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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A screening study conducted under GLP and according to OECD guideline 421 is available. Administration of 4-methylcyclohexanone, once daily, by oral gavage at 30, 100 or 300 mg/kg/day to male and female Crl:WI(Han) rats was well tolerated. There were no adverse effects on gonadal function, mating behaviour, conception, development of the conceptus or parturition associated with 4-methylcyclohexanone. Microscopic examination identified centrilobular hypertrophy in the liver of all males given 300 mg/kg/day. Although this finding was not identified for the females given this dose, liver weights were increased for the females, which may indicate an adaptive response. This, in combination with clinical signs, defined the NOAEL for general systemic toxicity as 100 mg/kg/day. The NOAEL for male and female reproductive performance and development of the conceptus was considered to be 300 mg/kg/day 4-methylcyclohexanone. The study is considered to be relevant and reliable for the purposes of risk assessment, and no further testing is foreseen at this tonnage band.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 February 2017 to 03 August 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
2016
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: EPA OPPTS 870.2550 Reproduction/Developmental Toxicity Screening Test
Version / remarks:
2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Justification for study design:
The rat is a suitable rodent species, acceptable to regulatory authorities and for which extensive background data are available. The Han Wistar rat is commonly used in reproduction studies because of the good fertility and fecundity of the strain. Background data on the rate of spontaneous malformations have been accumulated. All animal work was conducted under authority of a Project Licence in compliance with the Animals (Scientific Procedures) Act 1986 (as amended).
The test item was administered orally, by gavage, as the oral route had been defined by the Sponsor as a possible route of human exposure.
The dose levels were selected based on 14 and 28 day gavage rat studies with the test item.
The number of animals to be used on this study is the minimum number considered necessary to yield meaningful scientific results.
Species:
rat
Strain:
Wistar
Remarks:
Crl: WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Limited, Margate, UK.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: (P) 10-12 wks (males); 13-15 wks (females)
- Weight at study initiation: (P) Males: 289-384 g; Females: 191-247 g
- Fasting period before study: None
- Housing: Housed in groups of up to 3 for males and in groups of up to 4 for females until pairing and for males post-pairing, in solid-floor cages. For pairing, 1 male and 1 female were housed together in grid-floor cages suspended over paper-lined trays. On confirmation of mating, the males were returned to the group cages and the females were housed individually and with their litter, in solid-floor cages.
- Diet: Pelleted rodent diet, VRF1 (manufactured by SDS) ad libitum.
- Water: Mains tap water ad libitum
- Acclimation period: At least 18 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 40-70
- Air changes (per hr): not reported but air-conditioned
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: 23 February 2017 (animal arrival); 14 March 2017 (start of dosing); experimental termination date: 03 August 2017 (pathology)
Route of administration:
oral: gavage
Vehicle:
other: 0.5 % (w/w) methylcellulose (400 c.p.s) and 0.5 % (w/w) Tween 80 in purified water
Details on exposure:
PREPARATION OF DOSING SUSPENSIONS: The required amount of test item was added to a container and made up to final quantity with vehicle. Formulations were stirred until homogeneous, divided into daily aliquots and then stored refrigerated (2°C to 8°C), protected from light in amber glass bottles.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Not reported
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Up to 14 days
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): Individually in solid-floor cages
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples from each test item formulation prepared for use on the first day of dosing were analysed to confirm test item homogeneity and achieved concentrations. Samples were taken from all test item formulations prepared for use towards the end of the study and analysed for achieved concentration. Samples were taken from the vehicle used to dose Controls on the first day of dosing and towards the end of the dosing period and analysed to confirm absence of test item. All analyses fulfilled the acceptance criteria (within or equal to ±10 % of nominal for accuracy and ≤10 % RSD for homogeneity). No test item was detected in the vehicle used to dose the Controls.
Duration of treatment / exposure:
Males were dosed for 14 days before and during pairing and until the day before necropsy and the females were dosed for 14 days before pairing, during pairing and gestation and until Day 12 of lactation, inclusive.
Frequency of treatment:
Daily
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on 14 and 28 day gavage rat studies conducted on the test item. During those studies, clinical signs including convulsions, decreased activity, abnormal gait, salivation and irregular respiration were observed at 500 and 750 mg/kg bw/day, with clinical signs of lesser severity seen at lower doses. Most clinical signs resolved after 1 to 2 weeks of dosing and were indicative of development of tolerance to the test item. The high dose level for this study was selected as 300 mg/kg bw/day, as a dose likely to result in some, but non-severe clinical signs, with 30 and 100 mg/kg bw/day selected to potentially identify a no effect level.
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (mortality and morbidity). From the start of dosing, all animals were examined daily for clinical signs of toxicity or changes in behaviour and appearance and each animal was given a detailed clinical examination once each week. From the start of dosing, animals were observed before and shortly after dosing. On weekdays during the dosing period, animals were also checked at 1 and 4 hours after dosing; on Day 1, an additional observation was recorded at the end of the working day to monitor clinical signs. On weekends during the dosing period, a final check was made at 1 hour after dosing or at the end of the working day (wherever was soonest). Where the clinical condition of an animal gave cause for concern, monitoring was adjusted accordingly.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Males on first day of dosing and at weekly intervals
throughout the study until necropsy.
Females on the first day of dosing and then at weekly intervals until the day of mating. Females were also weighed on Days 0, 7, 14 and 20 of gestation and on Days 0 (if required for dose administration), 1, 4, 7, 10 and 13 of lactation.

FOOD CONSUMPTION: Yes
- The amount of food consumed by the animals in each cage was recorded at weekly intervals for males and females during their pre-pairing dosing period. Individual food intake of the females was also recorded over Days 0 to 4, 4 to 7, 7 to 10, 10 to 14, 14 to 17 and 17 to 20 of gestation and over Days 1 to 4, 4 to 7, 7 to 10 and 10 to 13 of lactation. Two weeks after the start of the pairing period, food intake for males recommenced and was recorded weekly until necropsy.

WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
From 14 days before the start of dosing and until the day of pairing#, vaginal smears were taken daily by lavage. The smears were examined under light microscopy and the stage of the oestrous cycle was determined. On the day of necropsy, vaginal smears were taken and the stage of the oestrous cycle was recorded.
(# Before the start of dosing, 10 females with the lowest identification numbers in each group (from 12 that started in each group), that were exhibiting typical 4-5 day cycles, were selected to start the study based on pre-dosing oestrous cycle evaluation).
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes
- Maximum of 4/sex/litter as nearly as possible; excess pups were killed and discarded.

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, anogenital distance (AGD), presence of nipples/areolae in male pups

GROSS EXAMINATION OF DEAD PUPS: Yes, for external abnormalities, particular attention paid to the external reproductive genitals. On Day 13 of age, where possible, the thyroid from 1 male and 1 female pup/litter (from pups that had not been sampled for thyroid hormone assessment or killed by decapitation) were preserved in neutral buffered formaldehyde and weighed (after fixation).

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after females had littered.
- Maternal animals: Females with litters were killed and subjected to necropsy on Day 13 of lactation

GROSS NECROPSY
- All animals were killed by exposure to carbon dioxide gas in a rising concentration. Dead body weight was recorded and the thoracic and abdominal cavities were opened by a ventral
mid-line incision and the major organs and uterus were examined. The number of implantation scars/sites for each female killed on Day 13 of lactation was recorded. Organs or tissues showing any macroscopic abnormalities were recorded and retained.

ORGAN WEIGHTS:
The following organs were weighed after trimming of fat and other contiguous tissue (contralateral organs were weighed together): epididymides, seminal vesicles (including coagulating gland), liver, testes, prostate, thyroids (including parathyroids).

MACROSCOPIC AND MICROSCOPIC PATHOLOGY: For all animals, either whole organs or samples of the tissues listed below were taken and processed and control and high dose examined microscopically: epididymides, testes, liver, thyroids (including parathyroids), ovaries and all gross lesions. Additionally, the liver slides for the low and intermediate dose groups were examined. The following tissues from all animals were taken, held in fixative and not processed further: uterus (including uterine cervix and oviducts), prostate, vagina, seminal vesicles (including coagulating gland).
Postmortem examinations (offspring):
SACRIFICE
- Culled pups were killed by decapitation and discarded without necropsy following blood sampling.
- Pups 13 days of age: Pups were killed by an intraperitoneal injection of sodium pentobarbitone solution or by decapitation for those subjected to blood sampling. Any pups killed or found dead during lactation, and all pups killed on Day 13 of lactation, were examined externally for gross abnormalities only, with particular attention paid to the external reproductive genitals. In cases where gross abnormalities were identified, the pups were retained in neutral buffered formaldehyde. On Day 13 of age, where possible, the thyroid from 1 male and 1 female pup/litter (from pups that had not been sampled for thyroid hormone assessment or killed by decapitation) were preserved in neutral buffered formaldehyde and weighed (after fixation). A dead body weight was recorded for these pups. Due to the age and size of pups, and to prevent damage, the thyroid was left in situ on the larynx and retained in neutral buffered formaldehyde. Following fixation of the carcass, the thyroid was removed and weighed. All remaining pups, including those sampled for thyroid hormone assessment, were discarded without further examination.

Statistics:
Data processed to give group mean values and standard deviations, where appropriate. All statistical tests were two-sided with minimum significance levels of 5% and 1%. When used, Dunnett’s test was conducted regardless of the outcome of the analysis of variance (ANOVA) or analysis of covariance (ANCOVA). After examining for any outliers, if the variances were clearly heterogeneous, transformations (e.g. log, double arcsine or square root) were used in an attempt to stabilise the variances. If the transformations failed, the data set was examined and a decision taken on further action.
Quantitative data: Body weight, food intake, cumulative body weight gain from the start of dosing (throughout gestation and lactation), pup body weights, cumulative pup body weight gain, litter size, oestrous cycle number and length, gestation length, pre-coital interval and total T4 concentrations were analysed using ANOVA. Group mean ano-genital distance was analysed, for each sex, using the adjusted cubed route as a covariance of analysis. Parental and F1a organ weights were analysed using ANOVA for the absolute weights and by analysis of covariance (ANCOVA) using terminal kill body weight as covariate. Group summaries (mean, SD, number of observations) and individual values were presented for organ weights as a percentage of body weight, but these were not evaluated for statistical significance. Statistical analysis was not conducted for nipple counts, only 1 male control pup had a nipple.
Percentages: Fertility, mating, implantation, pup survival, pup sex ratios and litter based mean percentages, fertility and copulation indices analysed using a parametric ANOVA, following a double arcsine transformation.
Dunnett's test: All parameters evaluated initially by ANOVA or ANCOVA, Dunnett’s test used to compare control and treated groups, based on the error mean square in the ANOVA or ANCOVA.
Reproductive indices:
Female copulation index (%), Male copulation index (%), Female fertility index (%), Male fertility index (%), Gestation index (%), Post-implantation loss (%) were calcluated.
Offspring viability indices:
The following were calculated for each litter: Live birth index (%), Viability index Day 4 (%), Viability index Day 7 (%), Viability index Day 13 (%), Lactation index (%), Cumulative survival index (%), Percentage of male pups (%)
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs after dosing the parental generation were primarily limited to the males and females given 300 mg/kg/day and females given 100 mg/kg/day on Day 1; these included decreased activity, partially closed eyes and/or slow breathing. Two males given 300 mg/kg/day also convulsed once during the dosing period. Excessive salivation at the time of dosing was also observed sporadically for males and females given 300 mg/kg/day, from the second week of dosing. This observation was also noted for the males given 100 mg/kg/day during 5th and 6th weeks of dosing only.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
At 300 mg/kg/day, the males gained slightly less body weight than the Controls during the first 3 weeks of dosing only. Thereafter, improvements were seen with similar weight gains to Controls recorded for the rest of the dosing period. There were variable differences from Controls in body weight for the females given 300 mg/kg/day, which were considered non-adverse overall. During the pre-pairing period, the females gained slightly more weight than the Controls (p≤0.05 or lower). During gestation, there was no effect on group mean weight gain; during the initial days of lactation (Days 1 to 4), there was a group mean body weight loss, which was attributed to weight losses of 8 g to 25 g in 4 females. Despite this, there was no overall effect on group mean body weight at the end of the pre-pairing, gestation or lactation periods. At 100 mg/kg/day, differences in body weight were limited to the lactation period for the females, where there was an overall reduction in body weight gain for the group. This was attributed to significant weight loss of 38 g for 1 female from Day 1 to 4 of lactation, with the female continuing to gain less weight throughout the rest of lactation. Since the difference in group body weight gain was primarily attributable to 1 female, this was considered not to be adverse. There was no effect of the test material on body weight for the males given 30 or 100 mg/kg/day or for the females given 30 mg/kg/day, with animals typically gaining weight similar to, or greater than, the Controls.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Minimal to slight centrilobular hypertrophy in all males given 300 mg/kg/day, thereby correlating with the liver weight increase. There were no test item-related histopathological findings in the livers examined from the low and intermediate dose group in males, or in any females.
One of the males with macroscopic kidney findings had eosinophilic inclusions in the tubular epithelium with evidence of early tubular degeneration in the kidney.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects on total T4 concentrations for the parental males. Slightly higher total T4 concentrations for the parental males given 30 or 100 mg/kg/day were considered not to be related to the test substance in the absence of similar findings at 300 mg/kg/day.
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Description (incidence and severity):
No abnormalities found in epididymides or testes.
Reproductive performance:
no effects observed
Fertility and mating performance was unaffected by the test item and there were no effects on pregnancy parameters. Parturition and pup survival in the treated groups were comparable with the current Controls or the historical control ranges.
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
A slight, non-adverse, reduction in body weight gain was noted for the pups at 300 mg/kg/day from Day 4 to Day 13 of age.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Sexual maturation:
no effects observed
Description (incidence and severity):
No effects on the ano-genital distance or nipple counts for the F1a pups.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Thyroid weights for the pups from the 300 mg/kg/day group were lower than the Controls, attaining statistical significance for absolute and weights adjusted for body weight for the males (p≤0.01) and absolute weights only for the females (p≤0.01) and absolute weights only for the females (p≤0.05). However, the thyroid weights were comparable with those recorded for the Control group from a previous study and therefore the difference from Control was considered to reflect the inherent variability in this measurement in animals of this age.
Gross pathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
There were no effects on total T4 concentrations for the F1a males and females on Day 13 of age
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
organ weights and organ / body weight ratios
gross pathology
Key result
Reproductive effects observed:
no

The No Observed Adverse Effect Level for male and female reproductive performance and development of the conceptus was considered to be 300 mg/kg/day test item.

Conclusions:
Administration of the test item, once daily, by oral gavage at 30, 100 or 300 mg/kg/day to male and female Crl:WI(Han) rats was well tolerated. There were no adverse effects on gonadal function, mating behaviour, conception, development of the conceptus or parturition. Microscopic examination identified centrilobular hypertrophy in the liver of all males given 300 mg/kg/day. Although this finding was not identified for the females given this dose, liver weights were increased for the females, which may indicate an adaptive response. This, in combination with clinical signs, defined the NOAEL for general systemic toxicity as 100 mg/kg/day.

The NOAELfor male and female reproductive performance and development of the conceptus was considered to be 300 mg/kg/day.
Executive summary:

Four groups of 10 male and 10 female rats of the Crl:WI(Han) strain were dosed by oral gavage at dose levels of 0, 30, 100 or 300 mg/kg/day test item. Males were dosed for 14 days before and during pairing and until the day before necropsy and the females were dosed for 14 days before pairing, during pairing and gestation and until Day 12 of lactation, inclusive. Before the start of the dosing period, the oestrous cycles of 12 females per group were monitored and the first 10 in each group, which were cycling normally, were selected to be dosed on the study. Oestrous cycle monitoring continued through the pre-pairing phase of the study. All selected animals were examined for effects on general condition, body weight and food intake. During the pairing period, vaginal smears were taken daily until sperm were detected or until the female was confirmed as pregnant by palpation. The females were allowed to litter and rear their offspring (F1a generation) to Day 13 of age. All parental males and females, all culled pups on Day 4 of age and 1 pup/sex/litter on Day 13 of age, had blood samples taken for thyroid hormone analysis; only those from the parental males and Day 13 of age pups were analysed. All Day 13 of age pups had a gross external examination and the thyroids were removed and weighed from 1 male and 1 female per litter. A macroscopic necropsy was performed on all parental animals and a selection of organs were weighed, fixed and examined microscopically.

There were no deaths during the study. Clinical signs after dosing the parental generation were primarily limited to the males and females given 300 mg/kg/day and females given 100 mg/kg/day on Day 1; these included decreased activity, partially closed eyes and/or slow breathing. Two males given 300 mg/kg/day also convulsed once during the dosing period. Excessive salivation at the time of dosing was also observed sporadically for males and females given 300 mg/kg/day, from the second week of dosing. This observation was also noted for the males given 100 mg/kg/day during 5th and 6th weeks of dosing only. There were no adverse effects on body weight or food intake for the parental generation.

Fertility and mating performance was unaffected and there were no effects on pregnancy parameters. Parturition and pup survival in the treated groups were comparable with the current Controls or the historical control ranges.

A slight, non-adverse, reduction in body weight gain was noted for the pups at 300 mg/kg/day only, from Day 4 to Day 13 of age. There were no effects on the ano-genital distance or nipple counts for the F1a pups.

There were no effects on total T4 concentrations for the parental males or the F1a males and females on Day 13 of age that were considered to be associated with the test item. Slightly higher total T4 concentrations for the parental males given 30 or 100 mg/kg/day were considered not to be related to the test item in the absence of similar findings at 300 mg/kg/day.

Liver weights (absolute and adjusted) were higher than the Controls for the treated groups. The effect was most pronounced at 300 mg/kg/day, where mean adjusted liver weights were 23% or 17% higher than Controls for males and females, respectively, compared with higher weights of 6% or 5% for males and 9% or 8% for females given 30 or 100 mg/kg/day, respectively. There was no effect on thyroid weight for the F1a pups considered related to the test item.

Test item-related necropsy findings of abnormal mottled colour to the kidneys were limited to 2 parental males given 300 mg/kg/day. Microscopically, 1 of these males had eosinophilic inclusions in the tubular epithelium with evidence of early tubular degeneration in the kidney. Microscopic examination of the liver for the parental generation showed minimal to slight centrilobular hypertrophy in all males given 300 mg/kg/day, thereby correlating with the liver weight increase. There were no test item-related histopathological findings in the livers examined from the low and intermediate dose group in males, or in any females. There were no external abnormalities for the F1a pups that were considered to be associated with the test item.

Administration of the test item, once daily, by oral gavage at 30, 100 or 300 mg/kg/day to male and female Crl:WI(Han) rats was well tolerated. There were no adverse effects on gonadal function, mating behaviour, conception, development of the conceptus or parturition. Microscopic examination identified centrilobular hypertrophy in the liver of all males given 300 mg/kg/day. Although this finding was not identified for the females given this dose, liver weights were increased for the females, which may indicate an adaptive response. This, in combination with clinical signs, defined the NOAEL for general systemic toxicity as 100 mg/kg/day.

The NOAEL for male and female reproductive performance and development of the conceptus was considered to be 300 mg/kg/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A relevant and reliable screening study on the reproductive/developmental toxicity of the substance in the rat is available.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

There were no adverse effects on gonadal function, mating behaviour, conception, development of the conceptus or parturition associated with 4-methylcyclohexanone at the top dose tested, which was above the NOAEL set in the study for general systemic toxicity. Therefore on the basis of the observations in this study, and in accordance with the criteria set out in Regulation (EC) No. 1272/2008, Annex I: 3.7.2.1.1, 4-methylcyclohexanone is not considered to be classified for reproductive toxicity.

Additional information