Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

An OECD screening study of reproductive toxicity revealed no functional changes in fertility or reproductive performance although histopathological examination revealed reduced spermatocytes &

spermatids in the testes of males given the substance at doses of 300 or 1000 mg/kg/day.

Such effects were not apparent at dose levels as high as 1000 mg/kg/day in a sub-chronic study of 90 days duration, the duration of exposure being approximately double that of the screening study.

A study of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substance does not cause repression of genes in the testicular mal-development pathway indicating that the substance is unlikely to cause testicular dysgenesis in rats as is seen with some phthalate esters.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crj:CD:SD
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan
- Age at study initiation: (P) x 10 wks;
- Weight at study initiation: (P) Males: 373-435 g; Females: 217257 g
- Fasting period before study: No
- Housing: wire mesh cages, in pairs for mating
- Use of restrainers for preventing ingestion (if dermal): Not applicable
- Diet (e.g. ad libitum): yes, pelleted diet, CRF-1. Oriental Yeast Co. Ltd.
- Water (e.g. ad libitum): yes, tap water via automatic watering system
- Acclimation period: 14d for males; 10d for females

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/- 3
- Humidity (%): 55+/-10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12:12

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Prepared weekly by dissolving required weight of TOTM in corn oil and stored in airtight containers in the dark until use.


VEHICLE
- Justification for use and choice of vehicle (if other than water): TOTM is poorly soluble in water
- Concentration in vehicle: As required to achieve nominal dose
- Amount of vehicle (if gavage): 5ml/kg
- Lot/batch no. (if required): No batch number reported but supplied by Katayama Chemical
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 14 d (until sperm detected in vagina).
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): singly
- Any other deviations from standard protocol: None reported
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Males: from 14 days before pairing for 46d;
Females: from 14d before pairing to d3 of lactation
Frequency of treatment:
Daily during treatment periods see above
Remarks:
Doses / Concentrations:
0 (control) 100 300 1000 mg/kg/day
Basis:
nominal conc.
No. of animals per sex per dose:
12 males & 12 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of 14d preliminary study. Effects on body weight in animals given 1000 mg/kg/day
- Rationale for animal assignment (if not random): Random, stratified body weight
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily, parents & foetuses

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Males: Predose, 2, 5, 7, 10 & 14d & weekly thereafter until sacrifice; females: Predose, 2, 5, 7, 10 & 14d. Gestation period: 0, 1, 3, 5, 7, 10, 17 & 20d. Lactation period: 0,1 & 4d.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - at same intervals as body weight except lactation period and day of sacrifice for males and 0d of gestation & lactation for females.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations:
Oestrous cyclicity (parental animals):
Examined pre-dose and during dosing period
Sperm parameters (parental animals):
Parameters examined in 5 P males/group : yes
[testis weight, epididymis weight, sperm count in testes, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm morphology
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 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, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals 1d after mating
- Maternal animals: All surviving animals d4 of lactation; if did not mate 1d after mating period ended
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations of all organs & including the cervical, thoracic, and abdominal viscera. Pups: all organs

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination and weighed, respectively. : organ weights: males Testis & epididymis; females ovary;
microscopic examination: Testis & epididymis, sertoli cell count, spermatocytes, round & elongated spermatids in seminiferous tubules of 5 animals /group (Stage 1-VI, VII-Viii, IX-XI, XII-XIV of spermatoan formative cycle).
Females: Ovary

Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination). Pups: found dead & abnormalities

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
Statistics:
Chi squared test for 1 grade positive data and Fisher's test for other. Bartlett's /Kruskal Wallis' test for 2 or more positive grade data. Dunnett's test or Mann-Whitney U test for assessment.
Reproductive indices:
Copulation Index: No. of pairs with successful copulation/no. of pairs mated X 100
Fertility Index: No of pregnant females/no. of pairs with successful copulation X 100
Implantation index: No. of implantation sites/no. of corporea lutea X 100
Delivery index: No. of pups born/no. of implantation sites X 100
Gestation index: No. of females with live pups delivered/no. of pregnant females X 100
Nursing index: No. of females nursing live pups/no. of females with normal delivery X 100
Offspring viability indices:
Live birth index: No. of live pups at birth/no. of pups at birth X 100
Viability index: No. of live pups on d4/no.of live pups at birth
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See below for males
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
See below for males
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): No effects

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): No effects

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): See histopathology (below)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No effects

ORGAN WEIGHTS (PARENTAL ANIMALS): No effects

GROSS PATHOLOGY (PARENTAL ANIMALS): No effects

HISTOPATHOLOGY (PARENTAL ANIMALS): Slightly reduced numbers of spermatocytes & spermatids in 2/12 & 11/12 animals given 300 & 1000 mg/kg/day TOTM respectively and a moderate decrease in 1/12 animals given 1000 mg/kg/day TOTM. In addition the number of cells/number of spermatids in seminiferous tubules was reduced in males given 300 mg/kg/day TOTM in stages I-VI. In males given 1000 mg/kg/day in stage I-IV numbers of spermatocytes &spermatids were reduced. In stages VII-XIV spermatocyte & spermatid numbers continued to be low & the sertolicell ratio was also reduced.

Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Histopathology; sperm characterization, numbers & ratio of sertoli cells in males given 1000 mg/kg/day TOTM & reduced numbers of spermatids in animals given 300 mg/kg/day.
Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of effects on pup weight; sex ratio; survival index; viability index following treatment of parents with TOTM at dosages of 100, 300 or 1000 mg/kg/day.
Remarks on result:
other: Generation: pups (migrated information)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
slightly low bodyweights & body weight gain in pups in 300 mg/day/kg group. No difference, relative to controls, at 100 and 1000 mg/kg b.w.
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
Description (incidence and severity):
Pups found dead or with abnormalities only
VIABILITY (OFFSPRING): No effects

CLINICAL SIGNS (OFFSPRING): No effects

BODY WEIGHT (OFFSPRING):Body weight & body weight gain in pups from the 300 mg/kg/day group were slightly low. However as the body weight & body weight gain in the 100 & 1000 mg/kg/day groups were unaffected this was not considered to be a definite effect of treatment.

GROSS PATHOLOGY (OFFSPRING): No effects

HISTOPATHOLOGY (OFFSPRING): No effects

Key result
Dose descriptor:
NOEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
Reproductive effects observed:
not specified

See attached document (MITI Repro sreen.pdf)

Conclusions:
Repeat dose toxicity: Histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given TOTM at doses of 300 or 1000 mg/kg/day. Treatment with TOTM had no effect on the appearance, condition or behaviour, body weight, food consumption, necropsy findings, weights of the testes, epididymis or ovaries, or histopathology of the ovaries. The NOELs are considered to be 100 & 1000 mg/kg/day for males & females respectively.
Reproductive & developmental toxicity: With the exception of the effects in male described above treatment with TOTM at dosages of 100, 300 or 1000 mg/kg/day had no effect on reproductive ability, organ weight or histopathology of the ovary, delivery or maternal behaviour of the dams. The NOELs are considered to be 100 & 1000 mg/kg/day for males & females respectively.

Pup post natal development: No effects of treatment with TOTM at dosages of 100, 300 or 1000 mg/kg/day were detected on viability, general appearance, body weights or autopsy findings. The NOEL is considered to be 1000 mg/kg/day for males & female offspring.
Executive summary:

In an OECD screening study of reproductive toxicity histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given the substance at doses of 300 or 1000 mg/kg/day. Treatment had no effect on the appearance, condition or behaviour, body weight, food consumption, necropsy findings, weights of the testes, epididymis or ovaries, or histopathology of the ovaries. The NOELs for systemic toxicity are considered to be 100 & 1000 mg/kg/day for males & females respectively.

With the exception of the effects in males, treatment at dosages of 100, 300 or 1000 mg/kg/day had no effect on reproductive ability, organ weight or histopathology of the ovary, delivery or maternal behaviour of the dams. The NOEL for reproductive / developmental toxicity is considered to be 1000 mg/kg/day for offspring.

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
subacute
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

An OECD screening study of reproductive toxicity revealed no functional changes in fertility or reproductive performance although histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given the substance at doses of 300 or 1000 mg/kg/day. The NOELs for systemic toxicity were considered to be 100 & 1000 mg/kg/day for males & females respectively. The NOEL for reproductive / developmental toxicity is considered to be 1000 mg/kg/day for offspring.

It is noted that, in a repeat dose toxicity study of 90 -days duration, approximately double that of the screening study, the testicular effects described above were not seen. Similarly, in a repeat-dose toxicity combined with a screening study of reproductive toxicity on a structural analogue of TOTM (the alcohol ester side chains of the molecule still being C8 but linear rather than branched) no significant effect on reproductive ability, organ weight or histopathology of the ovary, delivery or maternal behaviour was apparent. The NOEL for reproductive / developmental toxicity was considered to be 500 mg/kg/day for both parents and offspring, the highest dose examined.

In accordance with Regulation (EC) No 1907/2006, Annex X, 8.7.3, column 2, an Extended One-Generation Reproductive Toxicity Study (EOGRTS) is a standard data requirement.

 

In accordance with the general rules set out in Regulation (EC) No 1907/2006, Annex XI, section 1.2, a weight of evidence approach has consideredthe following:

-  Toxicokinetic behaviour assessment

-  Results from prenatal developmental toxicity studies in rats

-  Results from screening studies of reproductive toxicity

-  Results from repeat dose studies in rats

-  RNA transcriptional profiling studying reproductive toxicity potential towards the developing male testes

 

The substance has low bioaccumulation potential. Due to high molecular weight, high lipophilicity (log Pow >4), and slow hydrolysis of the ester, GI tract absorption is likely to be low. An evaluation of the outcome of repeat oral dose studies demonstrates that the registered substance, either in the form of the parent compound or its hydrolysis products, are of a low order of toxicity. Similarly, both QSAR modeling and ex-vivo skin permeability studies indicate dermal absorption to be minimal. The physico-chemical properties of the substance indicate that inhalation exposure is expected only to occur upon exposure to aerosols. Due to high lipophilicity and high molecular weight, absorption in the lungs is likely to be limited. Therefore, taking all relevant data into account, it is concluded that the registered substance is of a low order of systemic toxicity. 

 

An OECD screening study of reproductive toxicity revealed no functional changes in fertility or reproductive performance although histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given the substance at doses of 300 or 1000 mg/kg/day. Such effects were not apparent at dose levels as high as 1000 mg/kg/day in a sub-chronic study of 90 days duration, the duration of exposure being approximately double that of the screening study.

 

A study of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substance does not cause repression of genes in the testicular mal-development pathway indicating that the substance is unlikely to cause testicular dysgenesis in rats as is seen with some phthalate esters.

 

A pre- and post-natal developmental toxicity study revealed no effects on developmental toxicity at a dose level of 500 mg/kg/day. At the higher dose level of 1050 mg/kg/day Minor, transient, effects on post-natal development were observed post-natal day 13 which were no longer present post-natal day 18.

 

Because of the low bioavailability and an overall lack of significant findings in repeat dose and prenatal developmental toxicity studies, together the lack of findings from a RNA transcriptional profiling study investigating specific aspects of reproductive toxicity, it would not be envisaged that the conduct of an EOGRTS would provide novel information and that the outcome of testing would further inform risk assessment. 

 

Factoring all of these considerations into account with the collective goal of minimising animal suffering,further reproductive toxicity studies would be scientifically unjustified.

 


Short description of key information:
Fertility - Rat: NO(A)EL - Males - 100 mg/kg/day; Females - 1000 mg/kg/day

Effects on developmental toxicity

Description of key information

A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body

weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or

female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day

NOEL pre-natal developmental toxicity: 1050 mg/kg/day

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000-2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
No details available
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: No details available
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
No details available
Duration of treatment / exposure:
Gestation days 6-19 (prenatal development)
Gestation day 6 - post-partum day 20 (post-natal development)
Frequency of treatment:
Daily, except day of parturition for animals allowed to litter
No. of animals per sex per dose:
35 females/group - 20 for pre-natal development; 15 for post-natal development
Control animals:
yes, concurrent vehicle
Details on study design:
No details available
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: No data

POST-MORTEM EXAMINATIONS: No data
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: No data
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
ANOVA followed by William’s test, or Kruskal-WaIlis/Hollander & Wolfe followed by Shirley’s test, Steel’s test, Cochran-Armitage, Fisher’s exact test.
Indices:
No data
Historical control data:
No data
Clinical signs:
no effects observed
Mortality:
not specified
Body weight and weight changes:
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No significant effects on bodyweight or gravid uterus weight at any dose level, either during gestation or lactation. No inter-group differences regarding the number of implantations, post-implantation loss, gestation length and index, or (live) litter size.
Key result
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No significant differences in foetal body weights. No significant variations or malformations observed in gross external appearance, viscera, skeletal system, or anogenital distance of pups.
Key result
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
other:
Remarks on result:
other: prenatal developmental toxicity
Key result
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: retained areolar region PND 13, no longer present PND 18
Remarks on result:
other: Postnatal developmental toxicity
Key result
Dose descriptor:
LOAEL
Effect level:
1 050 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Retained areolar region PND 13, no longer present PND 18
Remarks on result:
other: Post natal developmental toxicity
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 050 mg/kg bw/day (nominal)

Post-natal development examinations did not reveal any significant differences relative to controls for survival of offspring, sex ratio, bodyweight or bodyweight gain, auditory startle and pupil closure responses, age at vaginal opening or preputial separation.

At necropsy, there were no effects attributable to treatment in either females (6 weeks of age) or males (15 weeks of age). Assessment included morphology of the male and female reproductive tract organs, weight of the male reproductive organs or microscopic pathology of the testis.

 

There was a slight but statistically significant (P<0.05) increase in the number of male animals with retained areolar regions on evaluation at post-natal Day 13 at 1050 mg/kg/day. Affected animals had only one or two more sites than those in the control group. The areolae present at post-natal Day 13 were no longer present on re-examination on post-natal Day 18. In the absence of any other supporting data, this finding was regarded as being of questionable toxicological significance.

There was a higher incidence of displaced testes in foetuses from the group treated at 1050 mg/kg/day when compared with controls. However, the incidence was within the range of recent historical control data of the test facility for this endpoint. No displaced testes were noted in any of the foetuses undergoing less rigorous examination prior to preparation for skeletal examination. There was no difference in the incidence of non-scrotal testes between males of treatment and control groups at 15 weeks of age.

The incidence of renal cavitation was higher controls in foetuses that were macroscopically assessed prior to skeletal examination. Again, this finding was within the range of recent historical control values, and was not found during examination of foetuses by the more rigorous serial sectioning technique.

The incidence of effects in the testes and kidneys appear to be related to the low incidence of these findings in the concurrent control group compared to the range of historical control values. The observed incidences of these findings in treated groups were within the range of historical controls from recent studies at the test facility and they were not supported by complimentary observations made in foetuses or offspring. They were therefore considered not to be related to treatment.

 

Conclusions:
A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day
NOEL pre-natal developmental toxicity: 1050 mg/kg/day
NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day
Executive summary:

A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day

NOEL pre-natal developmental toxicity: 1050 mg/kg/day

NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 050 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 developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day

NOEL pre-natal developmental toxicity: 1050 mg/kg/day

NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day (slight increase in retained areolar region in males treated at 1050 mg/kg/day post-natal Day 13, no longer present post-natal day 18 and slightly higher increase in displaced testes compared to controls although the observed incidence was within the range of historical control data).

It is considered that, by association with phthalate esters, the principle developmental toxicity potential may be expected to be towards the developing male testes. This aspect of the toxicology of the substance has been studied in detail using RNA transcriptional profiling in an assay that subscribes to the principle of the 3R’s.

Toxicity to reproduction: other studies

Description of key information

A study of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substance does not cause repression of genes in the testicular mal-development pathway indicating that the substance is unlikely to cause testicular dysgenesis in rats as is seen with some phthalates.

Additional information

A study of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substance does not cause repression of genes in the testicular mal-development pathway indicating that the substance is unlikely to cause testicular dysgenesis in rats as is seen with some phthalates.

Justification for classification or non-classification

An OECD screening study of reproductive toxicity revealed no functional changes in fertility or reproductive performance although histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given the substance at doses of 300 or 1000 mg/kg/day. Such effects were not apparent at dose levels as high as 1000 mg/kg/day in a sub-chronic study of 90 days duration, the duration of exposure being approximately double that of the screening study. A study of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substance does not cause repression of genes in the testicular mal-development pathway indicating that the substance is unlikely to cause testicular dysgenesis in rats. A pre- and post-natal developmental toxicity study revealed no pre-natal developmental toxicity at dose levels up to 1050 mg/kg/day. At this level a slight increase in retained areolar region was observed in males on post-natal Day 13 which was no longer present post-natal day 18. A slightly higher increase in displaced testes compared to controls was also seen although the observed incidence was within the range of historical control data.

In accordance with Regulation (EC) No. 1272/2008 effects such as small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments are considered to be of low or minimal toxicological significance insufficient to warrant classification.