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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Estimated NOAEL was considered to be 502 mg/kg bw when rats were treated with Poly (oxy-1,2-ethanediyl), .alpha.-(4-nonylphenyl)-.omega.-hydroxy-, branched orally.

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Data is predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached
Qualifier:
according to guideline
Guideline:
other: estimattion
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.4
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Tergitol NP-4
- Molecular formula (if other than submission substance): C23H40O5
- Molecular weight (if other than submission substance): 396.63 g/mol
- Substance type: Organic
- Physical state: Liquid
Species:
rat
Strain:
other: CD (Cr1 :CD(SD)IGS BR)
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
approx 52 days
Frequency of treatment:
Daily
Details on study schedule:
No data available
Remarks:
502 mg/kg bw
No. of animals per sex per dose:
12 male , 12 female
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
No data available
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
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: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
No data available
Dose descriptor:
NOAEL
Effect level:
502 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Remarks on result:
other: No effect on reproduction
Critical effects observed:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
No data available
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
No data available
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
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:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
No data available
Sex:
not specified
Remarks on result:
not measured/tested
Critical effects observed:
not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
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:
not specified
Histopathological findings:
not specified
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
No data available
Reproductive effects observed:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and "k" )  and ("l" and "m" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Nonionic Surfactants by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alcohol AND Alkane, branched with tertiary carbon AND Alkyl arenes AND Aryl AND Ether by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alcohol AND Alkyl arenes AND Ether AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Hydroxy, aliphatic attach [-OH] AND Olefinic carbon [=CH- or =C<] AND Oxygen, aliphatic attach [-O-] AND Oxygen, one aromatic attach [-O-] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Alcohol AND Alkylarylether AND Aromatic compound AND Dialkylether AND Ether AND Hydroxy compound AND Primary alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acidic [0,10) AND Basic [0,10) by Ionization at pH = 9

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Basic [70,80) OR No pKa value by Ionization at pH = 9

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Has superfragment AND OCCOR{*} by Superfragments ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.915

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.51

Conclusions:
estimated NOAEL was considered to be 502 mg/kg bw when rats were treated with Poly (oxy-1,2-ethanediyl), .alpha.-(4-nonylphenyl)-.omega.-hydroxy-, branched orally.
Executive summary:

In prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 2,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole). NOAEL was estimated to be 502 mg/kg bw when rats were treated with Poly (oxy-1,2-ethanediyl), .alpha.-(4-nonylphenyl)-.omega.-hydroxy-, branched orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
502 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 2 and from QSAR toolbox 3.4 (2017)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive toxicity: Oral

In different studies, 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) has been investigated for Reproductive toxicity. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole)). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 2,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole). NOAEL was estimated to be 502 mg/kg bw when rats were treated with Poly (oxy-1,2-ethanediyl), .alpha.-(4-nonylphenyl)-.omega.-hydroxy-, branched orally.

Also it is further supported by experimental data conducted by Tylet al(UNION CARBIDE CORP, NTRL: OTS0559310-1, 1999), Reproductive and developmental toxicity was evaluated in Sprague-Dawley female rat treated with Tergitol NP-4 in the concentration of 0, 50, 250 and 500 mg/kg/day in corn oil orally by gavage. One female rat were died at 500 mg/kg bw on day 6. Rust colored fur on the head, face, and back, a nonspecific indicator of stress (from hemoglobin breakdown products in the Harderian gland excreted via the tear ducts, so-called "bloody tears" or chromodacryorrhea, groomed from the eyes and nose) on gd 13 and 15, Rough coat (more severe than piloerection, indicative of more stress) on gd 12-15, Piloerection, another nonspecific sign of stress on gd 6 through 20, Lethargy on gd 6-15, Pica gd 6 and 7 and Prone positioning on gd 6-14 was observed at 500 mg/kg/day, and Piloerection, another nonspecific sign of stress on gd 6 through 20 and Pica on gd 6 and 8, at 250 mg/kg/day on gd 7-10 and 1315, and at 50 mglkg/day on gd 14 in one dam were observed. Decreased in body weight were observed in ten dams at 250 mg/kg/day and 12 dams at 500 mg/kg/day on gd 9 (first scheduled weigh time point during dosing), in two dams at 500 mg/kg/day on gd 12 (next scheduled weigh timepoint), and in two dams at 500 mg/kg/day on gd 15 (next scheduled weigh time point), all during the dosing period. Statistically significantly decreased in food consumption were observed at 250 and 500 mg/kg/day for gd 6-9, 9-12,12-15,6-1 and increased at 500 mg/kg/day for gd 18-20 and 15-20 (postdosing period), at 250 mg/kg/day for gd 18-20 and 15-20, and at 50 mg/kgfday for gd 18-20 and 15-20. No abortion or early delivery and no effect on numbers of litters (and fetuses) were observed in treated rats as compared to control. But, Significantly increased absolute and relative liver weights were observed in 50 and 250 and 500 mg/kg/day and no effect were observed on gravid uterine weight of treated rats as compared to control. Alopecia (various areas), were observed unrelated to treatment and blood present in urogenital opening, urinary bladder, mouth and nose, and lung lobes hemorrhagic and edematous were observed in unscheduled deaths one at 500 mg/kg/day and area of extra hard tissue on left median liver lobe at 50 mg/kg/day in one female rats were observed. In addition, no significant effect were observed on number of ovarian corpora lutea, total number of uterine implantation sites, on preimplantation loss, or on the incidence of resorptions and dead fetuses per litter, of nonlive implants (resorbed plus dead) per litter, or of adversely affected implants (nonlive plus malformed) per litter. No effect were observed such as number of live fetuses, sex ratio (% males) per litter, and the average fetal body weight per litter (all fetuses or separately by sex) were also unaffected by treatment. There was no dose effect or dose x sex interaction for fetal body weight parameters were observed in treated female rats as compared to control. No effects on external and visceral malformations were observed in treated rats as compared to control. Statistically significant skeletal variations such as cleft palate bilateral and unilateral rudimentary ribs on Lumbar I was observed in all fetuses or for male and female fetuses at 250 and 500 mg/kg/day as compared to control. Therefore, NOAEL was considered to be 50 mg/kg/day for P and F1 generation when Sprague-Dawley female rat by using Tergitol NP-4 orally by gavage from gd day 6 to 15.

Thus, based on the above studies and predictions on 2, 2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) and considering weight of evidence, 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) can be “Not classified” for reproductive toxicity.

Effects on developmental toxicity

Description of key information

NOAEL was considered to be 50 mg/kg/day for P and F1 generation when Sprague-Dawley female rat by using Tergitol NP-4 orally by gavage from gd day 6 to 15.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
October 20 - November 20, 1997 to January 30, 1998
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary literature
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Developmental Toxicity Evaluation of Tergitol NP-4 in rats
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Tergitol NP-4
- Molecular formula (if other than submission substance): C23H40O5
- Molecular weight (if other than submission substance): 396.63 g/mol
- Substance type: Organic
- Physical state: Liquid
- Impurities (identity and concentrations): polyethylene glycol, <3%,dinonylphenol ethoxylate, <3%,
Species:
rat
Strain:
Sprague-Dawley
Remarks:
CO
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC.
- Age at study initiation:
Female rats= 56 days
Male rats= 70 days
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: Males were housed singly in solid-bottom polycarbonate cages (8" x 19" x 10.5") with stainless steel wire lids. Non mated females were group housed (maximum three per cage), and mated females were singly housed in solid-bottom polycarbonate cages (8" x 19" x 10.5") with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ). Sani-Chips® animal bedding (P. J. Murphy Forest Products, Montville, NJ) was used in all cages.
- Diet (e.g. ad libitum): Pelleted feed (No. 5002 Purina Certified Rodent Diet®; PMI Feeds, Inc., St. Louis, MO). ad libitum
- Water (e.g. ad libitum): tap water (Durham, NC water system, in plastic bottles with stainless steel sipper tubes) available ad libitum
- Acclimation period: 7 days quarantine periods for the females

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
target temp: 64-79°F (17.8 - 26.1°C)
maintained temp: 70.7-73.2°F (21.5 - 22.9 °C)

- Humidity (%):
target humidity: 30-70%
maintained humidity 35.7 - 63.8%

- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12:12 hour light: dark cycle

IN-LIFE DATES:
From: Dosing: November 3-15,1997 (gestation day 6 through 15)
To: Necropsy: November 17-20,1997 (gestation day 20)
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The Tergitol NP-4 Surfactant for each dose was weighed out into a calibrated beaker (400 ml beaker to hold 200 ml, with adjustments for different volumes if needed). The appropriate volume of corn oil was added to each beaker, stirred with a stirring bar until the chemical was no longer visible, and then stirred for ten minutes more to give a dose range of 0, 50, 250 or 500 mg/Kg/day. The resulting formulation was sampled for archive and analytical samples and stored at 1-8°C in sealed, amber glass bottles protected from light. After storage and prior to use, the solutions were allowed to warm to room temperature and then stirred for ten minutes with a stirring bar. The formulations were then used for dosing.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 50, 250 or 500 mg/Kg/day
- Amount of vehicle (if gavage): 1.0 ml/kg
- Lot/batch no. (if required): 325A7
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to study dose formulation, formulations encompassing the range of dose employed (50 and 600 mg/mL) were assayed for homogeneity, stability, and dose level verification
Details on mating procedure:
- M/F ratio per cage: 1:1 (one male and one female)
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Each morning the females were examined for the presence of vaginal sperm and/or copulation plug.
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how): Sperm-positive females were individually housed until scheduled sacrifice on gestation day 20.
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
10 consecutive days
Frequency of treatment:
Daily
Duration of test:
Gestation day 6 through gestation day 15
Remarks:
0, 50, 250 and 500 mg/kg/day
No. of animals per sex per dose:
Total: 100
0 mg/kg/day: 25 females
50 mg/kg/day: 25 females
250 mg/kg/day: 25 females
500 mg/kg/day: 25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses was based on a range-finding study in pregnant rats performed at RTI. In range finding study, four group of eight sperm positive females were dosed once daily on gestation day 6 through 15 at concentartion 0, 500, 1500, and 3000 mg/kg/day at a dosing volume of 5.0 ml/kg. At 1500 and 3000 mg/kg/day, at least 50% of the dams died. At 500 mg/kg/day, all dams survived and were pregnant; seven of eight dams were pregnant at 0 mg/kg/day. Therefore, the highest dose level for the present study, 500 mg/kg/day, was chosen to induce overt maternal and developmental toxicity.

- Rationale for animal assignment (if not random): Sperm-positive female rats (dams) were assigned to treatment groups by a stratified randomization method, designed to provide uniform mean body weights across dose groups on gd 0 at the initiation ofthe study.
- Rationale for selecting satellite groups: No data available
- Post-exposure recovery period in satellite groups: No data available
- Section schedule rationale (if not random): No data available
Maternal examinations:
Mortality, Clinical sign, Body weight and Food consumption and Gross pathology were examined.
Ovaries and uterine content:
Number of ovarian corpora lutea, total number of uterine implantation sites, on preimplantation loss, or on the incidence of resorptions were examined.
Fetal examinations:
number of live fetuses and fetal body weight, Gross pathology and Histopathology were examined.
Statistics:
No data available
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Mortality: One female rat were died at 500 mg/kg bw on day 6 as compared to control.

Clinical sign: Rust colored fur on the head, face, and back, a nonspecific indicator of stress (from hemoglobin breakdown products in the Harderian gland excreted via the tear ducts, so-called "bloody tears" or chromodacryorrhea, groomed from the eyes and nose) on gd 13 and 15, Rough coat (more severe than piloerection, indicative of more stress) on gd 12-15, Piloerection, another nonspecific sign of stress on gd 6 through 20, Lethargy on gd 6-15, Pica gd 6 and 7 and Prone positioning on gd 6-14 was observed at 500 mg/kg/day, and Piloerection, another nonspecific sign of stress on gd 6 through 20 and Pica on gd 6 and 8, at 250 mg/kg/day on gd 7-10 and 1315, and at 50 mg/kg/day on gd 14 in one dam were observed as compared to control.

Body weight:
Decreased in body weight were observed in ten dams at 250 mg/kg/day and 12 dams at 500 mg/kg/day on gd 9 (first scheduled weigh time point during dosing), in two dams at 500 mg/kg/day on gd 12 (next scheduled weigh timepoint), and in two dams at 500 mg/kg/day on gd 15 (next scheduled weigh time point), all during the dosing period as compared to control.

Food consumption: Statistically significantly decreased on at 250 and 500 mg/kg/day for gd 6-9, 9-12,12-15,6-1 and increased at 500 mg/kg/day for gd 18-20 and 15-20 (postdosing period), at 250 mg/kg/day for gd 18-20 and 15-20, and at 50 mg/kgfday for gd 18-20 and 15-20 as compared to control.

Organ weights:
Significantly increased absolute and relative liver weights were observed in 50 and 250 and 500 mg/kg/day and no effect were observed on gravid uterine weight of treated rats as compared to control.

Gross pathology: Alopecia (various areas), were observed unrelated to treatment and blood present in urogenital opening, urinary bladder, mouth and nose, and lung lobes hemorrhagic and edematous were observed in unscheduled deaths one at 500 mg/kg/day and area of extra hard tissue on left median liver lobe at 50 mg/kg/day in one female rats were observed as compared to control.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
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
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified
Details on maternal toxic effects:
Reproductive function: estrous cycle: No significant effect were observed on number of ovarian corpora lutea, total number of uterine implantation sites, on preimplantation loss, or on the incidence of resorptions and dead fetuses per litter, of nonlive implants (resorbed plus dead) per litter, or of adversely affected implants (nonlive plus malformed) per litter were observed as compated to control.

Reproductive performance: No effect on number of live fetuses and sex ratio (% males) per litter were observed as compared to control.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
gross pathology
mortality
number of abortions
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption
other: No effect
Abnormalities:
not specified
Localisation:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
effects observed, treatment-related
Visceral malformations:
no effects observed
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
Mortality: No effects on number of live fetuses were observed as compared to control.

Body weight: No effect on fetal body weight was observed as compared to control.

Gross pathology: No effects on external malformations were observed as compared to control.

Skeletal malformations: Statistically significant skeletal variations such as cleft palate bilateral and unilateral rudimentary ribs on Lumbar I was observed in all fetuses or for male and female fetuses at 250 and 500 mg/kg/day as compared to control.

Visceral malformation: No effects on visceral malformations were observed as compared to control.
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations
visceral malformations
other: No effect
Abnormalities:
not specified
Localisation:
other: not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was considered to be 50 mg/kg/day for P and F1 generation when Sprague-Dawley female rat by using Tergitol NP-4 orally by gavage from gd day 6 to 15.
Executive summary:

In a developmental toxicity study, Sprague-Dawley female rat by using Tergitol NP-4 in the concentration of 0, 50, 250 and 500 mg/kg/day in corn oil orally by gavage. One female rat were died at 500 mg/kg bw on day 6. Rust colored fur on the head, face, and back, a nonspecific indicator of stress (from hemoglobin breakdown products in the Harderian gland excreted via the tear ducts, so-called "bloody tears" or chromodacryorrhea, groomed from the eyes and nose) on gd 13 and 15, Rough coat (more severe than piloerection, indicative of more stress) on gd 12-15, Piloerection, another nonspecific sign of stress on gd 6 through 20, Lethargy on gd 6-15, Pica gd 6 and 7 and Prone positioning on gd 6-14 was observed at 500 mg/kg/day, and Piloerection, another nonspecific sign of stress on gd 6 through 20 and Pica on gd 6 and 8, at 250 mg/kg/day on gd 7-10 and 1315, and at 50 mglkg/day on gd 14 in one dam were observed. Decreased in body weight were observed in ten dams at 250 mg/kg/day and 12 dams at 500 mg/kg/day on gd 9 (first scheduled weigh time point during dosing), in two dams at 500 mg/kg/day on gd 12 (next scheduled weigh timepoint), and in two dams at 500 mg/kg/day on gd 15 (next scheduled weigh time point), all during the dosing period. Statistically significantly decreased in food consumption were observed at 250 and 500 mg/kg/day for gd 6-9, 9-12,12-15,6-1 and increased at 500 mg/kg/day for gd 18-20 and 15-20 (postdosing period), at 250 mg/kg/day for gd 18-20 and 15-20, and at 50 mg/kgfday for gd 18-20 and 15-20. No abortion or early delivery and no effect on numbers of litters (and fetuses) were observed in treated rats as compared to control. Significantly increased absolute and relative liver weights were observed in 50 and 250 and 500 mg/kg/day and no effect were observed on gravid uterine weight of treated rats as compared to control. Alopecia (various areas), were observed unrelated to treatment and blood present in urogenital opening, urinary bladder, mouth and nose, and lung lobes hemorrhagic and edematous were observed in unscheduled deaths one at 500 mg/kg/day and area of extra hard tissue on left median liver lobe at 50 mg/kg/day in one female rats were observed. In addition, no significant effect were observed on number of ovarian corpora lutea, total number of uterine implantation sites, on preimplantation loss, or on the incidence of resorptions and dead fetuses per litter, of nonlive implants (resorbed plus dead) per litter, or of adversely affected implants (nonlive plus malformed) per litter. No developmental effect were observed such as number of live fetuses, sex ratio (% males) per litter, and the average fetal body weight per litter (all fetuses or separately by sex) were also unaffected by treatment. There was no dose effect or dose x sex interaction for fetal body weight parameters were observed in treated female rats as compared to control. No effects on external and visceral malformations were observed in treated rats as compared to control. Statistically significant skeletal variations such as cleft palate bilateral and unilateral rudimentary ribs on Lumbar I was observed in all fetuses or for male and female fetuses at 250 and 500 mg/kg/day as compared to control. Therefore, NOAEL was considered to be 50 mg/kg/day for P and F1 generation when Sprague-Dawley female rat by using Tergitol NP-4 orally by gavage from gd day 6 to 15.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimisch 4 and from study report
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

Developmental toxicity: Oral

In a study, 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) has been investigated for Developmental toxicity. study based on in vivo experiments in rodents, i.e. most commonly in rats for 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole)).

In a experimental study conducted by Tylet al(UNION CARBIDE CORP, NTRL: OTS0559310-1, 1999), developmental toxicity was evaluated in Sprague-Dawley female rat by using Tergitol NP-4 in the concentration of 0, 50, 250 and 500 mg/kg/day in corn oil orally by gavage. One female rat were died at 500 mg/kg bw on day 6. Rust colored fur on the head, face, and back, a nonspecific indicator of stress (from hemoglobin breakdown products in the Harderian gland excreted via the tear ducts, so-called "bloody tears" or chromodacryorrhea, groomed from the eyes and nose) on gd 13 and 15, Rough coat (more severe than piloerection, indicative of more stress) on gd 12-15, Piloerection, another nonspecific sign of stress on gd 6 through 20, Lethargy on gd 6-15, Pica gd 6 and 7 and Prone positioning on gd 6-14 was observed at 500 mg/kg/day, and Piloerection, another nonspecific sign of stress on gd 6 through 20 and Pica on gd 6 and 8, at 250 mg/kg/day on gd 7-10 and 1315, and at 50 mglkg/day on gd 14 in one dam were observed. Decreased in body weight were observed in ten dams at 250 mg/kg/day and 12 dams at 500 mg/kg/day on gd 9 (first scheduled weigh time point during dosing), in two dams at 500 mg/kg/day on gd 12 (next scheduled weigh timepoint), and in two dams at 500 mg/kg/day on gd 15 (next scheduled weigh time point), all during the dosing period. Statistically significantly decreased in food consumption were observed at 250 and 500 mg/kg/day for gd 6-9, 9-12,12-15,6-1 and increased at 500 mg/kg/day for gd 18-20 and 15-20 (postdosing period), at 250 mg/kg/day for gd 18-20 and 15-20, and at 50 mg/kgfday for gd 18-20 and 15-20. No abortion or early delivery and no effect on numbers of litters (and fetuses) were observed in treated rats as compared to control. Significantly increased absolute and relative liver weights were observed in 50 and 250 and 500 mg/kg/day and no effect were observed on gravid uterine weight of treated rats as compared to control. Alopecia (various areas), were observed unrelated to treatment and blood present in urogenital opening, urinary bladder, mouth and nose, and lung lobes hemorrhagic and edematous were observed in unscheduled deaths one at 500 mg/kg/day and area of extra hard tissue on left median liver lobe at 50 mg/kg/day in one female rats were observed. In addition, no significant effect were observed on number of ovarian corpora lutea, total number of uterine implantation sites, on preimplantation loss, or on the incidence of resorptions and dead fetuses per litter, of nonlive implants (resorbed plus dead) per litter, or of adversely affected implants (nonlive plus malformed) per litter. No developmental effect were observed such as number of live fetuses, sex ratio (% males) per litter, and the average fetal body weight per litter (all fetuses or separately by sex) were also unaffected by treatment. There was no dose effect or dose x sex interaction for fetal body weight parameters were observed in treated female rats as compared to control. No effects on external and visceral malformations were observed in treated rats as compared to control. Statistically significant skeletal variations such as cleft palate bilateral and unilateral rudimentary ribs on Lumbar I was observed in all fetuses or for male and female fetuses at 250 and 500 mg/kg/day as compared to control. Therefore, NOAEL was considered to be 50 mg/kg/day for P and F1 generation when Sprague-Dawley female rat by using Tergitol NP-4 orally by gavage from gd day 6 to 15.

Thus, based on the above studies and predictions on 2, 2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) and considering weight of evidence, 2 ,2'-(ethene-1,2-diyldi-4,1-phenylene)bis(1,3-benzoxazole) can be “Not classified” for developmental toxicity.

Justification for classification or non-classification

Based on the weight of evidence for target Poly (oxy-1,2-ethanediyl), .alpha.-(4-nonylphenyl)-.omega.-hydroxy-, branched (CAS no 127087-87-0 ) is likely to be non hazardous as a reproductive and developmental toxicant.

Additional information