Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A key study for reproductive toxicity in male and female rats was performed with hydrogenated terphenyl given in the diet in a two-generation reproductive toxicity study. 1000 ppm dietary level was the no-observed-adverse-effect-level (NOAEL) for reproductive effects (corresponding to 62-81 mg/kg bw/day), and the 300 ppm dietary level was the NOAEL for subchronic toxicity in this study (corresponding to 18-24 mg/kg bw/day).

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliance study report, availables as unpublished report, no restrictions, adequate for assessment.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
Other: Monsanto Agricultural Company, Environmental Health Laboratory method
Test conducted in general conformance with the GLP Standards with the following exceptions:
- Characterization of the test material and analytical reference standard may not have been performed in accordance with the Standard/Principles.
- Determination of the stability of the analytical reference standard may not have been performed in accordance with the Standard/Principles.
- A reserve sample of the analytical reference standard was not retained.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Portage, MI
- Age at study initiation: (FØ) Approximately 5 wks
- Weight at study initiation: (FØ) Males: 161.6-225.5 g; Females: 122.2-185.6 g
- Housing for premating and gestation day 0 through 13: Individual. During mating, females were housed with the male in the male's cage.
- Housing from day 14 of gestation through lactation: Females were housed in double wide cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: fifteen days
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Approximately weekly
- Method of mixing: Neat test material was blended into the basal diet using a high speed mixer.
- Type of food: Purina Mills Certified RODENT CHOW N° 5002
Details on mating procedure:
- M/F ratio per cage: One male and one female (non-littermates) in male's cage.
- Length of cohabitation: 7 days, unless copulatory evidence found sooner. If no evidence of mating was, observed during the initial 7 day cohousing period, the female was co-housed with a male having recorded copulatory activity for an additional 7 days (maximum), or until copulatory evidence was observed. Mating procedures for the F1a adults were the same as for FØ adults except as modified to exclude sibling matings.
- Proof of pregnancy: pulatory plug, or vaginal smear if unable to determine cage from which plug had fallen.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
-Test Material stability: Gas Chromatography with a flame ionization detector; assays against an analytical standard both before and after the study.
- Diet mixture stability: Analysis of 30 and 1000 ppm level samples kept frozen (closed container, 35 days) or at ambient temperature (open container, 7 and 14 days).
- Homogeneity of diet mixtures: Analyses of duplicate samples from top, middle and bottom of mixer.
- Dietary level verification: Extraction of Terphenyl, hydrogenated with hexane; analysis by gas chromatography with a flame ionization detector; all dietary levels the first four weeks; at least one level per week thereafter.
Duration of treatment / exposure:
F0: until 21 days postpartum (F1A litter)
F1: until 21 days postpartum (F2A litter)
F2A: until 21 days postpartum
Duration of test: 275 days
Frequency of treatment:
7 days/week
Details on study schedule:
- Gestation/Lactation Day Designations: Gestation day 0=day on which copulatory evidence found; lactation day 0=day on which delivery of pups was complete, with subsequent days numbered consecutively.
Dose / conc.:
0 ppm (nominal)
Remarks:
nominal in diet
Dose / conc.:
30 ppm (nominal)
Remarks:
nominal in diet
Dose / conc.:
100 ppm (nominal)
Remarks:
nominal in diet
Dose / conc.:
300 ppm (nominal)
Remarks:
nominal in diet
Dose / conc.:
1 000 ppm (nominal)
Remarks:
nominal in diet
Remarks:
Doses / Concentrations: 1.8, 6.1, 18.5 and 62.0 for males (for the FØ adults)
Basis: analytical conc.
Remarks:
Doses / Concentrations: 2.4, 8.1, 24.3 and 80.6 for females (for the F1a adults)
Basis: analytical conc.
Remarks:
Doses / Concentrations: 1.9, 6.1, 18.2 and 63.1 for males (for the F1a adults)
Basis: analytical conc.
Remarks:
Doses / Concentrations: 2.5, 8.3, 24.4 and 81.2 for females (for the FØ adults)
Basis: analytical conc.
No. of animals per sex per dose:
30 adult rats/sex/group (FØ study start and F1a selected for mating)
Control animals:
yes
Positive control:
None
Parental animals: Observations and examinations:
MORTALITY AND MORIBUNDITY: Yes
- Time schedule: Twice daily (am and pm)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Adult - Once weekly; Offspring - On days of body weight measurement.

BODY WEIGHT: Yes
- Time schedule for examinations: FØ and F1a adult males - Once weekly; FØ and F1a adult females - Weekly until copulation confirmed, then on days 0, 7, 14, 21 of gestation and lactation.

FOOD CONSUMPTION:
- Time schedule for examinations: FØ and F1a adult males - Weekly except during mating; FØ and F1a adult females - Weekly until mating. After copulation was confirmed, maternal food consumption was measured on days 0-7, 7-14 and 14-21 of gestation. Food consumption was not determined for females with no evidence of copulation during cohousing with the male.
Sperm parameters (parental animals):
Parameters examined in FØ and F1a male parental generations:
sperm count in epididymides
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 of lactation: yes
- If yes, maximum of 8 pups/litter; excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1a / F2a offspring:
Litter size, mortality, pup weight, survival (%)
Postmortem examinations (parental animals):
UNSCHEDULED NECROPSIES:
Those which died or were sacrificed in extremis were given a gross necropsy and selected tissues were saved.

SACRIFICE
- Male animals: All surviving animals after completion of mating phase.
- Maternal animals: Adult females which produced a litter - On or soon after day 21 of lactation; Nonpregnant adult females - At least 5 days after last expected parturition date

GROSS NECROPSY
- Gross necropsy: External and internal cavities were opened, and organs were examined in place, then removed. Hollow organs were opened and examined.

HISTOPATHOLOGY / ORGAN WEIGHTS
Organs Retained (when present): FØ and F1a adults - Coagulating gland, liver, ovaries, pituitary, prostate, seminal vesicle, skin/mammary gland, testes, epididymides, uterus, vagina and gross lesions;
Tissues Examined: Control and highest dietary levels - All retained tissues from all FØ and F1a adult animals and' all retained tissues from unscheduled adult deaths.
Organs Weighed: None
Postmortem examinations (offspring):
UNSCHEDULED NECROPSIES:
Pups found dead and culled pups had a gross necropsy; however, no tissues were saved and no organs were weighed.

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed on or soon after day 21 of lactation.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:

GROSS NECROPSY
- Gross necropsy: External and internal cavities were opened, and organs were examined in place, then removed. Hollow organs were opened and examined.

HISTOPATHOLOGY / ORGAN WEIGTHS
None
Statistics:
The following statistical procedures were used to detect statistically significant differences between treated animals and their respective controls:
- Dunnett's Multiple Comparison Test (two-tailed)
- EHL decision tree analysis
- Uncorrected Chi-Square Test
- Fisher's Exact Test
Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There were two adult deaths. A control level FØ female died on day 105, shortly after delivering a litter, with a retained fetus. The other was a T-1 level (30 ppm) F1a female which died on day 132 (29 days after her birth). Neither of these deaths were considered related to treatment.
There were no clinical signs considered, related to administration of the test material.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The only apparent adverse effects on body weight or weight gain in adult animals occurred during the last three weeks in T-4 level (1000 ppm) males of the FØ generation and in T-4 level F1a dams during gestation. There were no statistically significant differences in group mean body weights at lower dietary levels in males, or at any dietary level in adult females prior to mating. Maternal weight gain of T-4 level F1a dams was slightly reduced (approximately 93% of the control value) during the gestation day 0 to 21 period (regained during lactation), and was increased during the lactation day 0-7 period (1546% of controls). These dams also did not lose as much body weight as controls during the lactation day 14-21 period (lost approximately 12 grams as compared to approximately 23 grams for controls); however, this was not considered an adverse effect.

The only statistically significant decreases in food consumption occurred during the first week of gestation (gm/kg/day) and second week of gestation (gm/day), when T-4 level (1000 ppm) females of the FØ generation consumed slightly less food than did their controls. Food consumption by treated males during the study was similar to, or greater than, that of controls (except for T-2 level (100 ppm) males during week 17).

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
There were no findings in adult animals considered related to treatment. Decreased/absent sperm in the epididymis (unilateral) - was observed in one T-4 level FØ male, and a control male of the F1a generation, and was, therefore, not considered treatment-related.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Mating, fertility and gestation: There were no statistically significant differences in any of the measured parameters considered related to treatment in either the FØ or F1a generations.

GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no gross necropsy findings in adult animals of either generation considered related to treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Interstitial monocyte/lymphocyte infiltration of the prostate gland (a common lesion in older animals) was somewhat more frequently seen (not statistically significant) in T-4 level males (1000 ppm) of both generations than their respective controls, but was not considered an adverse effect attributable to administration of the test material.
Dose descriptor:
NOAEL
Effect level:
1 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: reproductive effects
Dose descriptor:
NOAEL
Effect level:
300 ppm
Sex:
male/female
Basis for effect level:
other: decrease in mean body weights
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
Litter size (live pups), dead pups/litter (day 0), and mean pup survival were not adversely affected when compared to controls.

CLINICAL SIGNS (OFFSPRING)
There were no clinical observations in offspring which were considered related to administration of the test chemical.

BODY WEIGHT (OFFSPRING)
There were no body weight effects in offspring considered treatment- related.

GROSS PATHOLOGY (OFFSPRING)
In offspring, distended/dilated stomachs were observed in four males and one female F1a weanlings at the T-4 level (1000 ppm). The cause of this abnormality was not definitively determined, but may have been a result of overeating; this change was not attributed to treatment.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: reproductive effects
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 ppm
Sex:
male/female
Basis for effect level:
other: decrease in mean body weights
Reproductive effects observed:
not specified
Conclusions:
Non-reproductive effects attributed to treatment in adult rats were limited to a minor decrease in group mean body weights of high level F0 males near the end of the study, and slightly decreased body weights of F1a dams during gestation.
There were no adverse reproductive effects in any of the measured parameter/indices in adult rats or their offspring.
NOAEL reproductive effects = 1000 ppm d (62-81 mg/kg bw/day), and NOAL subchronic toxicity = 300 ppm (18-24 mg/kg bw/day).
Executive summary:

Male and female Sprague-Dawley rats (30 adults/sex/dose) were continuously fed hydrogenated terphenyl through two generations at target levels of 0,30, 100, 300 and 1000 ppm in their diet. Analyses to verify the stability of the test material both neat and when mixed with the diet, the diet homogeneity and concentrations of the test material in the diet were all performed with satisfactory results. Overall study averages for consumption of test material (mg hydrogenated terphenyl/kilogram body weight/day), based on the target concentrations, were as follows: 1.8, 6.1, 18.5 and 62.0 for males and 2.5, 8.3,24.4 and 81.2 for females (for the F0 adults) and 1.9,6.1, 18.2 and 63.1 for males and 2.4, 8.1,24.3 and 80.6 for females (for the Fla adults), at the lowest to highest levels, respectively. Non-reproductive effects attributed to treatment in adult rats were limited to a minor decrease in group mean body weights of high level F0 males near the end of the study, and slightly decreased body weights of F1a dams during gestation. There were no adverse reproductive effects in any of the measured parameter/indices in adult rats or their offspring. On the basis of the above findings, the 1000 ppm dietary level was considered the no-observed-adverse-effect-level (NOAEL) for reproductive effects (corresponding with 62-81 mg/kg bw/day), and the 300 ppm dietary level was considered the NOAEL for subchronic toxicity in this study (corresponding with 18-24 mg/kg bw/day).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
62 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A key study for reproductive toxicity in male and female rats was performed with hydrogenated terphenyl in a two-generation reproductive toxicity study. The study was conducted according to OECD 416 and GLP guidelines, and was considered to be reliable, adequate and relevant Male and female Sprague-Dawley rats (30 adults/sex/dose) were continuously fed hydrogenated terphenyl through two generations at target levels of 0,30, 100, 300 and 1000 ppm in their diet (Naylor & Ruecker, 1991). Analyses to verify the stability of the test material both neat and when mixed with the diet, the diet homogeneity and concentrations of the test material in the diet were all performed with satisfactory results. Overall study averages for consumption of test material (mg hydrogenated terphenyl/kilogram body weight/day), based on the target concentrations, were as follows: 1.8, 6.1, 18.5 and 62.0 for males and 2.5, 8.3, 24.4 and 81.2 for females (for the F0 adults) and 1.9, 6.1, 18.2 and 63.1 for males and 2.4, 8.1, 24.3 and 80.6 for females (for the F1a adults), at the lowest to highest levels, respectively

Non-reproductive effects attributed to treatment in adult rats were limited to a minor decrease in group mean body weights of high level F0 males near the end of the study, and slightly decreased body weights of F1a dams during gestation. There were no adverse reproductive effects in any of the measured parameter/indices in adult rats or their offspring.

On the basis of the above findings, the 1000 ppm dietary level was considered the no-observed-adverse-effect-level (NOAEL) for reproductive effects (corresponding to 62 -81 mg/kg bw/day), and the 300 ppm dietary level was considered the NOAEL for subchronic toxicity in this study (corresponding to 18 -24 mg/kg bw/day).

Effects on developmental toxicity

Description of key information

Developmental toxicity was tested by dietary administration of hydrogenated terphenyl in rats from day 6 to 15 of gestation at 125, 500 and 1500 mg/kg bw/day. Maternal toxicity was observed from 500 mg/kg bw/day, leading to foetotoxicy and malformations at 1500 mg/kg bw/day.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant OECD guideline study, available as unpublished report, no restrictions, adequate for assessment
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breedirg Laboratories, Inc., Wilmington, Massachusetts 01887
- Age at study initiation: 66 days
- Weight at study initiation: 215.1 g (173.4-256.7)
- Housing: One per cage except during the first week of acclimation (two females/cage} and mating (one male and one female/cage).
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 23 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-77°F
- Humidity (%): 51-91% (R.H.)
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (7 am to 7 pm) via automatic timer
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared fresh weekly. Appropriate amounts of the test article were weighed into labeled 500 mL volumetric flasks (one flask per group). The appropriate amounts of corn oil were added to each flask and the solutions were then swirled. The solutions were allowed to settle for several minutes and then sonicated for ten minutes. Dosing solutions were then transferred to glass storage jars with plastic screw top lids and stored refrigerated until dispensing for dosing purposes. Dosing solutions were shaken vigorously prior to dispensing into labelled beakers for dosing. Dosing solutions in the beakers were stirred while animals were being dosed. Unused portions of dosing solution for each treatment day were discarded into an appropriate waste container.

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Purina Certified Rodent Chow No. 5002

VEHICLE
- Lot/batch no. (if required): JUN 30 84A
- Storage: room temperature
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Determination of the concentration in mg/mL of Terphenyl, hydrogenated in a corn oil dosing solution with gas chromatography method. Since hydrogenated terphenyl is a mixture of similar compounds an area summation is used to produce a summed peak area. This summed peak area is used to produce a standard curve from an analytical standards using linear regression. Corn oil dose solutions are then analyzed and their summed peak areas compared to the standard curve to determine the concentration of test material in mg/mL.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: one male and one female/cage
- Length of cohabitation: nightly on 10 days
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 6-15
Frequency of treatment:
once per day
No. of animals per sex per dose:
24 females per dose
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on a range-finding study (See report BD-84-67)
- Rationale for animal assignment (if not random): Females which mated were assigned to the groups daily in such a way as to most nearly equalize the Day 0 mean group body weights.
Maternal examinations:
PHYSICAL OBSERVATIONS: Yes
- Time schedule: Twice daily (morning and afternoon) for signs of pharmacologic or toxicologic effects and mortality. In addition, each female was given a detailed physical examination on Days 0, 6, 9, 12, 15 and 20 of gestation.

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on Days 0, 6, 9, 12, 15 and 20 of gestation.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Recorded for the following intervals during gestation: Days 0-6, 6-9, 9-12, 12-15 and 15-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: External surface, all orifices, the cranial cavity, carcass, the external surface of the spinal cord and sectioned surfaces of the brain, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs were examined for all animals. The carcass of each female was discarded at the completion of necropsy.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of live fetuses: Yes
- Number of dead fetuses: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: approximately half per litter
- Skeletal examinations: Yes: the remaining fetuses in each litter
- Head examinations: Yes: approximately half per litter (same as for soft tissue examinations)
Statistics:
Results of analysis by the indicated statistical procedure were reported for the following:
Mean body weights; Mean weight change; Mean food consumption; Reproduction data (Mean number of corpora lutea; Mean number of uterine implantation sites; Mean number of live fetuses; Mean number of resorptions; Pre-implantation loss ratio; Resorption/implant ratio); Mortality rates
Pregnancy rates; Incidence of fetuses with malformations/variations and the incidence of litters containing fetuses with malformations/variations; Incidence of females with resorption sites

Methods used:
Bartlett’s Test; ANOVA; Dunnett’s; Kruskal-Wallis; Summed Rank Test (Dunn); Regression Analysis/Trend/Lack of Fit; Jonckheere’s Statistic; Arc Sine
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No mortality occurred in the control, low- or mid-dose groups. At the high-dose level, a total of four females died; however, the death of one female was attributed to an intubation error. Excluding this one female, the mortality rate in the high-dose group was 12.5%.
No adverse effect of treatment was evident in pregnancy rate data. The pregnancy rate was 100% in the control, mid- and high-dose groups and, 91.7% (22/24) in the low-dose group.
At the low- and mid-dose levels, mean body weight and mean weight gain data during the treatment or post-treatment periods were not considered adversely affected by treatment. At the high-dose level, mean body weights were significantly lower than control on Days 9, 12, 15 and 20 of gestation and mean weight gain during the Day 6-15 gestation interval was significantly lower than control for this same group. No effect on food consumption data was evident at the low-dose level. In the mid-dose group, mean food consumption was significantly lower than control during the Day 8-9 and 9-12 gestation Intervals and in the high-dose group, mean food consumption was significantly lower than control only during the Day 8-9 gestation interval. A statistically significant increase in mean food consumption data for the high-dose group during the Day 15-20 gestation interval was not considered indicative of an adverse effect of treatment.
At the low-dose level, no adverse effect of treatment was evident from the detailed physical evaluations. At the mid-dose level, the incidence of females with areas of alopecia was notably increased at Days 16 and 20 of gestation; no other adverse effects of treatment at the mid-dose level were evident from the physical in-life observation data. At the high-dose level, the incidence of females with staining of the fur in the ano-genital area and/or soft stool was increased during the treatment interval of gestation. Additionally, several high-dose females were noted early in gestation (Day 9) as emaciated with red material about the snout.
No adverse effect of treatment at the low- or mid-dose level was evident from uterine implantation data. An increase in both the mean number of resorption sites and the mean ratio of resorptions to implants was seen at the high-dose level. These resorption data did not differ statistically from control data and the mean number of resorptions at the high-dose level was well within the range of historical control data for this laboratory. Thus, it is not clear if the increase in resorption data seen at the high-dose level represents an adverse effect of treatment.
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No adverse effect of treatment was evident in fetal weight data or fetal sex distribution data at the low- and mid-dose levels. In the high-dose group, mean fetal weight was significantly lower than control; however, fetal sex distribution data were not adversely affected at this same dose level.
No increase in the incidence of malformations was seen during the external, visceral or skeletal evaluations of fetuses recovered from females treated at the low- or mid-dose levels.
At the high-dose level, no increase in malformation rate was seen during fetal external evaluations; however, the incidence of fetuses with a glassy (shiny) appearance, considered to be an external variation observation, was significantly increased. Fetuses noted as having a glassy (shiny) appearance were usually the smaller fetuses within the litters and the observation was considered related to retarded fetal development within this group. No adverse effect of treatment at the high-dose level was evident from the fetal visceral evaluations. During the skeletal evaluations, the incidence of high-dose fetuses with malformations was statistically higher than control. Skeletal malformations were seen in seven high-dose fetuses (an incidence of 5.9%) in respect to the control incidence of 0.6% (one fetus with a skeletal malformation). Two of the seven high-dose fetuses (one fetus from each of two litters) had dissimilar, relatively minor malformations which were not considered related to treatment. Five high-dose fetuses (four fetuses from one litter and one fetus from a second litter) had one or more malformations from a syndrome of observations that involved misshapen and/or fusion defects of the exoccipital bones, fused ribs, cervical vertebral defects or misaligned thoracic vertebral centre. The two females whose litters contained fetuses with one or more skeletal malformations from the above stated syndrome of observations were quite stressed during the treatment period. Both females experienced weight loss during the Day 6-9 gestation interval and at Day 9, were noted with marked staining of the fur in the ano-genital area and extreme soft stool; therefore, it is not clear if this syndrome of skeletal malformations as seen with increased frequency among the high-dose fetuses represents a response to treatment or is secondary to maternal toxicity encountered at this same dose level.
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: fetotoxicity and embryotoxicity
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
No relevant effects were observed at 125 mg/kg bw/day. NOAEL for maternal toxicity was 125 mg/kg bw/day; NOAEL for fetotoxicity was 500 mg/kg bw/day.
Executive summary:

A developmental toxicity / teratogenicity was performed in a teratology study with hydrogenated terphenyl in Sprague-Dawley rats (24/group) from day 6-15 of pregnancy. No mortality occurred in the control, low- or mid-dose groups. At the high-dose level, 4 females died, however, the death of one female was attributed to an intubation error. Excluding this one female, the mortality rate in the high-dose group was 12.5%. No adverse effect of treatment was evident in pregnancy rate data. At the high-dose level, mean body weights were significantly lower than control. In the mid-dose and high group, mean food consumption was significantly lower than control. At the mid-dose level, the incidence of females with areas of alopecia was notably increased. At the high-dose level, the incidence of females with staining of the fur in the ano-genital area and/ or soft stool was increased during the treatment interval of gestation. Additionally, several high-dose females were noted early in gestation (Day 9) as emaciated with red material about the snout. No adverse effect of treatment at the low- or mid-dose level was evident from uterine implantation data. An increase in both the mean number of resorption sites and the mean ratio of resorptions to implants was seen at the high-dose level, however it was not clear if the increase represents an adverse effect of treatment. No increase in the incidence of malformations was seen during the external, visceral or skeletal evaluations of fetuses recovered from females treated at the low- or mid-dose levels. At the high-dose level, no increase in malformation rate was seen during fetal external evaluations; however, the incidence of fetuses with a glassy (shiny) appearance, considered to be an external variation observation, was significantly increased. Fetuses noted as having a glassy (shiny) appearance were usually the smaller fetuses within the litters and the observation was considered related to retarded fetal development within this group. No adverse effect of treatment at the high-dose level was evident from the fetal visceral evaluations. During the skeletal evaluations, the incidence of high-dose fetuses with malformations was statistically higher than control. Skeletal malformations were seen in seven high-dose fetuses (an incidence of 5.9%) in respect to the control incidence of 0.6% (one fetus with a skeletal malformation). Two of the seven high-dose fetuses (one fetus from each of two litters) had dissimilar, relatively minor malformations which were not considered related to treatment. Five high-dose fetuses (four fetuses from one litter and one fetus from a second litter) had one or more malformations from a syndrome of observations that involved misshapen and/or fusion defects of the exoccipital bones, fused ribs, cervical vertebral defects or misaligned thoracic vertebral centre. The two females whose litters contained fetuses with one or more skeletal malformations from the above stated syndrome of observations were quite stressed during the treatment period. Both females experienced weight loss during the Day 6-9 gestation interval and at Day 9, were noted with marked staining of the fur in the ano-genital area and extreme soft stool; therefore, it is not clear if this syndrome of skeletal malformations as seen with increased frequency among the high-dose fetuses represents a response to treatment or is secondary to maternal toxicity encountered at this same dose level.

In conclusion, NOAELfor maternal toxicity was 125 mg/kg bw/day; NOAEL for fetotoxicity was 500 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

A key study for developmental toxicity / teratogenicity was performed in a teratology study with hydrogenated terphenyl in Sprague-Dawley rats (24/group) from day 6-15 of pregnancy (Schroeder & Daly, 1986). The study was conducted according to OECD 414 and GLP guidelines, and was considered to be reliable, adequate and relevant. Oral doses given were 0, 125, 500, 1500 mg/kg bw/day, based upon a preceding dose range finding study. No mortality occurred in the control, low- or mid-dose groups. At the high-dose level, 4 females died, however, the death of one female was attributed to an intubation error. Excluding this one female, the mortality rate in the high-dose group was 12.5%.

No adverse effect of treatment was evident in pregnancy rate data. At the high-dose level, mean body weights were significantly lower than control. In the mid-dose and high group, mean food consumption was significantly lower than control. At the mid-dose level, the incidence of females with areas of alopecia was notably increased. At the high-dose level, the incidence of females with staining of the fur in the ano-genital area and/ or soft stool was increased during the treatment interval of gestation. Additionally, several high-dose females were noted early in gestation (Day 9) as emaciated with red material about the snout.

No adverse effect of treatment at the low- or mid-dose level was evident from uterine implantation data. An increase in both the mean number of resorption sites and the mean ratio of resorptions to implants was seen at the high-dose level, however it was not clear if the increase represents an adverse effect of treatment. No increase in the incidence of malformations was seen during the external, visceral or skeletal evaluations of fetuses recovered from females treated at the low- or mid-dose levels. At the high-dose level, no increase in malformation rate was seen during fetal external evaluations; however, the incidence of fetuses with a glassy (shiny) appearance, considered to be an external variation observation, was significantly increased. Fetuses noted as having a glassy (shiny) appearance were usually the smaller fetuses within the litters and the observation was considered related to retarded fetal development within this group. No adverse effect of treatment at the high-dose level was evident from the fetal visceral evaluations. During the skeletal evaluations, the incidence of high-dose fetuses with malformations was statistically higher than control. Skeletal malformations were seen in seven high-dose fetuses (an incidence of 5.9%) in respect to the control incidence of 0.6% (one fetus with a skeletal malformation). Two of the seven high-dose fetuses (one fetus from each of two litters) had dissimilar, relatively minor malformations which were not considered related to treatment. Five high-dose fetuses (four fetuses from one litter and one fetus from a second litter) had one or more malformations from a syndrome of observations that involved misshapen and/or fusion defects of the exoccipital bones, fused ribs, cervical vertebral defects or misaligned thoracic vertebral centre. The two females whose litters contained fetuses with one or more skeletal malformations from the above stated syndrome of observations were quite stressed during the treatment period. Both females experienced weight loss during the Day 6-9 gestation interval and at Day 9, were noted with marked staining of the fur in the ano-genital area and extreme soft stool; therefore, it is not clear if this syndrome of skeletal malformations as seen with increased frequency among the high-dose fetuses represents a response to treatment or is secondary to maternal toxicity encountered at this same dose level.


In conclusion, NOAEL for maternal toxicity was 125 mg/kg bw/day; NOAEL for fetotoxicity was 500 mg/kg bw/day.

A dose range finding supporting study was performed in a teratology study with hydrogenated terphenyl in Sprague-Dawley rats (5/group) from day 6-15 of pregnancy (Monsanto, 1985). Doses given were 0, 125, 250, 500, 1000, 2000 mg/kg bw/day. Females were sacrificed on Day 20 of gestation and uterine implantation data were evaluated. Fetuses recovered at this time were weighed, sexed and evaluated for external malformations. 250 mg/kg bw/day was the maternal NOAEL. At 500 and 1000 mg/kg bw/day, maternal food consumption was decreased, however there were no offspring effects; at 1000 mg/kg bw/day. 1000 mg/kg bw/day was the developmental NOAEL. At 2000 mg/kg bw/day, embryonic death and decreased fetal weights were observed.

A developmental toxicity study in the 2ndspecies (rabbit) is waived based on following reasons:

1.    The study in the first species (rat) was conducted under exaggerated conditions. Based on the relevant dose levels given, there was no concern for development toxicity.

2.    Based on existing data, a study in the 2ndspecies (rabbit) is expected lead to severe gastro-intestinal and other problems, and will not deliver added value to the existing information.

Justification for classification or non-classification

The endpoint does not meet classification criteria according to EU and/or CLP criteria.