O,O'-dioctadecylpentaerythritol bis(phosphite)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 December 2005 to 6 March 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3550 (Reproduction/ Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Advinus Therapeutics Private Ltd., Bangalore - 560 058, India
- Age at study initiation: 12 weeks
- Weight at study initiation:
Males: Control 375 ± 17.1 g, 100 mg/kg 378 ± 16.2 g, 400 mg/kg 378 ± 18.9 g and 1000 mg/kg 377 ± 13.9 g (mean ± SD)
Females: Control 235 ± 10.4 g, 100 mg/kg 234 ± 13.7 g, 400 mg/kg 233 ± 11.9 g and 1000 mg/kg 233 ± 9.9 g (mean ± SD)
- Housing: groups of 2 per sex in sterilised suspended standard polyproylene cages (males, females during pre-mating); individually in polypropylene cages with steam sterilised paddy husk and sterilised nesting material from gestation day 20 up to lactation day 4 (females)
- Diet: Ssniff rats/mice food (Sniff Spezialdiäten GmbH., Ferdinand-Gabriel-Weg 16, D-59494 Söest, Germany) ad libitum
- Water: purified deep bore-well water
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): 12 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

IN-LIFE DATES: From 31 December 1995 to 6 March 2006

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: test material suspensions in CMC were prepared daily before gavage administration. Test material was ground in a pestle and mortar before being added to 0.5 % aqueous carboxymethyl cellulose. The suspension was made up to the final volume of 90 mL to get test material concentrations of 10, 40 and 100 mg/mL.Test material was administered at an equivolume of 10 mL/kg bw.

VEHICLE
- Justification for use and choice of vehicle (if other than water): based on a solubility test, the test material was found to be insoluble in water but a clear suspension was formed in aqueous 0.5 % carboxymethyl cellulose.

Details on mating procedure:

- M/F ratio per cage: 1 male / 1 female
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

- Once daily for 2 weeks, continuing during mating period and approximately 2 weeks post mating (males)
- Once daily throughout treatment period. Treatment started 2 weeks prior to the mating period and continued through mating, pregnancy and up to lactation day 4 (females)

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 100, 400, 1000 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

10 males and 10 females per dose level

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: dose levels selected in consideration of results from a 7-day oral (gavage) toxicity study with 2,4,8,10-tetraoxa-3,9-diphosphaspiro [5.5]undecane, 3,9-bis(octadecyloxy)-(9Cl) in Wistar rats treated at 100, 400 and 1000 mg/kg bw/day. Under the conditions of the study no clinical signs were observed, there were no deaths and body weights, food intake, organ weights and gross pathology did not reveal any significant differences in treatment groups compared to the respective controls.
- Rationale for animal assignment (if not random): Grouping was done one day before treatment using an in-house method of bodyweight stratification and distribution. The rats procured for the study were weighed and segregated depending on bodyweight ragnes. The bodyweight randes were 331-410 for males and 201-270 g for females. Animals with bodyweight ranges 341-350, 351-360, 361-370, 371-380, 381-390 and 391-400 g for males and 211-220, 221-230, 231-240, 241-250 and 251-260 g for females were selected and rats within each bodyweight range were randomly distributed to all groups to attain groups whose mean bodyweight variation were not more than 20 %.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: checks for morbidity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: appearance, behaviour and clinical signs. Females were also observed for signs of difficult and prolonged parturition.

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 of treatment and at least weekly thereafter. All dams were weighed on gestation days 0, 7, 14 and 20 and on lactation days 0 and 4.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (based on weekly intakes).

Litter observations:

PARAMETERS EXAMINED:
The following parameters were examined in offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

GROSS EXAMINATION OF DEAD PUPS: yes, all dead and sacrificed pups were examined for malformations and subjected to gross pathological examination

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals following a minimum treatment period of 4 weeks (this included a minimum of 2 weeks prior to mating, during the mating period and approximately 2 weeks post mating)
- Maternal animals: All surviving animals following a minimum treatment period of 4 weeks (this included at least 2 weeks prior to mating to cover at least two complete oestrous cycles, the variable time to conception, the duration of pregnancy and at least 4 days after delivery)

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively: ovaries, testes, epididymides, seminal vesicles, coagulating glands, prostate together with all gross lesions. The testes and epididymides of all adult males were weighed. The organ weights as percentage of bodyweights were also determined and recorded.

Statistics:

The significance of group differences was tested using Dunnett's 't' test and the Student's 't' test.

Reproductive indices:

Gestation index = (no. of females with live pups / no. of pregnant females) x 100

Male fertility index = (no. of males impregnating females / no. of males exposed to females) x 100

Female fertility index = (no. of pregnant females / no. of paired females) x 100

Fecundity index = (no. of pregnant females / no. of mated females) x 100

Mean no. of corpora lutea = total no. of corpora lutea / no. of dams used for corpora lutea count

Mean no. of implantations = total no. of implantation / no. of dams used for implantation count

Implantations = (total no. of implantations / total no. of corpora lutea) x 100

Parturition = (no. of parturitions / no. of pregnancies) x 100

Pre-terminal deaths of pregnant dams = (no. of pregnant animals dead / total no. of pregnant animals) x 100

Live pups born = (no. of lives pups born / no. of implantations) x 100

Pre-implantation loss = (no. of corpora lutea – no. of implantations / no. of corpora lutea) x 100

Post implantation loss = (no. of implantations – no. of live pups / no. of implantations) x 100

Offspring viability indices:

Mean litter size index = no. of pups on day 0 / no. of females littered

Mean viable litter size = no. of viable pups on day 0 / no. of females littered

Live birth index = (no. of pups alive on day at first observation / no. of pups born at first observation) x 100

24 hour survival index = (no. of viable pups on lactation day 1 / no. of viable pups born) x 100

4th day survival index = (no. of pups viable pups on lactation day 4 / no. of viable pups born) x 100

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Description (incidence and severity):

Test substance intake: not applicable

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There were no pre-terminal deaths at any of the doses tested and no clinical signs were observed. The partial cannibalism of pups was observed in three females in control and three females of the high dose group and all pups cannibalism was observed in one female of the mid dose group.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weights and food consumption were unaffected by treatment with the test material at all dose levels.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no treatment related effects observed on the mean number of days of pre-coital interval between control and the treated groups and there were no treatment related effects observed in the length of the pregnancy between control and treated groups. The mean number of male and female pups and the mean number of pups for combined sex during different intervals of lactation period at all tested doses were unaffected by the treatment when compared to control. Fertility indices of sires and dams, fedundity index, percentage of implantations, gestation index, parturition percentage, percentage of pre-implantation loss, post-implantation loss and live pups born were unaffected by the treatment at all doses tested when compared to control. Incidentally, there were higher numbers of live pups born at the mid and high doses due to the lower percentage of post implantation loss. The significantly higher percentage of pre-implantation loss resulted in lower percentage of implantations at the low and mid doses. These findings were considered incidental as there were no changes observed at the high dose.

ORGAN WEIGHTS (PARENTAL ANIMALS)
There were no significant differences in organ weights and organ weight ratios in the males.

GROSS PATHOLOGY (PARENTAL ANIMALS)
There were no treatment related gross changes in males and females. the few incidences of lesions observed were randomly distributed among the various groups and were hence considered incidental.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No lesions were observed in the ovaries, testes and epididymides in the control and high dose animals examined for histopathology.

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment related effects were observed at this dose level in any of the parameters evaluated

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:

no effects observed

VIABILITY (OFFSPRING)
The number of live litters, mean litter size index, sex ratio at birth, number of pups dead at first observation, number of pups dead/cannibalised on day 1, up to day 4, the number of pups alive on day 0 and 1, live birth index and 24 hour survival index were unaffected by the treatment at all doses tested when compared to control. Any differences that occurred were a result of cannibalism and were considered incidental and not related to the treatment.

BODY WEIGHT (OFFSPRING)
the mean weight of males and female pups and the mean weight of pups for combined sex during different intervals of lactation period were unaffected by the treatment when compared to control.

GROSS PATHOLOGY (OFFSPRING)
There was a single incidence of a rudimentary tail in one high dose male pup. This was considered an incidental change and thus there were no treatment related gross changes observed in the pups.

Reproductive effects observed:

not specified

Conclusions:

It is concluded that the oral administration of the test material to rats at the concentration of 1000 mg/kg, had no effects on general health, body weights and food consumption. There were no treatment-related signs and no pre-terminal deaths. No treatment-related effects were observed on gestation and lactation body weights and food consumption, number and weight of pups, viability of pups, fertility indices of parental animals, terminal body weights, organ weights and their ratios in males. There were also no treatment-related gross and histopathological changes. Under the conditions of the study, the No Observed Effect Level was therefore determined to be 1000 mg/kg bw.

Executive summary:

The reproductive and developmental toxicity of the test material was investigated in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study rats were dosed test material by gavage, at daily concentrations of 0 (vehicle control), 100, 400 and 1000 mg/kg bw. Following two weeks of treatment, animals were mated and treatment continued for another two weeks (minimum). Animals were observed for mortality and clinical signs during the treatment period; body weights and food consumption were also recorded. At the end of the treatment period animals were sacrificed and subjected to gross and histopathological examination. Under the conditions of the study, it was concluded that the oral administration of the test material to rats at the concentration of 1000 mg/kg, had no effects on general health, body weights and food consumption. There were no treatment-related signs and no pre-terminal deaths. No treatment-related effects were observed on gestation and lactation body weights and food consumption, number and weight of pups, viability of pups, fertility indices of parental animals, terminal body weights, organ weights and their ratios in males. There were also no treatment-related gross and histopathological changes. In consideration of the findings, the No Observed Effect Level was determined to be 1000 mg/kg bw.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study was performed to GLP and in line with standardised guidelines. It was therefore assigned a Klimisch score of 1. The overall quality of the database is high. The conclusions of the supporting data were in good agreement with the key study.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the key study, the reproductive and developmental toxicity of the test material was investigated in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study rats were dosed test material by gavage, at daily concentrations of 0 (vehicle control), 100, 400 and 1000 mg/kg bw. Following two weeks of treatment, animals were mated and treatment continued for another two weeks (minimum). Animals were observed for mortality and clinical signs during the treatment period; body weights and food consumption were also recorded. At the end of the treatment period animals were sacrificed and subjected to gross and histopathological examination. Under the conditions of the study, it was concluded that the oral administration of the test material to rats at the concentration of 1000 mg/kg, had no effects on general health, body weights and food consumption. There were no treatment-related signs and no pre-terminal deaths. No treatment-related effects were observed on gestation and lactation body weights and food consumption, number and weight of pups, viability of pups, fertility indices of parental animals, terminal body weights, organ weights and their ratios in males. There were also no treatment-related gross and histopathological changes. In consideration of the findings, the No Observed Effect Level was determined to be 1000 mg/kg bw.

Suporting information is available in the form of a reproductive and developmental toxicity study in which rats were administered with 100 mg of test material per kg of feed powder for a period of 2 years. During the treatment period males and females were mated. Mortality and clinical signs were recorded during the study both in parental animals and in pups. The first generation animals were then mated in order to obtain a second generation. All pups were examined thoroughly macroscopically before being subject to histological examination. Under the conditions of the study, pups were found to develop normally. Findings at autopsy revealed no anomaly (craniocerebral, digestive, thoracovisceral, abdominal, genital). The histological examination of two animals (lungs, liver, kidneys) proved to be normal. It was therefore concluded that, in the absence of congential malformations and of teratogenesis, that the test material is not toxic to reproduction or development.

The available information is considered adequate for the assessment for risk assessment and classifcation and labelling purposes, and is considered to be an accurate reflection of the reproductive toxicity potential of the substance.

Short description of key information:
NOEL for reproduction and devleopmental toxicity 1000 mg/kg bw/day (rat); OECD 421, EPA OPPTS 870.3550; Ganiger (2006)

Justification for selection of Effect on fertility via oral route:
The key study was conducted to GLP and a standardised test guideline with a high level of reporting while the supporting study is a non-GLP study, not conducted to standardised guidelines with insufficient information available to assess the quality of the presented information.

Effects on developmental toxicity

Description of key information

NOEL for reproduction and devleopmental toxicity 1000 mg/kg bw/day (rat); OECD 421, EPA OPPTS 870.3550; Gangier (2006)

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 December 2005 to 6 March 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3550 (Reproduction/ Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Advinus Therapeutics Private Ltd., Bangalore - 560 058, India
- Age at study initiation: 12 weeks
- Weight at study initiation:
Males: Control 375 ± 17.1 g, 100 mg/kg 378 ± 16.2 g, 400 mg/kg 378 ± 18.9 g and 1000 mg/kg 377 ± 13.9 g (mean ± SD)
Females: Control 235 ± 10.4 g, 100 mg/kg 234 ± 13.7 g, 400 mg/kg 233 ± 11.9 g and 1000 mg/kg 233 ± 9.9 g (mean ± SD)
- Housing: groups of 2 per sex in sterilised suspended standard polyproylene cages (males); individually in polypropylene cages with steam sterilised paddy husk and sterilised nesting material from gestation day 20 up to lactation day 4 (females)
- Diet: Ssniff rats/mice food (Sniff Spezialdiäten GmbH., Ferdinand-Gabriel-Weg 16, D-59494 Söest, Germany) ad libitum
- Water: purified deep bore-well water
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23 ºC
- Humidity (%): 30 - 70 %
- Air changes (per hr): 12 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

IN-LIFE DATES: From 31 December 1995 to 6 March 2006

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: test material suspensions in CMC were prepared daily before gavage administration. Test material was ground in a pestle and mortar before being added to 0.5% aqueous carboxymethyl cellulose. The suspension was made up to the final volume of 90 mL to get test material concentrations of 10, 40 and 100 mg/mL.Test material was administered at an equivolume of 10 mL/kg bw.

VEHICLE
- Justification for use and choice of vehicle (if other than water): based on a solubility test, the test material was found to be insoluble in water but a clear suspension was formed in aqueous 0.5% carboxymethyl cellulose.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- M/F ratio per cage: 1 male / 1 female
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

- Once daily for 2 weeks, continuing during mating period and approximately 2 weeks post mating (males)
- Once daily throughout treatment period. Treatment started 2 weeks prior to the mating period and continued through mating, pregnancy and up to lactation day 4 (females)

Frequency of treatment:

Daily

Duration of test:

The males were dosed for a minimum period of 4 weeks, up to and including the day before scheduled sacrifice (this included a minimum of 2 weeks prior to mating, during the mating period and approximately 2 weeks post mating). Females were dosed throughout the treatment period. This included 2 weeks prior to mating (with the objective of covering at least 2 complete oestrous cycles), the variable time to conception, the duration of pregnancy and at least 4 days after delivery, up to and including the day before scheduled sacrifice.

Remarks:

Doses / Concentrations:
0, 100, 400, 1000 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

10 males and 10 females per dose level

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: dose levels selected in consideration of results from a 7-day oral (gavage) toxicity study with 2,4,8,10-tetraoxa-3,9-diphosphaspiro [5.5]undecane, 3,9-bis(octadecyloxy)-(9Cl) in Wistar rats treated at 100, 400 and 1000 mg/kg bw/day. Under the conditions of the study no clinical signs were observed, there were no deaths and body weights, food intake, organ weights and gross pathology did not reveal any significant differences in treatment groups compared to the respective controls.
- Rationale for animal assignment (if not random): Grouping was done one day before treatment using an in-house method of bodyweight stratification and distribution. The rats procured for the study were weighed and segregated depending on bodyweight ragnes. The bodyweight randes were 331-410 for males and 201-270 g for females. Animals with bodyweight ranges 341-350, 351-360, 361-370, 371-380, 381-390 and 391-400 g for males and 211-220, 221-230, 231-240, 241-250 and 251-260 g for females were selected and rats within each bodyweight range were randomly distributed to all groups to attain groups whose mean bodyweight variation were not more than 20 %.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: checks for morbidity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: appearance, behaviour and clinical signs including signs of difficult and prolonged parturition.

BODY WEIGHT: Yes
- Time schedule for examinations: day 1 of treatment and at least weekly thereafter. All dams were weighed on gestation days 0, 7, 14 and 20 and on lactation days 0 and 4.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION: No

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes. Detailed histological examination was performed on the ovaries.
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No data

Statistics:

The significance of group differences was tested using Dunnett's 't' test and the Student's 't' test.

Indices:

Mean no. of corpora lutea = total no. of corpora lutea / no. of dams used for corpora lutea count

Mean no. of implantations = total no. of implantation / no. of dams used for implantation count

Implantations = (total no. of implantations / total no. of corpora lutea) x 100

Pre-implantation loss = (no. of corpora lutea – no. of implantations / no. of corpora lutea) x 100

Post implantation loss = (no. of implantations – no. of live pups / no. of implantations) x 100

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
There were no pre-terminal deaths at any of the doses tested and no clinical signs were observed. The partial cannibalism of pups was observed in three females in control and three females of the high dose group and all pups cannibalism was observed in one female of the mid dose group.

BODY WEIGHT AND FOOD CONSUMPTION
Body weights and food consumption were unaffected by treatment with the test material at all dose levels.

REPRODUCTIVE PERFORMANCE
Percentage of implantations, parturition percentage, percentage of pre-implantation loss, post-implantation loss and live pups born were unaffected by the treatment at all doses tested when compared to control. The significantly higher percentage of pre-implantation loss resulted in lower percentage of implantations at the low and mid doses. These findings were considered incidental as there were no changes observed at the high dose.

GROSS PATHOLOGY
There were no treatment related gross changes in females. The few incidences of lesions observed were randomly distributed among the various groups and were hence considered incidental.

HISTOPATHOLOGY
No lesions were observed in the ovaries in the control and high dose animals examined for histopathology.

Dose descriptor:

NOEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
GROSS PATHOLOGY
There was a single incidence of a rudimentary tail in one high dose male pup. This was considered an incidental change and thus there were no treatment related gross changes observed in the pups.

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Under the conditions of the study, the No Observed Effect Level for maternal toxicity and developmental toxicity was determined to be 1000 mg/kg bw when dosed to Wistar rats via oral gavage.

Executive summary:

The reproductive and developmental toxicity of the test material was investigated in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study rats were dosed test material by gavage, at daily concentrations of 0 (vehicle control), 100, 400 and 1000 mg/kg bw. Following two weeks of treatment, animals were mated and treatment continued for another two weeks (minimum). Animals were observed for mortality and clinical signs during the treatment period; body weights and food consumption were also recorded. At the end of the treatment period animals were sacrificed and subjected to gross and histopathological examination. Under the conditions of the study, it was concluded that the oral administration of the test material to rats at the concentration of 1000 mg/kg, had no effects on general health, body weights and food consumption. There were no treatment-related signs and no pre-terminal deaths. No treatment-related effects were observed on gestation and lactation body weights and food consumption, number and weight of pups, viability of pups, fertility indices of parental animals, terminal body weights, organ weights and their ratios in males. There were also no treatment-related gross and histopathological changes. In consideration of the findings, the No Observed Effect Level was determined to be 1000 mg/kg bw.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The key study was performed to GLP and in line with standardised guidelines. It was therefore assigned a Klimisch score of 1. The overall quality of the database is high. The conclusions of the supporting data were in good agreement with the key study.

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

In the key study, the reproductive and developmental toxicity of the test material was investigated in accordance with standardised guidelines OECD 421 and EPA OPPTS 870.3550. During the study rats were dosed test material by gavage, at daily concentrations of 0 (vehicle control), 100, 400 and 1000 mg/kg bw. Following two weeks of treatment, animals were mated and treatment continued for another two weeks (minimum). Animals were observed for mortality and clinical signs during the treatment period; body weights and food consumption were also recorded. At the end of the treatment period animals were sacrificed and subjected to gross and histopathological examination. Under the conditions of the study, it was concluded that the oral administration of the test material to rats at the concentration of 1000 mg/kg, had no effects on general health, body weights and food consumption. There were no treatment-related signs and no pre-terminal deaths. No treatment-related effects were observed on gestation and lactation body weights and food consumption, number and weight of pups, viability of pups, fertility indices of parental animals, terminal body weights, organ weights and their ratios in males. There were also no treatment-related gross and histopathological changes. In consideration of the findings, the No Observed Effect Level was determined to be 1000 mg/kg bw.

 

Supporting information is available in the form of a study in which the effects of the test material on the survival rate of chick embryos was investigated. During the study, two replicate runs were conducted in which groups of 16 fertile White Leghorn eggs, obtained from a commercial source, were used per group (treatment). With each series, there were four comparison groups: untreated eggs, as a control on hatchability, eggs which were drilled and the needle inserted into the yolk sac (without the injection of anything), eggs injected with distilled sterile water, eggs injected with corn oil from the same lot used to prepare the test material solution, as well was eggs that were injected with the test material solution. Survival of the embryos was monitored over an 18 day incubation period and in terms of the number of live chicks which hatched. Findings showed that any manipulation which disrupts the integrity of the egg membrane causes some mortality of the embyros; this was shown by comparison of the intact eggs and those which were only drilled and the empty needle inserted. Mortality was further increased, slightly, by the injection of either water or corn oil. The injection of 5 mL of test material appeared to have little effect on survival of embryos. Examination of embryos which died before hatching and of the newly hatched chicks revealed no gross abnormalities or malfunctions which were peculiar to the test groups. Those chicks which hatched were considered normal and viable. Under the conditions of the study, it was concluded that the test material was not embryotoxic in incubating hen's eggs to any significant degree, when injected into the yolk sac at the rate of 5 mg per egg in a corn oil solution.

The available information is considered adequate for the assessment for risk assessment and classifcation and labelling purposes, and is considered to be an accurate reflection of the developmental toxicity/teratogenic potential of the substance.

Justification for selection of Effect on developmental toxicity: via oral route:
The key study was performed to GLP and to standardised guidelines and was written up with a high level of reporting while the supporting study was a non-GLP study performed to sound scientific principles.

Justification for classification or non-classification

In line with Directive 67/548/EEC and Regulation 1272/2008, the test material is considered to be unclassified for reproductive and developmental toxicity.