Registration Dossier

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 November 2017 - 6 January 2018 (in-life)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10 November 2017 - 6 January 2018 (in-life)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
July 29, 2016
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride and propylidenetrimethanol (HP1365)
Stability: 12 days ambient and refrigerated (2 to 8¿C), as established in MPI Research Study 2622-001
Correction Factor: 1.029 (purity 97.2%)
Storage Conditions: Room temperature

Date Received: June 21, 2017
Received From: PPG Industries Italia S.r.l. Quattordio, Italy
Label Identification: Epoxypropyl Neodecanoate, Oligomeric Reaction Products with Cyclohexane-1,2 Dicarboxylic Anhydride and Propylidenetrimethanol
Lot Number: CVR 83297
Physical Characteristics: Clear, yellow gel
Expiration Date: December 27, 2018
Storage: Controlled room temperature, protected from light
TMC Number: 1705BB
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Rat: CD®[Crl:CD®(SD)]. The rat is the usual rodent model used for evaluating the toxicity of various classes of chemicals and for which there is a large historical database.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 267-307 g (M), 174-220 g (F)
- Fasting period before study: No
- Housing: Individually, except during pairing, near parturition, and during lactation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

DETAILS OF FOOD AND WATER QUALITY: Block Lab Diet (Certified Rodent Diet #5002, PMI Nutrition International, Inc.) was available ad libitum, except during designated periods (overnight prior to clinical pathology blood sample collection intervals). The lot number from each diet lot used for this study was recorded. Certification analysis of each diet lot was performed by the manufacturer. Tap water was available ad libitum via an automatic watering system. The water supply is monitored for specified contaminants at periodic intervals according to SOP. The results of food and water analyses are retained in the Archives. The Study Director was not aware of any potential contaminants likely to be present in the diet or water that would have interfered with the results of the study. Therefore, no analyses other than those stated above were conducted.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-26
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 10 November 2017 To: 6 January 2018
Route of administration:
oral: gavage
Details on route of administration:
Animals were dosed daily by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/d and a dose volume of 10 mL/kg bw.
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on oral exposure:
The vehicle and test article formulations were continually stirred prior to and throughout dose administration. Individual doses were based on the most recent body weights.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken from dosing preparations for the assessment of achieved concentration and homogeneity. Samples were collected while the preparations are being stirred. All analytical work was conducted by MPI Research, Mattawan, MI using an analytical method developed by MPI Research and validated under MPI Research Study Number 2622-001.
Duration of treatment / exposure:
The males were dosed for 2 weeks prior to mating and through the mating period for a total of 28 days. Females used for reproductive/developmental toxicity assessment were dosed for 2 week prior to mating and through the mating period. Females that delivered and retained litters were dosed to LD13. Females that did not deliver and did not have evidence of mating were dosed for 24 days after the cohabitation period ended. Females used for toxicity assessment were dosed for 28 days. The recovery males and recovery females, which were not cohabitated, were dosed for 28 days and then remained on study for a 14-day recovery period.
Frequency of treatment:
Daily, with the exception of recovery animals
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle (PEG 400) control
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10/sex (reproductive/developmental toxicity assessment)
10/sex (toxicity assessment)
5/sex (recovery groups)
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels were selected on the basis of available data from a 14-day oral toxicity study in rats (MPI Research Study Number 2622-0037). No adverse findings were observed on body weights, food consumption, and macroscopic findings at dose levels ¿1000 mg/kg bw/d in the 14-day study. The only clinical observation was piloerection in a few animals in each dose group (100, 300, and 1000 mg/kg bw/d) on the last day of testing. The high dose level for this study was selected in accordance with the maximum dose level recommended in the testing guidance and the lower doses for determination of a dose-response.

10 rats/sex/group were assigned to the reproductive/developmental toxicity assessment. Males were treated for 14 days prior to mating and during mating, for at least 28 days. Females were treated for 14 days prior to mating, during mating, gestation and lactation (to LD13).

10 rats/sex/group were assigned to the toxicity assessment and were treated for 28 days. An additional 5 rats/sex (control and high dose groups) were treated for 28 days followed by a 14-day recovery period.
Positive control:
Not required for this study type.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily. All animals were observed for morbidity, mortality, injury, and the availability of food and water. General clinical observations (health condition including behavioural changes and signs of toxicity) were made daily post-dosing.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Pre-test and weekly during the study, post-dosing. Observations included, but were not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, as well as evaluation of respiration.

BODY WEIGHT: Yes
- Time schedule for examinations:
Males (weekly and on FOB and locomotor activity days)
Repro/Dev Tox females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0 and 4, 7, and 13. Females with no evidence of mating or that had not delivered were weighed weekly until euthanasia
28-day tox females: Weekly and on FOB and locomotor activity days
Recovery animals: weighed weekly and on FOB and locomotor activity days.
All animals were weighed at scheduled necropsy
Body weight change was calculated for the males and females between each weighing interval and over the entire premating and recovery period and for the Repro/Dev Tox females on GD 0-7, 7-14, 14-20, 0-20 and PND 0-4, 4-7, 7-13 and 0-13.

FOOD CONSUMPTION: Yes
Males and 28-Day Tox Females: Weekly
Repro/Dev Tox Females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0, 4, 7, and 13.
Recovery animals: Weekly
Food consumption was not recorded during mating as animals were cohoused.

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy).
Prothrombin time, Activated partial thromboplastin time, fibrinogen; leukocyte count (total and absolute differential), erythrocyte count, haemoglobin, haematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration (calculated), absolute reticulocytes, platelet count, RDW. Blood smears were preserved and stained for possible future evaluation.

CLINICAL CHEMISTRY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy).
Alkaline phosphatase, total bilirubin (with direct bilirubin if total bilirubin exceeds 1 mg/dL), aspartate aminotransferase, alanine aminotransferase, urea nitrogen, creatinine, total protein, albumin, globulin and A/G (albumin/globulin) ratio (calculated), glucose, total cholesterol, triglycerides, electrolytes (sodium, potassium, chloride), calcium, phosphorus, bile acids.

T4/TSH was assessed for all males at necropsy.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
10 animals/sex/group after 28 days of dose administration (Study Day 29) and 5 animals/sex/group following 14 days of recovery.

1) Assessment of signs of autonomic function: Ranking of the degree of lacrimation and salivation, with a range of severity scores from none to severe.
Presence or absence of piloerection and exophthalmus. Measurement of urination and defecation including polyuria and diarrhoea. Pupillary function as indicated by constriction of the pupil in response to light.
2) Description, incidence and severity of convulsions, tremors, or degree of palpebral closure, e.g., ptosis, abnormal motor movements, both in the home cage and the open field.
3) Ranking of the subject's reactivity to general stimuli such as removal from the cage or handling, with a range of severity from no reaction to hyperactivity.
4) Ranking of the subject's arousal level during observations of the unperturbed subject in the open field, with a range of severity scores from coma to hyperalertness.
5) Descriptions and incidence of posture abnormalities observed in the home cage and incidence of gait abnormalities observed in the open field.
6) Ranking of any gait abnormalities, with a range of severity scores from none to severe.
7) Forelimb and hindlimb grip strength measured using the procedure described by Meyer .
8) Quantitative measure of landing foot (hindfoot) splay as described by Edwards and Parker.
9) Sensorimotor responses to stimuli of different modalities were used to detect gross sensory deficits. Pain perception was assessed by ranking the reaction to a tail pinch and measuring the latency to a nociceptive (thermal) response when the subject is placed on a heated (52 ± 1°C) surface, as described by Ankier. The response to a mechanically produced ¿click¿ was ranked to assess audition and reactivity.
10) Body weight.
11) Description and incidence of any unusual or abnormal behaviours, excessive or repetitive actions (stereotypies), emaciation, dehydration,
hypotonia or hypertonia, altered fur appearance, red or crusty deposits around the eyes, nose, or mouth, and any other observations that may facilitate interpretation of the data.
12) Other measures recorded were count of rearing activity in the open field, ranking of air righting, body temperature measured rectally, spontaneous or excessive vocalizations, alterations in rate and ease of respiration (e.g. rales or dyspnoea), and sensorimotor responses to visual (approaching blunt object) and proprioceptive (touch on rump with blunt object) stimuli.

Motor activity was assessed in 10 animals/sex/group after 28 days of dose administration (Study Day 29) and 5 animals/sex/group following 14 days of recovery. The activity of each rat was assessed using an automated system over a test period of 60 minutes (twelve 5-minute samples/animal). The following activity was recorded: Basic movements, Fine movements, Rearing counts, Total distance.

IMMUNOLOGY: No

OTHER: Oestrus cyclicity (vaginal lavage)
All P females pre-exposure for 2 weeks (selection of only normal cycling females to continue on study), during the 2-week pre-mating dosing period, 14-day cohabitation period until evidence of copulation is detected, and terminal necropsy.
Sacrifice and pathology:
Gross necropsy was performed on males and 28-day tox females following treatment for 28-days; and on recovery animals after 14 days without treatment. Weights of the adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, prostate, seminal vesicles, spleen, testes, thymus, thyroid and uterus were recorded.

Histopathology was performed on tissues from the control and high dose group animals sacrificed following treatment for 28 days. Assessment of recovery group animals was limited to gross lesions.

Other examinations:
Oestrous smears were conducted on all toxicology phase females at necropsy.
Statistics:
Raw data were tabulated within each time interval, and the mean and standard deviation and/or incidence counts (categorical variables) calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group. Data for some endpoints, as indicated, were transformed by either a log or rank transformation prior to conducting the specified analysis. All analyses were two-tailed for significance levels of 5% and 1%. All means were presented with standard deviations. All statistical tests were performed by a computer.

Group Pair-wise Comparison (General ANOVA)
Endpoints: Parental In-life Data, Body Weights and Body Weight Change-Males, Premating and Gestation Body Weight and Body Weight Change-Females, Premating Food Consumption-Males and Females, Gestation Food Consumption, Postmating Food Consumption-Males, Haematology (except leukocyte counts), Coagulation, Clinical Chemistry, FOB, Lactation Body Weights (P), Lactation Body Weight Change (P), Lactation Food Consumption (P), Fertility Indices, Copulatory Interval, Gestation Length (P), Litter Size, Viable Pups, Stillborn Pups, Pathology, Organ Weights (Absolute Weights, Relative to Body and Brain Weights.

Generalized Linea Model:
Locomotor Activity (Continuous), Basic Movements, Fine Movements, Rearing, Distance.

Fisher¿s Exact Test with Stepdown Sidak Adjustment:
Male Fertility Index, Female Fertility Index, Female Mating Index, Male Mating Index, Female Fecundity Index, Male Fecundity Index, Gestation Index.

Arcsin-Square Root Transformation:
Pup Sex Ratio (% viable males/litter), Stillborn Index, Pup Survival (Days 0-4 pre-cull and 4-post-cull-Day 13)

Exact Mantel-Haenszel Test with Stepdown Sidak Adjustment:
Categorical FOB data

Covariate Analysis:
Pup Weights
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No adverse test article-related effects were noted on general clinical observations in males or females at any of the dose levels evaluated. In the males, there were general clinical observations of salivation at the 1000 mg/kg bw/d dose groups (4 of 15 males). There were no observations of salivation in the recovery males. While the increased observation of salivation may be test article-related, there was no impact on the overall health of the animals, and therefore this is not considered adverse. In the females, there were general clinical observations of salivation at the 300 and 1000 mg/kg bw/d dose groups (2 of 10, and 3 of 15 females, respectively). There were no observations of salivation in the recovery females. While the increased observation of salivation may be test article-related, there was no impact on the overall health of the animals, and therefore these are not considered adverse.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One male in the control group was euthanized in extremis on Study Day 19. Clinical observations included decreased activity, faeces mucoid, thin body composition and red hair discoloration on the face and body weight loss. All other animals in the 28-Day Tox phase survived to the scheduled study termination.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on mean body weight or body weight change during the treatment or recovery periods in the males or females at any of the dose levels evaluated.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test article-related effects were observed on caged food consumption during the treatment or recovery periods in the males or females at any of the dose levels evaluated.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no test article-related effects on haematology endpoints in any treatment group at the terminal collection, or in either sex at 1000 mg/kg bw/d following a 2-week recovery period
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no test article-related effects on clinical chemistry endpoints in any treatment group at the terminal collection, or in either sex at 1000 mg/kg bw/d following a 2-week recovery period
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No adverse test article-related effects were noted on detailed clinical observations in males or females at any of the dose levels evaluated. FOB and motor activity assessment did not reveal any effects of treatment.
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
There were no test article-related effects on oestrous stage at necropsy at any of the dose levels evaluated.
Details on results:
Mortality
One male in the control group (animal number 103) was euthanized in extremis on Study Day 19. Clinical observations included decreased activity, mucoid faeces, thin body and red hair discoloration on the face and body weight loss. All other animals in the 28-Day Tox phase survived to scheduled termination.

General clinical observations
No adverse effects were noted on general clinical observations in males or females at any dose level. In males, there were general clinical observations of salivation at 1000 mg/kg bw/d (4 of 15 males). There were no observations of salivation in the recovery males. While the increased observation of salivation may be treatment-related, there was no impact on the overall health of the animals, and these are therefore not considered adverse. In females, there were general clinical observations of salivation at 300 and 1000 mg/kg bw/d (2 of 10, and 3 of 15 females, respectively). There were no observations of salivation in the recovery females. While the increased observation of salivation may be test article-related, there was no impact on the overall health of the animals, and these are therefore not considered adverse. Other observations noted during the course of the study were not considered to be treatment-related due to alow incidence, concurrent finding in control animals, and/or expected findings for rats of this strain.

Detailed clinical observations
No adverse test article-related effects were noted on detailed clinical observations in males or females at any dose level. In males, there were only detailed clinical observations of salivation in one of the fifteen males in the control and 1000 mg/kg bw/d dose groups. In females, there were detailed clinical observations of salivation at 100 and 1000 mg/kg bw/d (1 of 10, and 4 of 15 females, respectively). There were no observations of salivation in the recovery females.While the increased observation of salivation may be treatment-related, there was no impact on the overall health of the animals, and these are therefore not considered adverse. Other observations noted during the course of the study were not considered to be treatment-related due to a low incidence, concurrent finding in control animals, and/or expected findings for rats of this strain.

Functional Observational Battery Evaluations
No treatment-related effects were observed on functional observational battery evaluations during the treatment or recovery periods in the males or females at any of the dose levels evaluated. No effect was observed in the FOB activity/arousal parameters evaluated (ease of removal, arousal, handling reactivity, posture, rearing, and vocalization) at any of the dose levels evaluated. No effect of treatment was observed in the FOB neuromuscular parameters evaluated (bizarre behaviour, clonic movements, gait, forelimb and hindlimb grip strength, hindlimb splay, mobility, righting reflex, stereotypy, and tonic movements) at any dose level. During the treatment period, forelimb grip strength in females at 300 mg/kg bw/d was significantly lower than controls. This decreased response time was not seen in males during the treatment period, was not seen during the recovery period in either sex, and lacked dose responsiveness. Therefore, this finding was considered to be incidental and not treatment-related. No effect of treatment was observed in the FOB sensorimotor parameters evaluated (approach response, click response, tail pinch response, touch response, and thermal response) at any of the dose levels evaluated. No effect of treatment was observed in the FOB autonomic parameters evaluated (exophthalmos, lacrimation, palpebral closure, piloerection, pupil response, salivation, defecation, and urination) at any of the dose levels evaluated. No effect of treatment was observed in the FOB physiological parameters evaluated. There were no treatment-related effects on motor activity during the treatment and recovery periods in males or females at any of the dose levels evaluated. Parameters evaluated to assess motor activity were basic movements, fine movements, rearing counts, and total distance travelled over a 60-minute evaluation period. During the treatment period, basic movements, fine movements, and total distance travelled in males at 300 mg/kg bw/d were significantly higher than controls at the 50-55 minute interval and rearing counts in males at 1000 mg/kg bw/d was significantly higher than controls at the 5-10 minute interval. These increases were not seen at any other intervals in the males, were not seen in females during the treatment period, and were not seen during the recovery period in either sex. Therefore this finding was considered to be incidental and not treatment-related.

Bodyweight
No treatment-related effects were observed on mean body weight or body weight change during the treatment or recovery periods in the males or females at any of the dose levels evaluated. The few statistically significant differences observed in these data between the control and treatment-treated groups occurred sporadically, lacked similarity in response between the sexes, and/or dose-responsiveness, and were considered incidental and unrelated to treatment.

Food consumption
No treatment-related effects were observed on caged food consumption during the treatment or recovery periods in the males or females at any of the dose levels evaluated.

Haematology
There were no treatment-related effects on haematology endpoints in any treatment group at the terminal collection, or in either sex at 1000 mg/kg bw/d following a 2-week recovery period. All fluctuations among individual and mean values, regardless of statistical significance, were considered sporadic, consistent with biologic variation and/or negligible in magnitude, and not related to treatment.

Clinical chemistry
There were no treatment-related effects on clinical chemistry endpoints in any treatment group at the terminal collection, or in either sex at 1000 mg/kg bw/d following a 2-week recovery period. All fluctuations among individual and mean values, regardless of statistical significance, were considered sporadic, consistent with biologic variation and/or negligible in magnitude, and not related to treatment. TSH and T4 levels in males were unaffected by treatment.

Gross necropsy
There were no treatment-related macroscopic findings at the terminal or recovery intervals. One female at 1000 mg/kg bw/d from the recovery interval had a unilateral kidney mass that correlated microscopically with a nephroblastoma. This was considered an incidental change as nephroblastoma occur at low incidences in young rats, it was a solitary incidence, and there were no similar neoplastic or pre-neoplastic findings in terminal animals at 1000 mg/kg bw/d. All other macroscopic changes in all animal at both the terminal and recovery intervals were considered incidental and not test article related due to their low incidence and severity, presence in concurrent controls, lack of microscopic correlates, or similarity to background or incidental changes that occur in rats of this age and strain.

Organ weights
There were no treatment-related organ weight changes at the terminal or recovery intervals. All organ weight variations at both the terminal and recovery intervals, including those that reached statistical significance, were considered incidental or background due to the low magnitude of the change, lack of a cleardose response or microscopic correlates, and/or an absence of a similar change in the opposite sex.

Histopathology
There were no treatment-related microscopic findings at the terminal or recovery intervals. One male at 1000 mg/kg bw/d from the terminal interval had mild bilateral germ cell degeneration in the testes affecting mature elongated and elongating spermatids with marked oligospermia and germ cell depletion in the epididymides. This was considered an incidental finding as it was a solitary occurrence, similar to an incidental finding that occurs in young male rats, and there were no progressive degenerative changes seen in recovery males. All other microscopic findings at both the terminal and recovery intervals, including focal necrosis in the liver, were considered incidental, procedural, or background due to their low incidence and/or severity, lack of dose response, similarity to known background findings, and/or presence in concurrent controls.
There were no treatment-related effects on oestrous stage at necropsy at any of the dose levels evaluated


Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Critical effects observed:
no

Homogeneity and concentration analyses confirmed that dose formulations were homogeneous (RSD 1.302 to 4.142%) and that animals received the targeted concentrations (94.8 to 101.7%).

Summary of findings

 

M

F

0

100

300

1000

0

100

300

1000

Mortality

1

-

-

-

-

-

-

-

Salivation

-

-

-

4/15

-

-

2/10

3/15

Day 29 bodyweight (g)

415.8

406.7

403.1

406.9

242.3

247.8

244.8

251.4

Day 43 recovery bodyweight (g)

477.2

-

-

469.4

269.4

-

-

276.8

Weight gain (g) Day 29

122.7

116.5

114.4

116.4

47.5

50.0

47.7

54.5

Weight gain (g) Day 43

38.4

-

-

30.0

7.2

-

-

1.2

Conclusions:
A NOAEL of 1000 mg/kg bw/d can be determined for this study in the absence of any toxicologically relevant findings at the highest dose level.
Executive summary:

The 28 -day repeated dose toxicity of the submission substance (epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride and propylidenetrimethanol) was investigated in male and female rats as part of an OECD 422 screening study. Groups of CD(Crl:CD(SD)) rats (10/sex) were gavaged with the test material (in PEG 400) at dose levels of 0 (vehicle control), 100, 300 and 1000 mg/kg bw/d. Additional recovery groups (5/sex) were treated for 28 days followed by a 14-day recovery period. Animals were observed daily for mortality and clinical signs; more detailed clinical investigations were performed at weekly intervals. FOB was performed and motor activity assessed in 10 animals/sex/group after 28 days of dose administration (Study Day 29) and 5 animals/sex/group following 14 days of recovery. Bodyweights and food consumption were recorded weekly. Blood samples were taken at the end of the treatment and recovery periods for the assessment of haematological and clinical chemistry parameters.  TSH and T4 were addtionally investigated in males. Gross necropsy was performed on all animals; weights of the adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, prostate, seminal vesicles, spleen, testes, thymus, thyroid and uterus were recorded. Oestrous smears were conducted on females at necropsy. Histopathology was performed on tissues from the control and high dose group animals sacrificed following treatment for 28 days. Assessment of recovery group animals was limited to gross lesions. There was no treatment-related mortality; one male in the control group was euthanized in extremis on Study Day 19. Clinical signs related to treatment were limited to post-dosing salivation in both sexes at the highest dose level of 1000 mg/kg bw/d and in females at 300 mg/kg bw/d. Bodyweights and food consumption were unaffected by treatment at any dose level. FOB did not reveal any effects of treatment. Haematology and clinical chemistry parameters were unaffected by treatment. Gross necropsy did not reveal an effects of treatment; organ weights were comparable in all groups. There were no effects of treatment apparent following microscopic investigation. Oestrus cyclicity was comparable in females from all groups at termination. There were no adverse effects of treatment in this study. Observations of post-dosing salivation observed in both sexes at 1000 mg/kg bw/d and in females at 300 mg/kg bw/d are likely to be treatment-related but are not considered to be of toxicological significance. A NOAEL of 1000 mg/kg bw/d is therefore determined for this study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
July 29, 2016
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Remarks:
Clear yellow resin
Specific details on test material used for the study:
Epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride
and propylidenetrimethanol (HP1365)
Stability: 12 days ambient and refrigerated (2 to 8¿C), as established in MPI Research Study 2622-00
1
Correction Factor: 1.029 (purity 97.2%)
Storage Conditions: Room temperature
Date Received: June 21, 2017
Received From: PPG Industries Italia S.r.l. Quattordio, Italy
Label Identification: Epoxypropyl Neodecanoate, Oligomeric Reaction Products with Cyclohexane-1,2
Dicarboxylic Anhydride and Propylidenetrimethanol
Lot Number: CVR 83297
Physical Characteristics: Clear, yellow gel
Expiration Date: December 27, 2018
Storage: Controlled room temperature, protected from light
TMC Number: 1705BB

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Rat: CD®[Crl:CD®(SD)]. The rat is the usual rodent model used for evaluating the toxicity of various classes of chemicals and for which there is a large historical database.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 267-307 g (M), 174-220 g (F)
- Fasting period before study: No
- Housing: Individually, except during pairing, near parturition, and during lactation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

DETAILS OF FOOD AND WATER QUALITY:
Block Lab Diet (Certified Rodent Diet #5002, PMI Nutrition International, Inc.) was available ad libitum, except during designated periods (overnight prior to clinical pathology blood sample collection intervals). The lot number from each diet lot used for this study was recorded. Certification analysis of each diet lot was performed by the manufacturer. Tap water was available ad libitum via an automatic watering system. The water supply is monitored for specified contaminants at periodic intervals according to SOP. The results of food and water analyses are retained in the Archives. The Study Director was not aware of any potential contaminants likely to be present in the diet or water that would have interfered with the results of the study. Therefore, no analyses other than those stated above were conducted.

ENVIRONMENTAL CONDITIONS
- Temperature (°C):
20-26
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light):
12/12

IN-LIFE DATES: From: 10 November 2017 To: 6 January 2018

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
Animals were dosed daily by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/d and a dose volume of 10 mL/kg bw. The vehicle and test article formulations were continually stirred prior to and throughout dose administration. Individual doses were based on the most recent body weights.
Details on mating procedure:
On Day 15, each Repro/Dev Tox female was housed in the cage of a male from the same treatment group. Positive evidence of copulation was established by daily inspection for a copulatory plug in the vagina and/or the presence of sperm in the vaginal lavage. The day on which positive evidence of copulation was observed was considered GD 0. After evidence of mating was observed, the female was returned to an individual cage for the remainder of the study. The maximum pairing period was 14 days, at the end of which any females with no confirmed evidence of mating were returned to individual cages until scheduled euthanasia. 28-Day Tox females and animals designated for the recovery period were not cohabitated.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples were taken from dosing preparations for the assessment of achieved concentration and homogeneity. Samples were collected while the preparations are being stirred. All analytical work was conducted by MPI Research, Mattawan, MI using an analytical method developed by MPI Research and validated under MPI Research Study Number 2622-001.
Duration of treatment / exposure:
The males were dosed for 2 weeks prior to mating and through the mating period for a total of 28 days. Females used for reproductive/developmental toxicity assessment were dosed for 2 week prior to mating and through the mating period. Females that delivered and retained litters were dosed to LD13. Females that did not deliver and did not have evidence of mating were dosed for 24 days after the cohabitation period ended. Females used for toxicity assessment were dosed for 28 days. The recovery males and recovery females, which were not cohabitated, were dosed for 28 days and then remained on study for a 14-day recovery period.
Frequency of treatment:
Daily
Details on study schedule:
Daily, with the exception of recovery animals
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Vehicle (PEG 400) control
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10/sex (reproductive/developmental toxicity assessment)
10/sex (toxicity assessment)
5/sex (recovery groups)
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels were selected on the basis of available data from a 14-day oral toxicity study in rats (MPI Research Study Number 2622-0037). No adverse findings were observed on body weights, food consumption, and macroscopic findings at dose levels ¿1000 mg/kg bw/d in the 14-day study. The only clinical observation was piloerection in a few animals in each dose group (100, 300, and 1000 mg/kg bw/d) on the last day of testing. The high dose level for this study was selected in accordance with the maximum dose level recommended in the testing guidance and the lower doses for determination of a dose-response. 10 rats/sex/group were assigned to the reproductive/developmental toxicity assessment. Males were treated for 14 days prior to mating and during mating, for at least 28 days. Females were treated for 14 days prior to mating, during mating, gestation and lactation (to LD13). 10 rats/sex/group were assigned to the toxicity assessment and were treated for 28 days. An additional 5 rats/sex (control and high dose groups) were treated for 28 days followed by a 14-day recovery period.
Positive control:
Not required for this study type.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily. All animals were observed for morbidity, mortality, injury, and the availability of food and water. General clinical observations (health condition including behavioural changes and signs of toxicity) were made daily post-dosing.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Pre-test and weekly during the study, post-dosing. Observations included, but were not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, as well as evaluation of respiration.

BODY WEIGHT: Yes
- Time schedule for examinations: Males (weekly and on FOB and locomotor activity days). Repro/Dev Tox females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0 and 4, 7, and 13. Body weight change was calculated for the males and females between each weighing interval and over the entire premating and recovery period and for the Repro/Dev Tox females on GD 0-7, 7-14, 14-20, 0-20 and PND 0-4, 4-7, 7-13 and 0-13.

FOOD CONSUMPTION: Yes
Males and 28-Day Tox Females: Weekly
Repro/Dev Tox Females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0, 4, 7, and 13.
Recovery animals: Weekly
Food consumption was not recorded during mating as animals were cohoused.

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy). Prothrombin time, Activated partial thromboplastin time, fibrinogen; leukocyte count (total and absolute differential), erythrocyte count, haemoglobin, haematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration (calculated), absolute reticulocytes, platelet count, RDW. Blood smears were preserved and stained for possible future evaluation.

CLINICAL CHEMISTRY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy). Alkaline phosphatase, total bilirubin (with direct bilirubin if total bilirubin exceeds 1 mg/dL), aspartate aminotransferase, alanine aminotransferase, urea nitrogen, creatinine, total protein, albumin, globulin and A/G (albumin/globulin) ratio (calculated), glucose, total cholesterol, triglycerides, electrolytes (sodium, potassium, chloride), calcium, phosphorus, bile acids. Additionally, blood was collected from all Repro/Dev Tox females delivering a litter and all males at necropsy for TSH and T4 hormone analysis.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Oestrous cyclicity (parental animals):
All P females pre-exposure for 2 weeks (selection of only normal cycling females to continue on study), during the 2-week pre-mating dosing period, 14-day cohabitation period until evidence of copulation was detected, and at terminal necropsy.
Sperm parameters (parental animals):
Not investigated
Litter observations:
Toward the end of the gestation period, females were examined twice daily for signs of parturition. The mated females were allowed to give birth (F1). Any female dying during parturition was subjected to gross necropsy, The duration of gestation was calculated, and any difficulties occurring at parturition recorded. The day on which all pups were delivered was designated LD0. The litters were examined as soon as possible after delivery. The following parameters were recorded for each litter. Litter size (total number live born pups, stillborn pups and partially cannibalized pups); Number of stillborn pups; Number of live born pups; Number of pups per sex; Individual pup body weights; Gross abnormalities of the pups. Litters were culled on LD4 to 8 pups (4/sex where possible). Blood was collected for TSH and T4 from at least two pups per litter (pooled) on LD4.

Litters weere housed with their dams to LD13. The dams and litters were observed daily for survival and behavioural alterations in nesting and nursing, and the presence of dead pups recorded. Pups were individually weighed and examined externally on LD0, 4, 7, and 13. The dam and litter remained together until LD 13. Anogenital distance was recorded for all pups on LD4 (post-cull) and the number of nipples counted on male pups on PND 12.
Postmortem examinations (parental animals):
Gross necropsy was performed all surviving males and all 28-day Tox females. For the Repro/Dev Tox females, gross necropsy was performed and the number of implantation scars recorded. The uteri from non-gravid females were stained with ammonium sulphide for the detection of implantation sites. Weights of the adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, prostate, seminal vesicles, spleen, testes, thymus, thyroid and uterus were recorded.
Postmortem examinations (offspring):
F1 pups will be euthanised on LD 4 were externally examined. Blood samples (pooled from at least 2 pups per litter) for T4 and TSH were collected. Any abnormalities were recorded and the carcasses discarded. The thyroid was collected from 1 F1 pup/sex sacrificed on LD 13. All F1 pups were externally examined. Any abnormalities were recorded, and the carcasses will be discarded. If a skeletal anomaly was suspected, the pups were eviscerated, cleared, and stained with Alizarin Red S and examined using Dawson's technique. The thyroid gland was collected from
one pup/sex/litter and saved in 10% neutral buffered formalin for possible histopathological evaluation.
Statistics:
Raw data were tabulated within each time interval, and the mean and standard deviation and/or incidence counts (categorical variables) calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group. Data for some endpoints, as indicated, were transformed by either a log or rank transformation prior to conducting the specified analysis. All analyses were two-tailed for significance levels of 5% and 1%. All means were presented with standard deviations. All statistical tests were performed by a computer.

Group Pair-wise Comparison (General ANOVA)
Endpoints: Parental In-life Data, Body Weights and Body Weight Change-Males, Premating and Gestation Body Weight and Body Weight Change-Females, Premating Food Consumption-Males and Females, Gestation Food Consumption, Postmating Food Consumption-Males, Haematology (except leukocyte counts), Coagulation, Clinical Chemistry, FOB, Lactation Body Weights (P), Lactation Body Weight Change (P), Lactation Food Consumption (P), Fertility Indices, Copulatory Interval, Gestation Length (P), Litter Size, Viable Pups, Stillborn Pups, Pathology, Organ Weights (Absolute Weights, Relative to Body and Brain Weights).

Generalized Linear Model:
Locomotor Activity (Continuous), Basic Movements, Fine Movements, Rearing, Distance.

Fisher¿s Exact Test with Stepdown Sidak Adjustment:
Male Fertility Index, Female Fertility Index, Female Mating Index, Male Mating Index, Female Fecundity Index, Male Fecundity Index, Gestation Index.

Arcsin-Square Root Transformation:
Pup Sex Ratio (% viable males/litter), Stillborn Index, Pup Survival (Days 0-4 pre-cull and 4-post-cull-Day 13)

Exact Mantel-Haenszel Test with Stepdown Sidak Adjustment:
Categorical FOB data

Covariate Analysis:
Pup Weights
Reproductive indices:
Male Fertility Index
Female Fertility Index
Female Mating Index
Male Mating Index
Female Fecundity Index
Male Fecundity Index
Gestation Index
Offspring viability indices:
Viability Index
Survival Index

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No adverse test article-related effects were noted on general clinical observations in females at any of the dose levels evaluated. There were observations of salivation in the 100, 300, 1000 mg/kg bw/d dose groups (1 of 10, 1 of 9, and 1 of 7 females, respectively) during the mating and gestation periods. Other observations noted during the course of the study were not considered treatmnet-related due to a low incidence, concurrent finding in control animals, and/or expected findings for rats of this strain.

No adverse test article-related effects were noted on detailed clinical observations in females at any of the dose levels evaluated. In the females, there were observations of salivation in the 100 and 1000 mg/kg bw/d dose groups (1 of 10 and 3 of 10 females, respectively) during the premating period and in the 300 mg/kg/bw/d group (1 of 9 females) during the lactation period. While the increased observation of salivation may be treatment-related, there was no impact on the overall health of the animals, and therefore not considered adverse. Other observations noted during the course of the study were not considered treatment-related due to a low incidence, concurrent finding in control animals, and/or expected findings for rats of this strain.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control female was found dead on Study Day 36. There were no clinical observations, body weight loss, or decrease in caged food consumption for this animal prior to being found dead. All other animals in the Repro/Dev Tox phase survived to the scheduled study termination.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on mean body weight or body weight change in the females at any of the dose levels evaluated. The few statistically significant differences observed in these data between the control and treated groups occurred sporadically and often due to the directions of the change were considered incidental and unrelated to treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No treatment-related effects were observed on caged food consumption in the females at any of the dose levels evaluated. The few statistically significany increases observed in these data between the control and treated groups occurred sporadically, lacked dose-responsiveness, and were considered incidental and unrelated to treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Description (incidence and severity):
FOB and motor assessment were assessed in this study in animals assigned to the toxicity group and are reported separately.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Description (incidence and severity):
No treatment-related effects were observed on mean cycle length in the Repro/Dev Tox females at any of the dose levels evacuated. At 300 and 1000 mg/kg bw/d there was a significant decrease in number of cycles compared to controls (-25 and -29%, respectively). While this decrease may be treatment-related, without effects on the reproductive and fertility parameters it was not considered adverse.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect of treatment was observed on mating, fertility or fecundity indices in males or females. These indices in each of the treated groups were comparable to control values. Likewise, the mean Copulatory Interval (mean days-to-mating) in the test article-treated groups which ranged from 2.6 to 3.9 days was comparable to the mean of 2.9 days in the control group.No test article-related effect was observed on parturition data in the P females at any of the dose levels evaluated. Pregnancy rates for the P females were 80, 100, 90, and 80%, providing 7, 10, 9, and 8 litters with viable pups in the control, 100, 300, and 1000 mg/kg bw/d groups, respectively. Parturition parameters (i.e., incidence of animals with stillborn pups, mean number of pups at birth [liveborn, stillborn and total], Gestation Index, Stillborn Index, and mean number of uterine implantation scars at necropsy) in the treated groups were comparable to controls.

Details on results (P0)

One control female died: there was no treatment-related mortality. Clinical signs attributable to treatment were limited to post-dosing salivation in all treated groups of females. Bodyweights and food consumption were unaffected by treatment. At 300 and 1000 mg/kg bw/d there was a significant decrease in number of cycles compared to controls (-25 and -29%, respectively); findings at the highest dose level are attributable at least in part to one dam with an oestrus cycle length of 11 days. While this decrease may be treatment-related, without effects on the reproductive and fertility parameters it was not considered adverse. No effects of treatment were seen on measures of fertility.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No effect of treatment was observed from F1 pup detailed clinical observations at any of the dose levels evaluated. The few findings observed in the pups from the treated groups occurred at low incidence or with similar frequency to controls and were considered unrelated to treatment.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect of treatment on F1 pup survival over LD 0-4 or LD 4-13 was observed in the treated groups in comparison to controls. Mean pup survival LD 0-4 ranged from 95.37% to 99.31% in the treated groups and was comparable to controls at 97.62%. Mean pup survival was 100% in all groups over LD 4-13. Litter size in the treated groups on LD 4 pre- and post-cull, and at LD 13 was comparable to controls.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effect was observed on F1 pup body weights (male, female, and male and female combined) at any of the dose levels evaluated.
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:
effects observed, treatment-related
Description (incidence and severity):
Moderate increases in serum Thyroid Stimulating Hormone (TSH) concentrations on Lactation Day 4 were seen in pups from dams at 300 and 1000 mg/kg bw/d. There were no associated alterations in serum thyroxine (T4) concentrations or microscopic findings in the thyroid gland, and increases in TSH concentrations were not considered to be adverse.
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No effects were observed from macroscopi examination of stillborn pups, pups dying on study, LD 4 culled pups, or LD 13 pups.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
No treatment-related effect was observed on F1 pup anogenital distance or nipple count at any of the dose levels evaluated.

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

Pup viability and growth were unaffected by treatment at any dose level. Moderate increases in serum Thyroid Stimulating Hormone (TSH) concentrations on Lactation Day 4 were seen in pups from dams at 300 and 1000 mg/kg bw/d. There were no associated alterations in serum thyroxine (T4) concentrations or microscopic findings in the thyroid gland, and increases in TSH concentrations were not considered to be adverse.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Summary of fertility parameters

 

0

100

300

1000

Males paired (#)

9

10

10

10

Males mated (#)

8

10

9

8

Males impregnating females (#)

8

10

9

8

Male mating index

88.9

100

90.0

80.0

Male fertility index

88.9

100

90.0

80.0

Male fecundity index

100

100

100

100

Females paired (#)

10

10

10

10

Females mated (#)

8

10

9

8

Females pregnant (#)

8

10

9

8

Female mating index

80.0

100

90.0

80.0

Female fertility index

80.0

100

90.0

80.0

Female fecundity index

100

100

100

100

Summary of findings in dams

 

F

 

0

100

300

1000

Mortality

1

-

-

-

Salivation

-

1

1

3

Bodyweight (g) pre-mating

241.4

234.0

239.7

234.2

Bodyweight (g) GD20

414.0

401.9

395.0

383.6

Bodyweight (g) LD20

351.0

338.3

336.7

339.5

Weight gain (g) pre-mating

41.2

37.2

42.0

35.5

Weight gain (g) gestation

154.9

158.7

148.1

148.6

Weight gain (g) lactation

30.9

32.8

31.3

41.1

Oestrus cycle length (d)

4.6

4.7

4.6

5.6

[No. cycles]

2.8

2.4

2.1*

2.0*

*significantly different to controls (p<0.05)

Summary of litter parameters

 

0

100

300

1000

Females on study (#)

10

10

10

10

Females pregnant (#)

8

10

9

8

Litters (#)

7

10

9

8

Gestation length (d)

21.4

21.6

21.5

21.8

Litter size (#)

15.71

14.40

14.56

13.50

Stillborn (#)

0.0

0.1

0.0

0.1

Summary of offspring viability and growth

 

0

100

300

1000

Live pups PND0 (#)

15.7

14.3

14.6

13.4

Live pups PND4 (#) pre-cull

15.3

13.6

14.4

13.1

Live pups PND4 (#) post-cull

8.0

8.0

8.0

8.0

Live pups PND7 (#)

8.0

8.0

8.0

8.0

Live pups PND13 (#)

8.0

8.0

8.0

8.0

Viability index (%)

97.6

95.4

99.3

98.0

PND 4-13 Survival index (%)

100

100

100

100

Pup weight (g) PND0

6.51

6.45

6.36

6.63

Pup weight (g) PND4

9.92

9.79

10.08

10.00

Pup weight (g) PND7

15.94

16.24

16.17

16.35

Pup weight (g) PND13

31.07

30.17

31.20

31.41

AGD (mm) PND4

3.286

3.475

3.278

4.094

Summary of thyroid hormone measurements

 

0

100

300

1000

T4 (µg/dL)

Pups PND4

2.701

2.715

3.003

3.116

Dams LD13

3.871

4.237

4.042

4.073

Pups LD13

7.674

7.898

8.331

8.095

Males Day 29

4.597

5.181

5.328

5.533

TSH (ng/dL)

Pups PND4

1.687

2.603

4.329

8.664

Dams LD13

6.774

8.300

5.739

7.793

Pups LD13

4.921

5.554

5.501

3.890

Males Day 29

2.896

3.292

3.354

4.302

Applicant's summary and conclusion

Conclusions:
In the absence of any findings of toxicological significance, a parental NOAEL of 1000 mg/kg bw/d can be determined for this study. A reproductive NOAEL of 1000 mg/kg bw/d can also be determined in the absence of any effects on fertility or development.
Executive summary:

This OECD 422 screening study was conducted to evaluate for possible adverse effects of the submission substance (epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride and propylidenetrimethanol) following repeated dosing to male and female rats, including systemic toxicity, neurotoxic potential, reproductive performance (gonadal function, mating behavior, conception, development of the conceptus, and parturition), and F1 offspring growth and maturation up through LD 13. No effects on treated males and females were observed on survival, clinical observations, body weights and body weight change, food consumption, oestrous cycle parameters, reproductive performance (mating, fertility, and fecundity), behavioural evaluations (functional observational battery and locomotor activity), clinical pathology parameters, organ weights, macroscopic observations, and microscopic observations. No effects of treatment were observed on F1 survival, clinical observations, body weights, and macroscopic findings. Based on these findings, 1000 mg/kg bw/d, the highest dose level evaluated, was considered to be the NOAEL.