Bromomethane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Materials and methods

Test guideline

Qualifier:

no guideline available

Guideline:

other:

Principles of method if other than guideline:

There are no deviations from the recommended guidelines EEC B30 (Teratogenicity Study – rodent and non- rodent) evident in this study report.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Bromomethane

EC Number:

200-813-2

EC Name:

Bromomethane

Cas Number:

74-83-9

Molecular formula:

CH3Br

IUPAC Name:

bromomethane

Details on test material:

Methyl Bromide: purity: 99.6 % pure, batch no. 041889 Source: Hyyield- Bromide, Rocky Point, NC

Test animals

Species:

rabbit

Strain:

New Zealand White

Administration / exposure

Route of administration:

inhalation

Details on exposure:

In Part I, 7 groups of 26 inseminated rabbits were exposed to via inhalation for 6 hours/day to 0 (chamber control, filtered air), 20, 40 or 80 ppm Methyl Bromide on days 7 through 19 of gestation. This part of the study was conducted to observe fetal abnormalities, if any, that may be test article-related.

In Part II, groups of 17 inseminated rabbits were exposed for 6 hours/day to 0 or 80 ppm Methyl Bromide on days 7 through 19 of gestation. This part of the study was conducted in order to establish whether fetal observations made in Part I were reproducible and/or if these observations are attributed to a particular male used for insemination.

An additional group of 16 females inseminated by a single male and withheld from chamber housing acted as naïve controls. On day 28 of the study, all surviving animals were necropsied.

Examinations

Maternal examinations:

Pregnant animals were evaluated for toxic changes to internal organs.

Fetal examinations:

Litters were evaluated for embryotoxicity and live fetuses were examined for external, visceral, and skeletal malformations.

Results and discussion

Results (fetuses)

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Part I :

Mortality and Clinical Observations :

All rabbits survived, except for one rabbit from the 80 ppm group that delivered its litter early on Day 27 and had to be sent for necropsy. It was considered that severe maternal toxicity was a major contributing factor to early delivery. Significant clinical observations considered to be test article – related were limited to rabbits in the 80 ppm group. These included incidences of decreased feces (animal apparently not eating), lethargy, right-sided head tilt, ataxia and lateral recumbency. Right-sided head tilt, ataxia and lateral recumbency are suggestive of adverse neurologic effects. No adverse clinical observations attributed to methyl bromide exposure were observed in the 20 or 40 ppm groups.

Mean body weights:

Mean body weights in the 80 ppm group decreased throughout most of the exposure period (Days 7 – 20), with statistically significant decreases occurring in body weight on Day 16 and in body weight gain during Days 13 – 16. Two pregnant rabbits appeared more severely effected than the other rabbits in the group – due to the amount of weight loss suffered by these animals during the exposure period. This weight loss was considered test article-related.

Organ weights :

No significant effects attributed to exposure to test article were observed on organ weights or on reproductive and fetal observation made at the time of necropsy at any exposure level.

External, visceral and skeletal observations :

No effects attributed to treatment were noted on fetal malformations or variations in the 20 and 40 ppm groups. A high incidence of malformations was observed in fetuses from rabbits in the 80 ppm group compared to the control group. These malformations included missing gallbladder or missing caudal lobe of the lung. The occurance of a missing gallbladder was thought to result from the use of one male for insemination. However, this is classified as a minor malformation.

Fetal variations noted included fused sternebra in the 80 ppm group; this type of malformation is specifically related to maternal toxicity in rabbits. Other fetal variations observed were concurrent with the norm for the New Zealand White Rabbit and were not considered test article-related.

Part II :

This experiment was carried out to determine whether fetal abnormalities noted in the 80 ppm group in Part I were reproducible or were attributed to a particular male used for artifical insemination.

 

Mortality :

All rabbits survived, except for one pregnant rabbit from the 80 ppm group that was found dead on Day 19 of gestation. This rabbit was not eating for five days prior to her death. Gross pathological examination of this rabbit revealed congestion and edema in the lungs, frothy fluid in the trachea, a hairball and mucus in the stomach. The specific cause of death was not discovered but was thought to be treatment related.

 

Clinical Observations :

Clinical observations attributed to the test article were limited to rabbits in the 80 ppm group. These included incidences of decreased feces (apparently not eating) and perineal soiling in one rabbit. No adverse clinical observations attributed to test article exposure were observed in the 20 or 40 ppm groups.

Mean body weights:

No significant differences in body weights were noted between control rabbits, rabbits in the 80 ppm group or the naive control group. Weight gain for rabbits in the 80 ppm group were generally lower than for the chamber control group. Pregnant rabbits from the naive control group (withheld from chambers) showed statistically increased (days 7 – 10) and decreased (days 20 – 28) weight gain during the study in comparison to the chamber control group. This was linked to the method of housing of the animals.

Reproductive and Fetal Observations :

No significant effects attributed to test article exposure were observed on the pregnancy rate, the number of implantations, preimplantation loss, the resorption rate, litter size, or fetal sex ratio. The body weights of fetuses and gravid uterine weights of dams from the 80 ppm exposure group were statistically decreased in comparison to the chamber controls. The significant decrease in uterine weights of females was a reflection of both a slightly smaller litter size and decreased fetal weights. 

 

External, visceral and skeletal observations :

No statistically significant increases in fetal variations or malformations were observed between fetuses from the 80 ppm or naive control group. No statistically significant increases in fetal variations or malformations were observed between fetuses from the 80 ppm group or the naïve control group. The overall incidences of malformed fetuses were similar between the chamber controls (12.3%) and the 80 ppm group (14.1%) but were sharply lower in the naïve control group (5.9%). In addition, the increase in malformed fetuses (2.1% in control, vs 14.5% at 80 ppm) observed at 80 ppm in Part I was not reproducible. However, the incidence of missing gallbladder was increased in the 80 ppm exposure group (4.3%) when compared to either the chamber controls (0.9%) or the naïve controls (0.0%), although the increase was not statistically identified when compared to the chamber control group. The increases in missing gallbladder in the 80 ppm exposure groups from Part I and Part II of this study were consistent, though the magnitude of the increase varied somewhat (8.2% in Part I vs 4.3% in Part II). The lower incidence of missing gallbladder in Part II was consistent with the less severe indications of maternal toxicity observed in these rabbits. These differences further suggest that maternal toxicity and/or general stress may have contributed to the expression of this malformation. Missing gallbladder was not observed in the naïve control group, demonstrating that this observation is not associated with genetic factors in a particular male used for artificial insemination.

 

The incidences of missing caudal lobe of the lung in the chamber controls and the 80 ppm group were similar but were also clearly elevated above the incidence of the naïve controls from Part II of this study, as well as the incidences observed in the 80 ppm and control groups from Part I of this study and historical control for New Zealand White rabbits used in this laboratory. These results indicate that the increased incidence of missing caudal lobe of the lung observed in the 80 ppm group from Part I of this study was not attributed to treatment, but rather a reflection of the normal variability of the observation of this group of rabbits. The high incidence of missing caudal lobe of the lung in the chamber controls and 80 ppm exposure group during Part II of this study also suggests that the rabbits used for this study may be predisposed this malformation, or that stress due to housing in chambers 6 hours/day without feed/water may increase the expression of this malformation.

 

All other malformations and variations observed in fetuses from dams exposed to methyl bromide in Part II occurred at low incidences, were within the incidence observed in the concurrent control group or were within the incidence observed in the historical control New Zealand White rabbits used in this laboratory and were not attributed to exposure to methyl bromide. Skeletal examination of fetuses was not conducted in Part II.

Applicant's summary and conclusion

Conclusions:

The NOEL (No Observed Effect Level) for maternal and developmental toxicity was 40 ppm. The results of this study indicate a low potential for developmental toxicity at exposure levels that do not produce overt maternal toxicity.