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Key value for chemical safety assessment

Effects on fertility

Description of key information

No effects on fertility in mice were seen in a reproductive toxicity study, considered as screening study, but performed over two generations.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Principle of test: The evaluation of the effects of the product tetramethrin on the reproductive function and on fertility were carried out on both male and female Swiss strain albino mice after oral administration of the test item.
Short description of test conditions: The study began with a total of 72 animals. The mice were sexually mature: the males weighed 45 ±5 grams and the females 40 ±5 grams. The animals were kept at a stalling environment and were given a diet of food pellets and fountain water.
Following a stalling period of 7 days, they were subdivided into 4 groups in order to then be given the pharmacological treatment. The treatments were carried out by mixing the tetramethrin powder in the food mixture and then stirring them together in the fountain water. The mixture was then placed in special stainless steel containers in order to avoid the dispersion of the food and to assure it was all eaten. The mixtures were prepared in such a way as to administer the tetramethrin in 3 dosage levels corresponding to 500, 1000, and 2000 mg/kg. The animals were therefore divided into 4 groups of 12 females and 6 males each.
1st Group - Treatment: standard diet in powder (untreated group)
2nd Group - Treatment: standard diet in powder integrated with a dose of 500 mg/kg of tetramethrin
3rd Group - Treatment: standard diet in powder integrated with a dose of 1000 mg/kg of tetramethrin
4th Group - Treatment: standard diet in powder integrated with a dose of 2000 mg/kg of tetramethrin
The male mice were treated for 64 days before mating, the female mice for 14 days proceeding mating and subsequently , without interruption, for the entire mating, pregnancy and lactation period until the 21st day (first Generation = F1) of age.
The animals of the 1st and 2nd generation did not receive treatment.
Mating was obtained by putting 2 females into the same cage with a male and moving the male from one cage to another every day. The ascertainment of fecundation was obtained through the observation of the vaginal plug which was repeated for 8 days in the morning and afternoon.
At the 19th day of pregnancy, half of the females of each group (Subgroup A) were sacrificed; the remaining females were left to give birth normally (Subgroup B).
- Parameters analysed / observed:
The following parameters were examined on the animals sacrificed on the 19th day:
1) mortality of the mothers
2) body growth of the mothers
3) number of implants
4) number of resorption sites
5) fetus mortalities
6) total litter size
7) weight of fetus (gr)
8) number of malformations
The fetuses belonging to Subgroup A removed on the 19th day by Caesarean section, were immediately examined for research on head, mouth, trunk, limb and tail malformations. Half of them were subjected to a necroscopic examination for the ascertainment of eventual visceral malformations, while the remaining half was prepared for the examination of the skeletrical apparatus following diafanization of the soft tissues and coloration in alizarin red of the bone tissue.
The mothers were subjected to a necroscopic exam with particular regard to the uterine walls in order to verify the number of resorption sites.
The animals belonging to Subgroup B born spontaneously at the end of the pregnancy were kept under observation until the 25th day of lactation (F1). Or, these animals the following parameters were observed:
1) behavior
2) mortality
3) body growth
4) physical development (growth of hair, teeth eruption, opening of eyes)
5) sight and hearing functions
Following the study of these parameters, the animals belonging to the first generation (F1) were untreated up to the eighth week of life.
At this point, for each experimental group 12 females and 6 males were chosen which were untreated until maturity.
When sexual maturity was reached, these were then mated in order to evaluate the effect of tetramethrin on the 2nd generation (F2). The evaluation method is the same as that described previously for the study of generation (F0).
GLP compliance:
no
Specific details on test material used for the study:
Lot/batch No.of test material: 10/84
Purity: 95.37%, 23.2% cis-isomer and 76.8% trans-isomer
Species:
mouse
Strain:
Swiss
Remarks:
Albino
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
see section "principle of method if other than guideline"
Details on mating procedure:
see section "principle of method if other than guideline
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
n/a
Duration of treatment / exposure:
The male mice were treated for 64 days before mating, the female mice for 14 days proceeding mating and subsequently , without interruption, for the entire mating, pregnancy and lactation period until the 21st day (first Generation = F1) of age.
Frequency of treatment:
not indicated
Details on study schedule:
see section "principle of method if other than guideline"
Dose / conc.:
0 mg/kg diet
Remarks:
1st (untreated group)
Dose / conc.:
500 mg/kg diet
Remarks:
2nd group
Dose / conc.:
1 000 mg/kg diet
Remarks:
3rd group
Dose / conc.:
2 000 mg/kg diet
Remarks:
4th group
No. of animals per sex per dose:
12 females + 6 males/each group
Control animals:
yes, concurrent no treatment
Positive control:
no
Parental animals: Observations and examinations:
Symptomatology and behavior
Mortality
Body Growth (only for females)
Oestrous cyclicity (parental animals):
not examined
Sperm parameters (parental animals):
not examined
Litter observations:
For both F1 and F2 litter:
Symptomatology and behavior
Mortality
Body Growth (only for females)
Postmortem examinations (parental animals):
The following parameters were examined on the female animals sacrificed on the 19th day:
1) mortality of the mothers
2) body growth of the mothers
3) number of implants
4) number of resorption sites
Postmortem examinations (offspring):
The following parameters have been observed:
- fetus mortalities
- total litter size
- weight of fetus (gr)
- number of malformations
Statistics:
The obtained results were subject to statistical analysis by making a comparison between the various sequences relative to the experimental groups, according to the CHI-square test.
Clinical signs:
no effects observed
Description (incidence and severity):
No symptomatology nor particularity in behavior was observed due to treatment.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
no cases of mortality were verified amongst treated and untreated
Body weight and weight changes:
no effects observed
Description (incidence and severity):
F0 (Subgroups A and B) = no significant difference among the treated and untreated females.
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
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
no symptomatology nor particularity in behavior was observed due to treatment.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined
F0 (Subgroup A) = no statistical difference in the number of implants and resorption sites among females treated with TETRAMETHRIN and those untreated.
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg diet
Based on:
test mat.
Sex:
female
Remarks on result:
not determinable due to absence of adverse toxic effects
Clinical signs:
no effects observed
Description (incidence and severity):
absence of symptomatology, normal behavior
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
no mortality that occurred during lactation could be related to the treatment of the parents (F0)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Normal body growth of offspring both from treated and untreated parents, ascertained at time of birth and on the 21st day of life.
Also the body growth of the pregnant F1 females was found to be normal from the beginning of the pregnancy to the 21st day of lactation.
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
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
absence of symptomatology, normal behavior

Developmental immunotoxicity:
no effects observed
F1 (Subgroup B) = the appearance of hair, the eruption of teeth and the opening of eyes of the offspring from mothers treated with all doses of TETRAMETHRIN were completel comparable to those offspring from untreated mothers.
Even the reactions to strong sonorous stimulus and strong light were shown to be normal in all newborns.Implants and resorption sites:
F1 (Subgroup A) = no influence on the number of implants and re- sorptions shown on the Fl mothers could be attributed to the treatment with TETRAMETHRIN on the F0 parents.

Fetal development:
F1 (Subgroup A) = the number of fetuses per pregnancy, the number of live and still births and the body weight do not prove to be influenced by treatment with TETRAMETHRIN carried out on the F0 parents, when compared to the values obtained from fetuses of untreated parents.
Physical and neurological development of the newborn
F1 (Subgroup B) = the appearance of hair, the eruption of teeth and the opening of eyes of the offspring from mothers treated with all doses of TETRAMETHRIN were completel comparable to those offspring from untreated mothers.
Even the reactions to strong sonorous stimulus and strong light were shown to be normal in all newborns.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
2 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Clinical signs:
no effects observed
Description (incidence and severity):
absence of symptomatology, normal behavior
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
mortality occurring during nursing could not be attributed to the treatment of the first generation animals (F1)
Body weight and weight changes:
no effects observed
Description (incidence and severity):
F2 (Subgroup B) = the body growth found at birth, on the 21st day of life and, for the pregnant females, from the beginning to the termination of the pregnancy and 21 days after giving birth, was not influenced negatively by the treatment carried out on the first generation F0
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
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
no effects observed
Developmental immunotoxicity:
not examined
Implants and resorption sites
F2 (Subgroup A) = treatment carried out on the 1st generation F0 had no influence on the number of implants and resorptions of the mothers belonging to the F2 group.

Fetal development
F2 (Subgroup B) = even the number of fetuses per pregnancy, the number of live and still births and the weight of the fetuses from F1 parents do not prove to be influenced negatively by the treatment with TETRAMETHRIN carried out on the parents of the first generation F0.

The parameters relative to fetal development were shown to be normal, even for the offspring of the F2 generation.

Physical and neurological development of the newborn
F2 (Subgroup A and B) = the appearance of hair, the eruption of teeth and the opening of eyes of the offspring from mothers treated with all doses of TETRAMETHRIN were completel comparable to those offspring from untreated mothers.
Even the reactions to strong sonorous stimulus and strong light were shown to be normal in all newborns.
No malformations of any type were observed at birth in offspring of the F2 generation.
Key result
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
2 000 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
body weight and weight gain
other: behaviour, physical and neurological development of the newborn
Key result
Reproductive effects observed:
no
Treatment related:
no
Conclusions:
The study conducted on the preparation denominated tetramethrin has demonstrated that following the oral administration of the product up to a dose of 2000 mg/kg diet, no alterations occur in the reproductive and fertility functions of Swiss strain albino mice.
No alterations were noted in the descendents observed throughout the second generation (F2) either.


Executive summary:

A study regarding the effects on the reproductive function and fertility of the mouse has been conducted on test item tetramethrin.

The study conducted on the preparation denominated tetramethrin has demonstrated that following the oral administration of the product up to a dose of 2000 mg/kg diet, no alterations occur in the reproductive and fertility functions of Swiss strain albino mice.

No alterations were noted in the descendents observed throughout the second generation (F2) either.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
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

Description of key information

A study regarding the effects on the reproductive function and fertility of the mouse has been conducted on test item tetramethrin, including 2 generations.

The study conducted on the preparation denominated tetramethrin has demonstrated that following the oral administration of the product up to a dose of 2000 mg/kg, no alterations occur in the reproductive and fertility functions of Swiss strain albino mice and also no developmental effects were noted in this pre-guideline study.

No alterations were noted in the descendents observed throughout the second generation (F2) either.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 000 mg/kg bw/day
Study duration:
subchronic
Species:
mouse
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

Based on data from a reproductive toxicity study, in which no adverse effects were seen over two generations, the substance does not require classification and labelling for reproductive toxicity according to CLP (Regulation EC No. 1272/2008).