Reaction mass of Benzenamine, N,N-dimethyl- , molybdate, tungstate & phosphates

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data from secondary source

Data source

Reference

Reference 1

Reference Type:

secondary source

Title:

Screening-Level Hazard Characterization Monocyclic Aromatic Amines Category

Author:

U.S. Environmental Protection Agency

Year:

2009

Bibliographic source:

U.S. Environmental Protection Agency, Hazard Characterization Document , September, 2009

Reference 2

Reference Type:

secondary source

Title:

Reproductive toxicity of test material

Author:

NTRL report

Year:

1990

Bibliographic source:

NTRL report , 1990

Reference 3

Reference Type:

other: Authoritative database

Title:

Toxicological Study of Metam-Sodium (CAS No: 137-42-8)

Author:

HSDB

Year:

2018

Bibliographic source:

U.S. National Library of Medicine National Institutes of Health, Health & Human Services; 2018

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: EPA OTS 798.4900

Principles of method if other than guideline:

Reproductive and developmental toxicity study of test material was performed on Sprague Dawley rats.

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Test material

Test material information

Constituent 1

Reference substance name:

N,N-diethylaniline

EC Number:

202-088-8

EC Name:

N,N-diethylaniline

Cas Number:

91-66-7

Molecular formula:

C10H15N

IUPAC Name:

N, N-diethyl aniline

Test material form:

liquid

Details on test material:

- Name of test material: N,N-diethylaniline- Substance type: Organic- Physical state: Liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

No data available

Sex:

female

Details on test animals or test system and environmental conditions:

Details on test animals and env. conditionsTEST ANIMALS- Source: Charles River Breeding Laboratories. Inc. Shaver Road Portage. Michigan 49081- Age at study initiation: female: Six weeks ,male : Seven weeks- Weight at study initiation: mean: 207grams(167.6-311.1g)- Fasting period before study:- Housing: Individually. except during the first week of the acclimation period (two females/cage) and mating. in stainless steel suspended cages with wire mesh floors.- Use of restrainers for preventing ingestion (if dermal): yes/no- Diet (e.g. ad libitum): Purina. Certified Rodent Chow No. 5002 (mash) fed ad libitum.- Water (e.g. ad libitum): Tap water delivered by automatic watering system, ad libitum (Elizabethtown Water Company).- Acclimation period:21 days ENVIRONMENTAL CONDITIONS- Temperature (°C):18.88-23.33°C- Humidity (%):26-68%- Air changes (per hr):- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (7 AM to 7 PM) via automatic timerIN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

Details on exposurePREPARATION OF DOSING SOLUTIONS:Test material dissolved in corn oil DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): corn oil - Concentration in vehicle: 0, 50,250,500mg/kg bw/day- Amount of vehicle (if gavage): 5ml/kg bw/day - Lot/batch no. (if required): No data available- Purity: No data available

Details on mating procedure:

Mated females were used

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

10 days ( from day 6 through day 15 of gestation )

Frequency of treatment:

daily

Details on study schedule:

No data available

Doses / concentrations

Remarks:

0, 50,250,500 mg/kg bw/day

No. of animals per sex per dose:

Total:1010 mg/kg bw/day:2450mg/kg bw/day:24250mg/kg bw/day:24500 mg/kg bw/day:29

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Examinations

Parental animals: Observations and examinations:

Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Twice daily (morning and afternoon) for signs of pharmacologic or toxicologic effects and mortality. In addition. eachfemale was given a detailed physical examination on Days 0. 10. 12. 15 and 20 of gestation. On Days 6. 10. 12 and 15 of gestation the examinations were given after dosing. Time schedule: twice daily BODY WEIGHT: YesTime schedule for examinations: Recorded on Days 0. 6. 10. 12, 15 and 20 of gestation.FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes Recorded for the following intervals during gestation: Days 0 to 5. 6 to 10. 10 to 15 and 15 to 20. Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations: OTHER:

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

All fetuses were given a gross examination for external malformations/variations to include observation for palatal defects. Subsequently. Each fetus was weighed and individually identified. The sex of each fetus was noted externally (ano-genital distance) and was confirmed by internal inspection of the gonads at subseqaent evaluation

Postmortem examinations (parental animals):

Postmortem examinations (Parent Animal)SACRIFICE: Day 20 of gestation using Lethal exposure to ether.GROSS NECROPSY: Complete gross postmortem examinations were performed on all mated females including those dying spontaneously or sacrificed in a moribund condition. External surface, all orifices, thecranial cavity, carcass, the external surface of the spinal cord and sectioned surfaces of the brain, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs were examined for all animals. The carcass of each female was discarded at the completion of the gross post-mortem evaluationHISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively. macroscopic examination was performed

Postmortem examinations (offspring):

Postmortem examinations (offspring)SACRIFICEApproximately one-half of the fetuses in each litter (alternating fetuses within the litter) were evaluated for soft tissue malformations/variations

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In the 50mg/kg bw dose group three females were noted with excessive salivation during the physical evaluations. No other adverse effects of treatment at this dose level were noted from the physical evaluations.Rats in the 250mg/kg and 500mg/kg dose groups also had excessive lacrimation and staining of the skin/fur in the ano-genital region

Dermal irritation (if dermal study):

not specified

Mortality:

mortality observed, treatment-related

Description (incidence):

No mortality occurred in the control. 50mg/kg and 250mg/kg dose groups. In the 500mg/kg dose group two females died and three females were sacrificed in a moribund condition (17.2 %mortality rate).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the 50mg/kg bw dose group mean weight gains for the Day 6-15 treatment interval of gestation and for the Day 6-20 gestation interval using corrected Day 20 weights were lower than control (-14.3 %and -12.1%, respectively); however, these differences from control data were not statistically significant. In the 250mg/kg dose group. Mean weight gains for the Day 6-15 and 6-20 gestation intervals were lower than control (-19.0% and -16.4%, respectively); however, only for the Day 6-15 gestation interval did these data differ statistically from control data. In the 500mg/kg dose group mean weight gain data for the Day 6-15 and 6-20 gestation intervals were markedly lower than control (--71.4 % and- 56.8%, respectively) and these data differed statistically from control data.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

During the treatment period mean food consumption was lower than control in each of the treated groups. In the low-dose group, mean food consumption was significantly lower than control during the Day 6-10 gestation interval (-12.1%) but was comparable to control for the day 10-15 intervals. In the mid-dose group. Mean food consumption was significantly lower than control during both the Day 6-10 and 10-15 gestation intervals (-22.0% and -11.7%. respectively). Similarly, in the high-dose group. mean food consumption was significantly lower than control during both the Day 6-10 and 10-15 gestation intervals (-47.3% and -13.8%. respectively).

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

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 specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Description (incidence and severity):

The pregnancy rate was 100% in 50mg/kg bw dose group. 95.8% (23/24 females) in the control and 250mg/kg bw dose groups and 96.6% (28/29 females) in the 500mg/kg bw dose group. No adverse effect of treatment was evident from pregnancy rate data.The mean number of corpora lutea and uterine implantations was considered comparable between the control and treated groups.The mean number of resorption sites per pregnant female was comparable between the controls. 50mg/kg bw and 250mg/kg bw dose groups. In the 500mg/kg bw dose group, the mean number of resorption sites was higher than control; however, this difference was not statistically significant.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: No effects on reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Description (incidence and severity):

The mean number of viable fetuses per pregnant female was comparable between the control and treated groups

Body weight and weight changes:

no effects observed

Description (incidence and severity):

mean fetal weight unaffected at 50mg/kg bw and 250mg/kg bw dose mean fetal weight statistically lower than control

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Description (incidence and severity):

Evaluation of fetuses recovered from treated group females for external, visceral and skeletal malformations indicated no adverse effect of treatment. At the 500mg/kg bw dose level, the incidence of fetuses with unossified sternebral elements (particularly the fifth and sixth sternebrae) was increased suggestive of a retardation in ossification.

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

body weight and weight gain

gross pathology

Remarks on result:

other: overall no developmental toxic effects observed

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 250mg/kg bw .When female Sprague Dawley rats were treated with test material orally.

Executive summary:

The reproductive and developmental toxicity study of test material was performed on mated female Sprague Dawley rats according EPA OTS 798.4900. The test material dissolved in corn oil and administered in dose concentration0, 50,250,500 mg/kg bw/day by oral gavage route from day 6 to 15 of gestation in dose volume 5ml/kg bw .The control, 50mg/kg and 250 mg/kg dose groups contained 24 females each; the 500mg/kg dose group contained a total of 29 females. All the animals were observedtwice daily for signs of pharmacologic or toxicologic effects and mortality. In addition, Each female was given a detailed physical examination on Days 0, 10,12, 15 and 20 of gestation. On Days 6, 10, 12 and 15 of gestation the examinations were given after dosing. Body weight recorded on Days 0, 6, 10,12, 15 and 20 of gestation. Food Consumption recorded for the following intervals during gestation Days 0 to 5, 6 to 10 ,10 to 15 and 15 to 20. Females were sacrificed on Day 20 of gestation and given a gross postmortem examination. Ovaries were evaluated for number of corpora lutea and uterine implantation data were evaluated for number of live, dead and resorbed fetuses. Fetuses recovered at this time were weighed,sexed and evaluated for external malformations; approximately one-half of the fetuses in each litter (alternating fetuses Within the litter) were processed for soft tissue examination (micro dissection procedure) and the remaining fetuses were processed for skeletal evaluations (Alizarin Red S).

Some maternal toxicity was evident at each dose level. 50mg/kg bw dose group females experienced depressed weight gain during the treatment period; however, these data did not differ statistically from control. Mean food consumption for the Day 6-10 interval of treatment in the 50mg/kg bw dose group was statistically lower than control and three 50mg/kg bw dose females experienced excessive salivation during the treatment period. Similar manifestations of maternal toxicity were seen at the 250mg/kg bw and 500mg/kg bw dose levels; however, the effects were more extreme. Physical examination of females in the 250mg/kg bw and 500mg/kg bwdosegroups revealed an increased incidence of females with excessive salivation, staining of the skin/fur in the ano-genital area and excessive lacrimation. At the 500mg/kg bw dose level, two females died and three females were sacrificed in a moribund condition (mortality rate:l7.2%)no mortality occurred in the 50mg/kg bw or 250mg/kg bw dose groups. No adverse effect of treatment was evident from uterine implantation Mean fetal weight and fetal sex distribution were unaffected by treatment at the 50mg/kg bw or 250mg/kg bw dose levels. In the 500mg/kg bw dose group, mean fetal weight data as a composite for both sexes and when distinguished by sex, were statistically lower than control. Evaluation of fetuses recovered from treated group females for external, visceral and skeletal malformations indicated no adverse effect of treatment. At the 500mg/kg bw dose level, the incidence of fetuses with unossified sternebral elements (particularly the fifth and sixth sternebrae) was increased suggestive of a retardation in ossification. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 250mg/kg bw .When femaleSprague Dawley rats were treated withtest materialorally.