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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-06 to 2013-01
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Experimental test run under GLP conditions and according to OECD Guidelines with no deviations identified. Study conducted in an AAALAC – Accredited Test Facility in conformity with the applicable rules for animal welfare and humane use and care of laboratory animals.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Test material form:
liquid
Specific details on test material used for the study:
Test substance: JEFFCAT ZF-10
Chemical name (IUPAC): N,N,N'-Trimethyl-N'-hydroxyethyl-bis-aminoethyl ether
CAS number: 83016-70-0
BIOAGRI code: AGR-1892/11
Sample arrival date: 28/Dec/2011
Batch number: IK703
Expiration date: 18/Jun/2013
Storage: stored in a specific room (Test Item Storage Room), at room temperature, protected from humidity and light

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
a) Species: rat (Rattus norvegicus)
b) Strain: Wistar Hannover
c) Source: BIOAGRI Laboratórios – DF’s breeding house
d) Sex: males and females (nulliparous and non-pregnant)
e) Age at starting of dosing: 7 to 8 weeks old
f) Number of animals: 13 males/group and 26 females/group.

- Weight at study initiation: no details
- Fasting period before study: yes
- Housing: polypropylene cages (41x34x19 cm) with wire mesh tops and bedding material (wood shavings)
- Diet (e.g. ad libitum): Nuvilab CR-1 diet for rats supplied by Nuvital Nutrientes Ltda. available ad libitum
- Water (e.g. ad libitum): filtered drinking water was autoclaved. Water was supplied by CAESB (Companhia de Saneamento Ambiental do Distrito
Federal)
- Acclimation period: 3 males/cage and up to 2 females/cage examined and acclimated for minimum 6 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.6 – 24°C
- Humidity (%): 42.5 – 69.6%
- Air changes (per hr): 10-20 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deionized
Details on exposure:
Dosing began 70 days before mating for males and 14 days for females and continued until the day prior to necropsy (after twenty-one days of
lactation for females and at the end of the mating period for males).
Details on mating procedure:
Premating :
At the end of acclimation period, animals were randomly assigned to the experimental groups, housed (up to 3 males/cage and up to 2 females/cage) and the treatment began.
Mating :
After a premating period of 70 days for males and 14 days for females, two females were cohabited with an assigned male (2 female: 1 male) from the same dose level until evidence of copulation was observed, or 3 weeks had elapsed. Care was taken to avoid sibling mating. Vaginal smears were collected daily during mating period and examined for the presence of sperm. Day 0 of gestation was defined as the day a sperm is found in the vaginal smear. Female No 10 (control group) that showed no evidence of copulation at the end of the mating period (3 weeks) was placed with a second male at the same group and mating was confirmed 2 days later.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Parental animals (males) were treated 70 days before mating and until the end of the mating period.
Male animals were dosed for a total of 94 days.
For females, this included 14 days prior to mating, during the mating period (up to 4 weeks), during gestation and up to lactation day 20, for a total of 41 to 80 days.
Frequency of treatment:
Daily, by gavage, on a 7-day-week-basis.
The volume administered each day was 4 mL/kg body weight.
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
In deionized water
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
In deionized water
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
In deionized water
No. of animals per sex per dose:
3 groups of 13 male and 26 female rats per dose
Control group of 13 males and 26 females
Control animals:
yes, concurrent vehicle
Details on study design:
- dose level selection: the dosage levels were selected following consultation with the Sponsor on the basis of the results of previous testing with the test substance. The following doses were chosen for this study:
* 10 mg/kg bw/day as the expected dose which causes no signs
* 50 mg/kg bw/day as the intermediate dose level
* 100 mg/kg bw/day as the expected dose which causes signs of systemic toxicity, but not death or severe suffering

Test group Dose Concentration Number of animals Animal identification
(mg/Kg/day) (mg/mL) Male Female Male Female
1 Vehicle (a) 0 13 26 105-117 1-26
2 10 (b) 2,5 13 26 118-130 27-52
3 50 (b) 12,5 13 26 131-143 53-78
4 100 (b) 25 13 26 144-156 79-104

(a) Vehicle (deionized water).
(b) test substance (Test Solutions).

Examinations

Parental animals: Observations and examinations:
Throughout the treatment period, each animal was observed at least once daily for mortality, morbidity, pertinent behavioral changes, signs of difficult or prolonged parturition, and all signs of overt toxicity through cage side observations. At least once weekly throughout the treatment period (except during mating and gestation), each animal was handled and examined for signs of ill health or reaction to treatment, abnormal behavior or appearance.
Litter observations:
Litters were weighed on days 0 and 4 (before standardization) and after standardization on days 7 and 14. Live pups were weighed individually after standardization on day 21.
Postmortem examinations (parental animals):
All animals were euthanized by CO2 inhalation:
- Males: until the end of mating period;
- Females: from day 21 post-partum;
- Females which have not delivered at day 25 post-coitum: From day 25 post-coitum.
At termination, all parental animals were examined macroscopically for any abnormalities or pathological changes, with special attention paid to the organs of the reproductive system.
Postmortem examinations (offspring):
All animals were euthanized by CO2 inhalation:
- Surviving pups: on day 4 of lactation which were eliminated after standardization: From day 4 post-partum;
- Surviving pups: from day 21 post-partum.
Dead pups and pups euthanized at day 4 were necropsied for macroscopic evaluation, preserved and studied for possible defects.
Statistics:
Quantitative variables such as body weights, food consumption, number of fetuses and corpora lutea were analyzed by One Way Analysis of Variance (ANOVA), followed by Dunnett’s test if significance was detected, or by non-parametric test of Kruskal-Wallis, according to the results of tests for normality and homogeneity of variance. The Chi-Square Test was used for statistical evaluation of clinical findings, macroscopic and microscopic findings and loss of offspring. The level of significance was set at 5%, and the statistical program used was SAS Software (SAS Institute Inc., Cary, NC).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
Test substance did not cause clinical signs.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
Test substance did not cause mortality.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects on body weight, body weight gain were observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effect on food consumption was observed.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
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:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no microscopic alterations that could be attributed to the test item.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
The male and female mating indices were 100% in all groups, as were the male fertility index and the gestation index. However, the female fertility index was lower than male, although it was similar across all groups.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
parental toxicity
Effect level:
> 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
> 100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs were observed in pups through day 21 postnatal.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
No test item related pup mortality occurred.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Statistically significant lower mean body weight in pups from dams exposed to 10 mg/kg/day. difference was very slight in magnitude and occurred in the low dose level, it was considered to be incidental.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
The necropsy evaluation did not reveal treatment related findings in pups.
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Physical evaluation of male and female pups did not reveal any effects of test item administration in the different groups. This includes the statistically significant delayed day of pinna detachment appearance in females at 100 mg/kg/day (+5.2%) when compared to the control group.
Despite that this finding was observed at the high dose level, it was not considered to be treatment related because was an isolated finding and occurred in very slight magnitude.
In the reflex evaluation of the pups, no important alteration occurred in treated males or females compared to the control group. Only numerical differences were found and considered as normal biological variations, even in the statistically significant observations which were not dose
proportional.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
embryofetal toxicity
Generation:
F1
Effect level:
> 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Any other information on results incl. tables

Test substance did not cause mortality or clinical signs of toxicity during the study. No effects on body weight, body weight gain or food consumption were observed. No treatment related macroscopic changes were noted in male or female rats. There were no microscopic alterations that could be attributed to the test item. None of the mating, gestation or lactation parameters were considered to have been affected by treatment with the test item. No biologically significant differences were found between the numbers of live or dead pups from treated and control dams during whole treatment period. No clinical signs were observed in pups through day 21 postnatal. No test item related pup mortality occurred. The mean body weight of pups on days 0, 4, 7, 14 and 21 postnatal were similar in all groups. Physical and reflex evaluation of male and female pups did not reveal effects of test item administration in the different groups. The necropsy evaluation did not reveal treatment related findings in pups.

Applicant's summary and conclusion

Conclusions:
In the experimental conditions of this one generation reproduction toxicity study, the No Observed Adverse Effect Level (NOAEL) of the test item test substance in Wistar rats was considered to be greater than 100 mg/kg/day for males and females and greater than 100 mg/kg/day for maternal-embryo-fetal toxicity.

This test was requested by the National Competent Authority in accordance with Article 16(1) of Directive 67/548/EEC.