Registration Dossier

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:
read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Read across from the analogous 2 Ethylhexyl methacrylate category member donor substance.
REPORTING FORMAT FOR THE CATEGORY APPROACH
see attached category document

1. HYPOTHESIS FOR THE CATEGORY APPROACH
see attached category document

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
see attached category document

3. CATEGORY APPROACH JUSTIFICATION
see attached category document, chapter 5.9 (Toxicity for reproduction) and endpoint specific chapters

4. DATA MATRIX
see attached category document, tables in endpoint specific chapters
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Combined Repeated Dose and Reproductive / Developmental Toxicity Screening Test (Precursor Protocol of GL 422)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Co. (Hino Breeding Center)
- Age at study initiation: 10 weeks old for males and females
- Weight at receipt: 351~384g for males and 212~237 for females
- Fasting period before study: no
- Housing: Stainless steel cage systems (W: 240 x D: 380 x H: 200mm) were used during quarantine and acclimatization, and 5 rats were housed in each cage. After dividing into groups, a rack of five stainless steel cages (W: 755 x D: 210 x H: 170mm) were used for individual housing. Mating was conducted in stainless steel cage systems. Also, on the 18th day of gestation, pregnant animals were moved to plastic cages (W: 310 x D: 360 x H: 175mm) in which autoclaved floors (Sunflake, Charles River Japan Co.) had been inserted to facilitate natural delivery and lactation
- Diet (ad libitum): CRF-1, Oriental Yeast Co.
- Water (ad libitum): tap water
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 44-59
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The amount of the test substance needed at each concentration was estimated, and the substance administered was produced in the required concentration by diluting with corn oil

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 6, 20 or 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug or sperm in vagina referred to as day 0
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The 6, 20 and 200 mg/ml prepared solutions were confirmed to have no problems with stability for 7 days under cool and dark conditions after preparation, and for four hours under dark conditions at room temperature.
The concentration of the test substance in the administration substance at each concentration used on the administration starting date and the administration ending date for males was measured by HPLC. The results of the test substance concentration were 99.5~110% of the displayed concentration, and as they were within the range of acceptable concentration (within ±10% of the displayed concentration).
Duration of treatment / exposure:
Males: 14 days before mating and 35 days after, for a total of 49 days
Females: 14 days before mating and a total of 41~47 days during mating, gestation and day 4 of lactation to the day before necropsy
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0(vehicle), 30, 100, 300, 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 1 day
- Dose selection rationale:
The dose was determined by the results of the preliminary testing (administration doses: 0, 125, 250, 500 and 1000 mg/kg, 5 in each group) with oral administration using male rats for a period of two weeks. Salivation was noted immediately after administration in the groups greater than 125 mg/kg, and low body weight values were noted in the 1000 mg/kg group but there were no confirmed fatalities in any of the groups. Therefore, the dose for this study was set with a maximum dose of 1000 mg/kg in conjunction with the dose limits found in the OECD guidelines, and included ratio of approximately 3, with doses of 300, 100 and 30 mg/kg. Furthermore, a group administered the same quantities of a medium (corn oil) as the test substance was considered the control group.
- Rationale for animal assignment (if not random):
To divide into groups, the computer was used to separate by weights and then random sampling was performed to make each group uniform in terms of average weight and distribution for the administration starting date. Animals remaining after allocation into groups were euthanized under ether anesthesia on the administration starting date and discarded
Positive control:
not required

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations:
Males: twice weekly (Days 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39, 43, 46 of administration and the necropsy day)
Female: 14 days before mating started and two times each week during mating season (Measurement days: Days 1, 4, 8, 11, 15 and 18 of administration), and measured on day 0, 7, 14 and 21 during gestation, and day 0 and 4 during lactation.

FOOD CONSUMPTION : Yes
Males: twice weekly (Days 3, 6, 10, 13, 24, 27, 31, 34, 38, 41, 45 and 48 of administration)
Female: twice weekly (14 days before mating, on day 2, 9, 16 and 21 during gestation as well as on day 4 of lactation)
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: No

Oestrous cyclicity (parental animals):
Estrous cycles were observed daily from the date administration started to the date mating was confirmed. If heat was observed continuing for two consecutive days, it was calculated as one occurrence.
Sperm parameters (parental animals):
Parameters examined in all 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:
- Observations at Birth
Observations were made on the total number and gender of pups at birth, number of stillbirths, number of live births and presence of external abnormalities. Stillbirths were fixed in 20% neutral buffered formalin and stored.
- Observations of the Pups
Observations were made daily on the general status and fatalities during their lifetimes. After necropsy, stillbirths were fixed in 20% neutral buffered formalin and stored (excluding those with dramatic changes after death).
- Body Weight
Body weights were measured on day 0 of lactation (date of birth) and day 4.

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):
GROSS PATHOLOGY: Yes

ORGAN WEIGHTS: Yes
Ovaries, testes and epididymides.

HISTOPATHOLOGY: Yes
H-E stained tissue specimens were produced from the ovaries, uterus, vagina, testes, epididymides, seminal vesicle, prostate, pituitary gland and histopathological examinations performed. During the necropsy for one case (No. 308) in the 300 mg/kg group, an abnormality was confirmed so the epididymides were also examined. section 7.5.1
Postmortem examinations (offspring):
SACRIFICE
After completing the observations on day 4 of lactation, the pups were euthanized under ether anesthesia after blood was collected from the abdominal aorta, and necropsy was performed. Pups with abnormalities confirmed during necropsy were fixed in 20% neutral buffered formalin and stored.
Statistics:
The mean values and standard deviations were calculated for each group for body weight (parent animals, pups), food consumption, number of mating seasons, number of conceiving days, gestation term (delivery day (day 0 of lactation) – day fertilization confirmed), number of implantation scars, total number of births (live births + stillbirths), number of live births, number of stillbirths, number of corpus luteum, reproductive indices, offsping viability indices, gender ratio (males/females), absolute and relative weights of organs results. Next, equal distribution examination was conducted using the Bartlett method, and if there was equal distribution, a distribution analysis was performed using analysis of variance, and if significant, the Dunnett method was performed. On the other hand, if equal distribution was not confirmed, analysis of variance was conducted using a ranking (Kruskal-Wallis test), and if significant, the ranking was used and a Dunnett type of examination method was performed.
The copulation rate, fertilization and delivery rate was conducted using χ2 calibration.
In the histopathological examination, in addition to the suggestion that there was a toxicological impact in the group with the maximum dose, the findings on the organs and tissues from the other groups that were subject to examination were conducted by using the Dunnett method with the ranking given above to compare the groups with the control group. If a significant difference with the control group was confirmed, the dose response was studied using the Cochran Armitage test for trend.
Reproductive indices:
- Reproductive indices:
Delivery rate [(overall birth rate/number of implantation scars) x 100], pup birth rate [(number of pups at day 0 of lactation/number of implantation scars) x 100], implantation rate [(number of implantation scars/number of corpus luteum) x 100], birth rate [(number of pups at day 0 of lactation/total number of births) x 100], rate of external abnormalities [(number of pups with external abnormalities/number of new pups) x 100]
- Copulation rate [(number of animals mating/number of animals cohabitating) x 100],
- Fertilization rate [(number of fertilized females/number of animals mating) x 100]
- Delivery rate [(number of females delivering pups/number of fertilized females) x 100
Offspring viability indices:
- number of pups at day 4 of lactation
- survival rate at day 4 of lactation [(number of live pups at day 4 of lactation/number of new pups at day 0 of lactation) x 100]

Results and discussion

Results: P0 (first parental generation)

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
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, treatment-related
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

- Clinical signs:
MALES: There were no confirmed deaths or near-deaths in any of the groups.
In the observations on the overall condition, nothing abnormal was noted in any of the animals in the control group during the observation period. In the 30 mg/kg group, there were 1~3 cases where salivation was noted on day 9, 10, 12, 13 and 24 of administration. In the 100 mg/kg group, there were 1~3 cases where salivation was noted on day 5, 9, 10, 12~18, 23~28, 30, 33 and 43 of administration. In the 300 mg/kg group, there were 1~4 cases where salivation was noted on day 4~28, 33, 35, 39, 44~46, 48 and 49 of administration. In the 1000 mg/kg group, there was 1 case of soiled fur on days 16~23 of administration, and there were 4~all cases where salivation was noted on days 2~49 of administration. Salivation was seen for approximately 3~30 minutes after administration in all groups, and no changes were seen in the length of time that salivation continued, even during administration.
FEMALES: Neither dead nor moribund animal was observed in the control group and the 30, 100 and 300 mg/kg group. In the 1000 mg/kg group, one animal died on Day 15 of administration. In the dead animal, salivation and abnormal gait were observed from Days 2 and 8 of administration to the day before death, respectively. In clinical observation in the surviving animals, there was no abnormality in any animal in the control group throughout the observation period. In the 30 mg/kg group, there were 1~2 cases where salivation was noted on day 10, 12~14 of administration. In the 100 mg/kg group, there was 1 case where salivation was noted on day 12 and 13 of gestation. In the 300 mg/kg group, there were 1~3 cases where salivation was noted on day 10, 12~15 and 17 of administration, day 0, 3, 4, 9, 12~14 and 17 of gestation. In the 1000 mg/kg group, there was 1 case of soiled fur on days 16~19 of administration and day 0~3 of gestation, and there were 1~11 cases where salivation was noted on days 2, 4~19 of administration, 0~23 days of gestation, and day 0 and 1 of lactation. Salivation was seen for a period of approximately 3~30 minutes after administration in all groups.

- Body weight:
MALES: The body weight of animals in the 30, 100 and 300 mg/kg groups showed almost similar changes to those in the control group, and no significant difference was observed on any determination day. In the 1000 mg/kg group, significantly low body weights were observed from Day 18 to Day 50 of administration compared with the control group.
FEMALES: The body weight of animals in the 30, 100 and 300 mg/kg groups showed almost similar changes to those in the control group before mating, and no significant difference was observed on any day of determination. In the 1000 mg/kg group, significantly low body weights were observed from Day 4 to Day 15 of administration compared with the control group. In the dead animal in the 1000 mg/kg group, decreased body weight was observed before death. During the gestation period, the body weights in the 30, 100 and 300 mg/kg groups showed almost similar changes to the control group, and no significant difference was observed on any determination day. In the 1000 mg/kg group, significantly low body weights were observed on Days 14 and 21 of gestation compared with the control group. During the lactation period, the body weights in the 30, 100 and 300 mg/kg groups showed almost similar changes to the control group, and no significant difference was observed on any day of determination. In the 1000 mg/kg group, significantly low body weight was observed on Days 0 and 4 of lactation compared with the control group.

- Food consumption:
MALES: Food consumption in the 30 mg /kg group was almost similar to as that in the control group, and no significant difference was observed on any determination day. In the 100 mg /kg group, significantly high food consumption was observed compared with the control group on Day 3 of administration, but it was not a dose-dependent change. Food consumption in the 300 mg /kg group was almost similar to that in the control group, and no significant difference was observed on any day of determination. In the 1000 mg/kg group, significantly low food consumption was observed on Days 6, 10, 31 and 34 of administration compared with the control group.
FEMALES: Food consumption in the 30, 100 and 300 mg/kg groups showed almost the same changes as that in the control group before mating, and no significant difference was observed on any determination day. In the 1000 mg/kg group, significantly low food consumption was observed compared with the control group on Days 3 and 6 of administration. In the dead animals in the 1000 mg/kg group, a marked decrease in food consumption was observed before death. During the gestation period, food consumption in each group showed almost the same change as that in the control group, and no significant difference was observed on any day of determination. During the lactation period, food consumption in the 30, 100 and 300 mg/kg groups showed no significant difference compared with the control group. In the 1000 mg/kg group, no significant difference was observed compared with the control group, but food consumption tended to be low on Day 4 of lactation.

- Organ Weight:
MALES: there were no significant differences in any of the absolute and relative testis or epidydimis organ weights compared with the control group.
FEMALES: there were no significant differences in the absolute and relative ovary weight compared with the control group.

- Histopathology:
MALES: in the 1000 mg/kg group, hemiatrophy of the seminiferous tubule of the testis, unilateral spermatic granuloma of the epididymis, decreased sperms and intraluminal cell debris were observed in 1/12 animals. Since they were the changes sometimes observed in the control group and observed in one animals, they were judged as incidental changes. There were no abnormalities in the pituitary gland, prostate gland and seminal vesicles in the control group and the 1000 mg/kg group.
FEMALES (Table 7): there were no abnormalities in the ovaries, uterus, vagina, pituitary gland and mammary gland in the control group and the 1000 mg/kg group.

- Impact on Reproduction/Development of Parent Animals (P)
1) Number of Estrous Cycles
There were no significant differences in the number of estrous cycles during the administration period (14 days) prior to mating between the control group and the 30, 100 and 300 mg/kg groups. In the 1000 mg/kg group, there were significantly low values noted in the number of estrous cycles when compared to the control group.
2) Number of Conceiving Days, Copulation Rate, Fertilized Females and Fertilization Rate
Copulation was confirmed in all cases, so the copulation rate for all groups was 100%. There were no significant differences between the control group and any of the administration groups for the number of conceiving days.
There were two unfertilized females in the 30 mg/kg group, one case in the 100 mg/kg group, one case in the 300 mg/kg group and two cases in the 1000 mg/kg group so there were 9~12 fertilized females in each group. However, there was no significant difference in the fertilization rate between the control group and each of the administration groups. There were two cases of fertilized females not resulting in pups noted in the 1000 mg/kg group (No. 451 and 452).
3) Gestation Period and Delivery Status
There were no significant differences in gestation period between the control group and the 30, 100 and 300 mg/kg groups. In the 1000 mg/kg group, the gestation period was significantly longer than that of the control group. There were no abnormalities in the delivery status of any mother animals in the control group, 30, 100, 300 and 1000 mg/kg groups.
4) Number of Corpus Luteum, Number of Implantation Scars and Implantation Rate
There were no significant differences in the number of corpus luteum, number of implantation scars and implantation rate between the control group and the 30, 100 and 300 mg/kg groups. In the 1000 mg/kg group, significantly lower values were noted in the number of corpus luteum and number of implantation scars when compared to the control group.
5) Birth Rate and Lactation Status
The birth rate in the control group, and the 30, 100 and 300 mg/kg groups was 100%. In the 1000 mg/kg group, two mother animals (No. 451 and 452) did not have pups so the birth rate was 77.8%. In the control, 30, 100 and 300 mg/kg groups, nothing abnormal was noted with the lactation status. In the 1000 mg/kg group, there was one case (No. 454) with insufficient mammary gland growth and three cases (No. 453, 454 and 461) where all of the pups perished during lactation.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male
Basis for effect level:
other: highest dose tested; no effect on copulation and fertility
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Sex:
female
Basis for effect level:
other: low values of the number of corpora lutea and the number of implantation sites at 1000 mg/kg

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
mortality observed, treatment-related
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)


1) Overall Birth Rate and Delivery Rate
There were no significant differences in overall birth rate and delivery rate between the control group and the 30, 100 and 300 mg/kg groups. In the 1000 mg/kg group, significantly lower values were noted in the overall birth rate when compared to the control group.

2) Birth Rate, Survival Rate, Sex Ratio
In the 30 and 100 mg/kg groups, there were no significant differences for survival rate, number of new pups at day 0 of lactation, number of stillbirths, birth rate and sex ratio when compared to the control group. In the 300 mg/kg group, the number of new pups at day 0 of lactation had significantly lower values when compared to the control group. In the 1000 mg/kg group, the survival rate, number of new pups at day 0 of lactation and birth rate had significantly lower values when compared to the control group and significantly higher values for the number of stillbirths.

3) General Status of Pups, Number of Surviving Pups at Day 4 of Lactation, Survival Rate at Day 4 of Lactation and Observation of External Abnormalities
In the 30, 100 and 300 mg/kg groups, there were no significant differences for the number of new pups at day 4 of lactation, and sex ratio when compared to the control group. In the 1000 mg/kg group, the number of new pups at day 4 of lactation and survival rate at day 4 of lactation had significantly lower values when compared to the control group.
For observation of external abnormalities of pups, nothing abnormal was noted for the surviving pups in any of the groups. For stillbirths, there was one case of a short tail in the 30 mg/kg group, one case of a missing tail in the 1000 mg/kg group but both were deemed accidental.
For the general status of pups, there was one case of a damaged tail in the 30 mg/kg group but it was deemed accidental.

4) Body Weight of Pups
In the 30, 100 and 300 mg/kg groups, there were no significant differences for the average by gender, average stomach and total stomach weight at day 0 and day 4 of lactation when compared to the control group. In the 1000 mg/kg group, significantly low values were noted for the average by gender, average stomach and total stomach weight at day 0 of lactation, and significantly low values for total stomach weight were noted at day 4 of lactation.

5) Necropsy Findings of Pups
In the 30 mg/kg group, there was one case each of bilateral renal pelvis dilatation and damaged tail but both were deemed to be accidental. Otherwise, nothing abnormal was noted in any of the groups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
body weight and weight gain
organ weights and organ / body weight ratios
Remarks on result:
other:
Remarks:
There are two elements which indicate that the lower number of F1 at day 0 of lactation are biologically not significant: Firstly, the difference is transient and not statistically significant by day 4 of lactation (due to reduced survival of neonates in the control group) and secondly, the observed mean number of neonates (13.4) is within the range of newborn F1 in the controls of other 422 studies in the same laboratory (13.1 – 15.2, n=10).

Target system / organ toxicity (F1)

Critical effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
stomach

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

(1) Number of estruses, copulation index and fertility index

------------------------------------------------------------
Dose level (mg/kg/day)
      0         30        100         300         1000
No. of females
     12         12         12          12           12
 No. of estrous cases before mating (Mean± SD)
   3.3±0.5    3.3±0.9     3.6±0.5     3.4±0.5      2.4±0.8*
Significantly different from control (*: p < 0.05)
------------------------------------------------------------



(2) Body weight of neonates 
------------------------------------------------------------
Dose level (mg/kg/day)
    0         30        100         300         1000
 Body weight of pups (g) (Mean± SD)
  Male  Day 0
 6.59±0.59  6.80±0.66  6.37±0.47  6.70±0.34   5.62±0.60** (6)
  Male  Day 4
 9.94±1.11 10.73±1.26 10.247±1.01  10.34±0.70   8.83±0.91 (4)
  Female  Day 0
 6.18±0.52  6.43±0.65  6.14±0.42   6.25±0.29   5.37±0.56**(7)
  Female  Day 4
 9.43±1.17 10.15±1.01  9.857±0.99   9.83±0.80   8.40±1.31 (4)
Significantly different from control (**: p < 0.01)
------------------------------------------------------------


Applicant's summary and conclusion

Conclusions:
The reproductive and developmental toxicological NOAEL is considered as 1000 mg/kg/day for males since there was no effect on copulation and fertility; 300 mg/kg/day for females since low values of the number of corpora lutea and the number of implantation sites were observed after administration at a dose of 1000 mg/kg.
Executive summary:

In an OECD Guideline 422 and GLP study, 2 -ethylhexyl methacrylate (EHMA) in corn oil was administered by oral gavage to 10 male and 10 female rats at 0, 30, 100, 300, or 1000 mg/kg/day. Male rats were dosed for 49 days and female rats were dosed from 14 days prior to mating through Day 3 of lactation. Only one high-dose female rat died during the study. Treatment-related decreases in body weight and food consumption were observed in high dose animals only. Relative to reproductive parameters, treatment-related effects observed primarily at 1000 mg/kg/day included: significantly low number of estrus cycles, prolonged gestation period, decreased number of corpora lutea and implantation sites, and decreased parturition index [77.8%]. Maldevelopment of the mammary gland was observed in one animal, and three dams’ neonates all died during the lactation period in the 1000 mg/kg/day dose group. There was a significantly low number of total offspring in the high dose group compared to controls. In the 300 mg/kg/day dose group, there was a significantly low number of neonates on Day 0 of lactation compared with the control group. At 1000 mg/kg/day, there were significantly low body weights of male and female neonates on Day 0 of lactation compared to controls. However, no gross abnormalities were observed in neonates at any dose level. Based on effects observed in parental females in the 1000 mg/kg/day dose group (i.e. decreases in the number of corpora lutea and the number of implantation sites), the NOAEL for reproductive toxicity is considered to be 300 mg/kg/day EHMA. There are two elements which indicate that the lower number of F1 at day 0 of lactation are biologically not significant: Firstly, the difference is transient and not statistically significant by day 4 of lactation (due to reduced survival of neonates in the control group) and secondly, the observed mean number of neonates (13.4) is within the range of newborn F1 in the controls of other 422 studies in the same laboratory (13.1 – 15.2, n=10).