in all surviving non-pregnant females.
- Organs examined: Complete gross pathology examination. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes, and weighed, measured and sex determined.
- Other: Live and dead fetuses. Internal sex determination of fetuses. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: No data - Statistics:
- Maternal body weight and reproduction data: Bartlett's test followed by one-way ANOVA (equal variance) followed by Dunnett's test or Kruskal-Wallis test (unequal variance) and summed rank test (Dunn). Pregnancy and fetal parameters: Chi square analysis followed by Fisher Exact test with Bonferroni correction. Armitage test for linear trend.
- Indices:
- No data
- Historical control data:
- No data
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No treatment-related deaths occurred. The only deaths that occurred were a result of dosing errors. One death occurred in a control animal on gestation day 11.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- no effects observed
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal
- Effect level:
- >= 1 000 mg/kg bw/day
- Basis for effect level:
- other: No adverse toxicity effects observed.
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- External malformations:
- no effects observed
- Description (incidence and severity):
- The incidence of fetal external malformations were comparable between control and treated groups. No malformations were noted in the treated groups during the gross evisceration examinations.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The type and incidence of ossification variations during the skeletal evaluations were similar to the controls. However, the incidence of skeletal malformations in the mid-dose group was significantly increased depending on one single mid-dose litter where six fetuses had skeletal malformations. The malformations included misshapen tibia and fibula, angulated ribs and defective sternebrae. These effects were not observed in the highest dose groups and consequently, considered to not be treatment-related.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- The incidence of fetal soft tissue malformations were comparable between control and treated groups. No malformations were noted in the treated groups during the gross evisceration examinations.
- Other effects:
- no effects observed
- Description (incidence and severity):
- Anogenital distance was unaffected.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse teratogenic effects observed.
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse fetotoxic effects were observed.
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- In a developmental toxicity study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H was administered by oral gavage to pregnant CD-1 mice (35 mated females/dose) on gestation days 6 -15. The doses tested were 100, 500 and 1000 mg/kg bw/day. The NOAEL for maternal toxicity, fetal toxicity and teratogenicity was concluded to be >1000 mg/kg bw/day.
Referenceopen allclose all
Table 1 - Summary of Malformations found during the fetal skeletal examination.
| Group (mg/kg bw/day) | Malformation | Fetuses | Litter | ||
| No. with malf./total examined | % | No. with malf fetuses/total examined | % | ||
| 0 | None | 0/138 | 0/24 | ||
| 100 | Cervical vertebral defect | 1/156 | 0.6 | 1/28 | 3.6 |
| 500 | Tibia misshapened - alone | 1/203 | 0.5 | 1/34 | 2.9 |
| - with misshapened fibula and angulated ribs | 2/203 | 1.0 | 1/34 | 2.9 | |
| - with misshapened fibula, angulated ribs and sternebrae defects | 1/203 | 0.5 | 1/34 | 2.9 | |
| - with angulated ribs | 1/203 | 0.5 | 1/34 | 2.9 | |
| Angulated ribs and scrambled sternebrae | 1/203 | 0.5 | 1/34 | 2.9 | |
| Cervical rib | 1/203 | 0.5 | 1/34 | 2.9 | |
| 5 lumbar vertebrae | 2/203 | 1.0 | 1/34 | 2.9 | |
| Total | 9/203 | 4.4* | 3/34 | 8.8 | |
| 1000 | Scrambled sternebrae | 1/183 | 0.5 | 1/32 | 3.1 |
| Vertebral defects | 1/183 | 0.5 | 1/32 | 3.1 | |
*Difference from the control group statistically significant p<0.05 (Fisher Exact test).
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- Klimisch score 2
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
There are no developmental toxicity test data available for ATMP-N-Oxide-xK. Therefore, read across data from developmental toxicity studies for ATMP-H (CAS 6419-19-8) in the rat and mouse respectively were used for this endpoint.
In a developmental toxicity study, ATMP-H was administered by oral gavage to pregnant Charles River SD rats (24/dose) on gestation days 6-15. The doses tested were 100, 500 or 1000 mg/kg bw/day. Control animals received the vehicle (water) only. Dams were sacrificed on gestation day 21 and recovered foetuses evaluated for external, soft-tissue and skeletal malformations. Maternal mortality, pregnancy rate, body weight gain, uterine implantation data, foetal size, sex data, ossification variation data and teratological evaluations were evaluated. High dose females gained less weight than the controls during the dosing period. In the high dose group, six foetuses from a single litter had common multiple malformations that included flexed forepaws, shortened and thickened torso, abdominal distension and exaggerated flexure of the head. Soft tissue examination revealed two of these foetuses had a malformation defect of the heart. The findings were observed in one litter only to a dam showing signs of toxicity in the form of reduced body weight gain of 50%. Therefore, the malformations were considered as secondary to maternal toxicity. No other foetuses in the high dose group had any effects.
The maternal NOAEL was concluded to be 500 mg/kg bw/day and the NOAEL for fetotoxicity and teratogenicity were concluded to be ≥1000 mg/kg bw/day respectively. This was based on females exposed to 1000 mg/kg bw/day gained less weight compared to the controls during the dosing period and was considered as treatment related. No other treatment-related effects were observed (BioDynamics Inc., 1979c).
In the key developmental toxicity study, ATMP-H was administered by oral gavage to pregnant CD-1 mice (35 mated females/dose) on gestation days 6 -15. The doses tested were 100, 500 and 1000 mg/kg bw/day whereas the control group received the vehicle only. Parameters for evaluation included mortality, body weight, clinical signs and uterine implantation data, ossification variation data and teratological evaluation. The occurring deaths in the treated animals depended on dosing errors and one death of a control animal occurred on gestation day 11. No adverse clinical effects, effects on body weights or body weight gains, effects during the macroscopic examination or on reproductive parameters (pregnancy rates, numbers of live and dead fetuses, implantations and resorptions) occurred. In the fetuses, the fetal sex distribution and anogenital distance were unaffected by the treatment. The NOAEL for maternal toxicity, fetal toxicity and teratogenicity was concluded to be ≥1000 mg/kg bw/day (BioDynamics Inc., 1980).
In a supporting developmental toxicity study, conducted in a similar manner to OECD Test Guideline 414 but pre-GLP, ATMP-H was concluded to has a maternal and a teratogenicity NOAEL of ≥1000 mg/kg bw/day based on no adverse findings. ATMP-H was administered by oral gavage to pregnant CD-1 mice from Day 6 to 15 of gestation at doses of 100, 300 or 1000 mg/kg bw/day. Control animals received equal volumes of distilled water. Females were sacrificed on gestation Day 18 and fetuses were examined for external malformations. Maternal mortality, body weight gains, implantation data, in-life physical observations and gross postmortem examination data, fetal body weights, sex distribution and external malformation data did not reveal any signs of an adverse toxicological effect. No obvious or consistent test substance-related effects on reproduction were observed at any dose. Consequently, the maternal and teratogenicity NOAELs were concluded to be ≥1000 mg/kg bw/day (BioDynamics, 1979b).
In a pilot teratology study, conducted prior to the adoption of OECD test guidelines and pre-GLP, ATMP-H did not cause any adverse effects on dams or fetuses in Long-Evans rats. The rats were administered by oral gavage at doses of 100, 500 or 1000 mg/kg bw/day. No obvious or consistent test substance-related effects on reproduction were observed at any dose. Maternal physical observations and necropsy data as well as fetal gross findings did not reveal evidence of adverse effects. Therefore, maternal and teratogenicity NOAEL were concluded to be at least 1000 mg/kg bw/day in rats (BioDynamics, 1978).
Justification for classification or non-classification
Based on the available read across results from the key studies, no classification is required for ATMP-N-oxide-5K for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
