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Toxicological information

Toxicity to reproduction

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Administrative data

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:
no data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 1a - OECD Guideline GLP-compliant study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
The relative humidity recorded in the animal room was sometimes out of the target range specified in the study plan.
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 11-aminoundecanoic acid
- Physical state: white powder
- Purity test date: 04/03/2008
- Lot/batch No.: 0808204 and 0808295
- Expiration date of the lot/batch: 4 march 2009 for batch 0808204/ 3 april 2009 for batch 0808295
- Stability under test conditions: 10 days in closed bags and 9 days in open feeders
- Storage condition of test material: at room temperature, away from humidity and under nitrogen atmosphere
no other data



Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Janvier, Le Genest-Sainte-Isle, France.
- Age at study initiation: (P) x 10 wks
- Weight at study initiation: (P) Males: 403-458 g; Females: 253-284 g
- Fasting period before study: no
- Housing: individually, except during prairing in wire-mesh cages (43.0. x 21.5 x 18.0 cm)
- Diet : ad libitum, A04 C P2.5 powder rodent maintenance diet, batch No. 71219 (SAFE, Augy, France)
- Water : ad libitum, tap water (filtered with a 0.22 µm filter)
- Acclimation period: 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-2
- Humidity (%): 50 +/- 20
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air
- Photoperiod : 12 hrs dark / 12 hrs light (7:00-19:00)


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: For each concentration, a premix containing the total amount of test item was prepared in the diet using a mixer. The final mix was prepared by dispersing the premix in the remaining diet in the mixer and then mixing for at least 10 minutes.


DIET PREPARATION
- Rate of preparation of diet (frequency): The dietary admixtures were prepared on a weekly basis in weeks 1 and 2 then two or three times a week from week 3 by the CIT Pharmacy.
- Mixing appropriate amounts with (Type of food): rodent diet A04 C P2.5, batch No. 71219.
- Storage temperature of food: in closed bags at room temperature prior to use


Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: each female was placed with the same male until mating ocurred or 14 days had elapsed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smearreferred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: no
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of the test item was determined in samples of each control and test item dosage form prepared for use during weeks 1, 4 and 6. On each day of analysis, duplicate samples were taken at three different levels (top, middle and bottom) of the mixer (groups 2, 3 and 4) and a single level of the container (control group) for determination of the test item concentration.
Duration of treatment / exposure:
in the males:
- 2 weeks before pairing,
- during the pairing period (3 weeks),
- until sacrifice (at least 5 weeks in total),

in the females:
- 2 weeks before pairing,
- during the pairing period (3 weeks),
- during gestation,
- during lactation until day 4 p.p. inclusive (or until sacrifice),
- until sacrifice for non-pregnant females.
Frequency of treatment:
continuous (in diet)
Doses / concentrations
Remarks:
Doses / Concentrations:
1250, 5000 and 20000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: The dose-levels were selected in agreement with the sponsor, following the results of a previous 4-week toxicity study.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Each animal was checked for mortality or signs of morbidity once a day before the treatment period and twice a day during the treatment period including weekend and public holidays.



DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: From arrival, the animals were observed once a day as part of routine examinations. From the start of treatment period, each animal was observed once a day, at approximately the same time for the recording of clinical signs.


BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded on the first day of treatment (day 1), then once a week until sacrifice. The body weight of each female was recorded on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7, 14 and 20 postcoitum (p.c.) and days 1 and 5 post-partum (p.p.).


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes




Oestrous cyclicity (parental animals):
The estrous cycle stage was determined from a fresh vaginal lavage (stained with methylene blue) each morning during the pairing period until the females had mated.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:
testis weight, epididymis weight.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no


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 not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after the end of the mating period (at least 5 weeks of treatment in total).
- Maternal animals: All surviving animals on day 5 p.p.


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


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 1 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 5 days of age.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: Pups were carefully examined externally for gross external abnormalities and a macroscopic examination was performed.


GROSS NECROPSY
- Gross necropsy consisted of external examinations.


HISTOPATHOLOGY / ORGAN WEIGTHS
No tissues were preserved and organ weights were not examined.
Statistics:
PathData (version 6.2b5) was used for the statistical analysis of organ weight data (level of significance: 0.05 or 0.01). The other data are compared by one-way analysis of variances and Dunnett test (mean values being considered as normally distributed, variances being considered as homogenous) or by fisher exact probability test (proportions).
Reproductive indices:
The following parameters were calculated:
- pre-implantation loss: (number of corpora lutea - number of implantation sites)/ (number of corpora lutea) x 100
- post-implantation loss (manually calculated): (number of implantation sites - number of live concepti) / (number of implantations)x 100
- mating index: (number of mated animals) / (number of paired animals) x 100
- fertility index: (number of pregnant female partners)/ (number of mated pairs) x 100
- gestation index: (number of females with live born pups) / (number of pregnant females) x 100
Offspring viability indices:
The following parameters were calculated:
- live birth index: (number of live born pups)/ (number of delivered pups) x 100
- viability index on day 4 p.p.: (number of surviving pups on day 4 p.p.) / (number of live born pups) x 100

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
There was no premature deaths that could be related to treatment in the groups treated at 1250, 5000, or 20000 ppm. One male treated at 20000 ppm had abnormal growth of teeth from day 8 and was emaciated during the last week of the study. This observation coincided with low body weight gain recorded from the start of the dosing period and with body weight loss between days 29 and 36 (-5%).

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
The group mean body weight gain of males treated at 20000 ppm was affected. Differences were considerable (-34 % over the whole treatment period) and statistically significant when compared to the mean control values. This effect was observed from the beginning of the study and led to statistically significant differences in mean body weight from day 8. At the end of the pre-mating period (day 15), the body weight of males was 8% lower than controls (p<0.01).
The group mean body weight gain of females treated at 20000 ppm was 56% lower than controls during the premating period and mean body weight was 6% lower than controls (p<0.01) on days 8 and 15. During the first week of gestation, the mean body weight gain of females treated at 20000 ppm was 33% lower than controls (and statistically significant, p<0.01). This initial effect was responsible for the lower global body weight gain (-14%) recorded during this phase. Although this difference was not statistically significant at the end of gestation, it was considered to be treatment-related since the body weight was between 6 and 8 % lower than controls on days 7, 14 and 20 of gestation. The group mean body weight recorded on day 5 of lactation was lower than controls (-13%: p<0.001) as was the mean body weight gain from days 1 to 5 of lactation (32%).
At 5000 ppm, the group mean body weight recorded on day 5 of lactation was 6% lower than controls and statistical significant (p<0.01). The differences in the group mean body weight gain of males treated at 5000 ppm and males and females treated at 1250 ppm were considered not to be of biological importance as they were not dose-related.
(See Table 1 for succinct view of the data in the field "remarks on results including tables and figures")

Food consumption of males and females treated at 20000 ppm was 19 to 26% lower than controls during the premating period (p<0.001). During gestation, the females were still affected and food intake was 17 to 23 % lower than controls (with p values<0.01 or <0.001). Between days 1 and 5 of lactation, the food consumption of females treated at the highest concentration was 20 % lower than the control group (p<0.05). At 5000 ppm, this parameter was affected (or altered) by treatment in females during the first week of the premating period (p<0.05) and during gestation and lactation. Differences were slight (-6% to -14%) and did not correlate well with body weight gain. No effect was observed on male mean food consumption at 5000 or 1250 ppm.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
The mean achieved dosages increased in a near dose-proportionnal manner, except for males and females treated at 20000 ppm during premating. (See Table 2 for succinct view of the data in the field "remarks on results including tables and figures")

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effect was observed on the estrous cycle

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
not performed

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were 0, 3, 2 and 0 non-pregnant females in the groups treated at 0, 1250, 5000 or 20000 ppm, respectively. The incidence of non-pregnant females was not dose-related and was therefore considered not to have been affected by treatment with the test item. Thus, the fertility index was considered not to be affected by treatment with the test item.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No differences were noted between treated and control males in the absolute and relative testis or epididymis weights.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Renal test item-related findings were noted in a dose-related manner, i.e. there were dilated pelvis in 2/10 males given 5000 ppm test item and in 4/10 males given 20000 ppm test item, and granular kidneys with green content in 1/10 females given 20000 ppm test item.

HISTOPATHOLOGY (PARENTAL ANIMALS)
Treatment-related changes were observed in the kidney and consisted of dilated pelvis (correlated with macroscopic examination), tubular dilation and/or basophilia, interstitial, intra-vascular, and/or tubular inflammatory cells sometimes associated with myxoid papilla stroma in some treated males and female given 5000 or 20000 ppm test item. The female given 20000 ppm had moderate suppurative nephritis associated with urothelium hyperplasia.

Effect levels (P0)

Dose descriptor:
NOEL
Effect level:
1 250 ppm (nominal)
Sex:
male/female
Basis for effect level:
other: (Corresponding to 79 or 103 mg/kg/day for males or females, respectively)

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
It was considered that there was no effect of treatment with the test item on pup mortality

CLINICAL SIGNS (OFFSPRING)
No test item-related findings were noted.

BODY WEIGHT (OFFSPRING)
The body weight gain of male and female pups in the group treated at 20000 ppm was, respectively, 34% and 38% lower than controls on day 5 p.p.. This treatment-related effect coincided with the lower body weight gain recorded in parental animals in this group between days 1 and 5 p.p.. The terminal body weight differences were statistically significant for females only (p<0.05). No change on pups body weight was observed at the to lowest doses.

SEXUAL MATURATION (OFFSPRING)
not examined.

ORGAN WEIGHTS (OFFSPRING)
not examined.

GROSS PATHOLOGY (OFFSPRING)
not examined.

HISTOPATHOLOGY (OFFSPRING)
not examined.

OTHER FINDINGS (OFFSPRING)
Sex ratio: the percentage of male pups was between 44.2% and 54.4% on days 1 and 5 post-partum, which is considered to be within the normal range.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1: Body weight change (g) and percentage difference from controls (parental animals)

Sex Male Female
Concentration (ppm) 0 1250 5000 20000 0 1250 5000 20000
Treatment period (males) or premating period (females) days 1-15 +89 +76 (-15%) +80 (-10%) +51**(-43%) +34 +27 (-21%) +31 (-9%) +15# (-56%)
days 1-36 +165 +148 (-10%) +150 (-9%) +109# (-34%) na na na na
Gestation period GD 0-20 (overall mean) na na na na +165 +155 (-6%) +152 (-8%) +142 (-14%)
Lactation period LD 1-5 na na na na +22 +31 (+41%) +30 (+36%) +15 (-32%)

**: p<0.01, #: p<0.001, na: not applicable; GD: Gestation Day; LD: Lactation Day;

(): variations from controls.

Table 2: Mean achieved dosages (mg/kg/day)

Concentration (ppm)   1250 5000 (x4.0) 20000 (x4.0)
F0 generation Male premating (days 1-5) 79 319 (x4.0) 1099 (x4.0)
Female premating (days 1-5) 97 376 (x3.9) 1242 (x3.3)
gestation (GD 0-20) 90 356 (x4.0) 1285 (x3.6)
lactation (days 1-5 p.p.) 121 446 (x3.7) 1758 (x3.9)
Overall mean  103 393 1428

GD: Gestation Day, p.p.: post-partum,

(): ratio to the preceding concentration.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this test, 11-aminoundecanoic acid has no effect on mating, fertility, gestation or delivery.
Executive summary:

In a reproduction/developmental toxicity screening test following guideline OECD 421 (CIT, 2008), 11-aminoundecanoic acid (batch Nos. 0808204 and 0808295) was given to male and female Sprague-Dawley rats (10 animals per group) by dietary admixture for 2 weeks before mating, during mating, gestation and until day 4 post-partum, at the constant concentrations of 1250, 5000 or 20000 ppm. Another group of 10 males and 10 females received the untreated diet under the same experimental conditions and served as a control group. The concentrations of dietary admixture were checked in weeks 1, 4 and 6. Test item admixtures were within the acceptable concentration range of -7% to +19%. The nominal concentrations of 1250, 5000 or 20000 ppm corresponded to achieved dosages of 79, 319 or 1099 mg/kg/day for the males and 103, 393 or 1428 mg/kg/day for the females, thus demonstrating a satisfactory intake of the test item. There were no unscheduled deaths at any concentration. In-life findings recorded for the F0 animals were limited to one case of emaciated appearance in a male treated at 20000 ppm from day 36. Body weight was statistically significantly lower at 20000 ppm throughout the study and on day 5 of lactation in females treated at 5000 ppm. Food consumption was lower than controls during the study in goup treated at 20000 ppm and transiently in females treated at 5000 ppm (premating). No effects on mating, fertility, gestation or delivery were detected. There were no treatment-related effects on pup mortality or clinical signs. The body weight gain of pups at 20000 ppm was lower between days 1 and 5 of lactation. There were no relevant macroscopic abnormalities in pups sacrificed as scheduled or in pups found dead. There were no treatment-related effects on organ weights. Test item-related findings were observed in the kidneys of 2/10 males given 5000 ppm and 4/10 males and 1/10 females given 20000 ppm. These findings included dilated pelvis and granular kidneys with green content. Treatment-related changes were observed at microscopic examination in the kidney at 5000 and 20000 ppm and consisted of dilated pelvis, tubular dilatation and/or basophilia, interstitial, intra-vascular and/or tubular inflammatroy cells sometimes associated with myxoid papilla stroma. Based on the results of this study, the concentration of 1250 ppm was considered to be the No Observed Effect Level (NOEL) for parental toxicity and the concentration of 20000 ppm was considered to be the NOEL for reproductive performance.