Trimethyl borate

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards with acceptable restrictions.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Blood boron concentrations in pregnant rats fed boric acid throughout gestation

Author:

Price CJ, Strong PL, Murray FJ and Goldber MM

Bibliographic source:

Reproductive Toxicology, Vol 11, No 6 pp 833-842

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Timed-mated Sprague-Dawley rats were exposed to boric acid in the diet from Gestational day 0 to 20. Dietary concentrations of Boric acid yielded average daily intakes equivalent to 0, 3, 6, 10, 13 and 25 mg/kg/d. At termination on Gestational day 20, maternal whole blood was collected in heparinized vacutainer tubes, stored frozen (-20°C) and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry.

GLP compliance:

yes

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Boric acid

EC Number:

233-139-2

EC Name:

Boric acid

Cas Number:

10043-35-3

IUPAC Name:

10043-35-3

Constituent 2

Reference substance name:

Boric acid

IUPAC Name:

Boric acid

Details on test material:

- Name of test material (as cited in study report): BA (CAS No 10043-35-30
- Analytical purity:
99% by ICP
98% by titration with 0.1 N sodium hydroxide
- Lot/batch No.:872703

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River Laboratories Inc. (Raleigh, NC)
- Diet: ad libitum
- Water: ad libitum

Further details are reported in: Price et al, Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation, Funamental applied toxicology. 1996 32: 179-93

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

ICP
LOQ 0.00281%

Duration of treatment / exposure:

Gestation day 0 to 20

Frequency of treatment:

In feed, ad libitum

Duration of test:

20 days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0.025%, 0.050%, 0.075%, 0.100%, 0.200%
Basis:
analytical conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 19, 36, 55, 76, 143 mg Boric acid/kg BW/day
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
Equivalent to 0, 3, 6, 10, 13, 25 mg Boron/kg BW/day
Basis:
actual ingested

No. of animals per sex per dose:

28 to 32

Control animals:

yes, plain diet

Statistics:

In order to determin the degree to which calculated maternal boron intake predicted maternal blood boron concentration on gestation day 20, a linear regreassion by least square estimation was performed using the regression tool in Excel.

Results and discussion

Any other information on results incl. tables

Blood boron concentrations on gestation day 20:

Almost all of the boron concentration in the control group and 2 of 29 in the low dose group fell between the LOD and the LOQ (LOD = 0.105µg B/g blood, LOQ = 0.350µg B/g blood).All remaining samples where above the LOQ. Blood samples had boron concentrations that were clearly related to the concentration of boric acid in the diet.

 

Table 1: Boron concentration (µg boron/g) in whole blood on gestation day 20

Boric acid in feed (% in feed gestation day 0 to 20)	Control	0.025%	0.050%	0.075%	0.100%	0.200%
Boron intake   (mg B/kg BW/day)	-	3.3±0.1	6.3±0.1	9.6±0.1	13.3±0.2	25.4±0.4
Blood boron (µg B/g blood)	0.229±0.143 (n=24)	0.564±0.211*  (n=29)	0.975±0.261*  (n=27)	1.27±0.298*  (n=25)	1.53±0.546*  (n=26)	2.82±0.987*  (n=24)
Relative SD (%)	62.6	37.5	26.8	23.4	35.7	35.1
Minimum (µg B /g blood)	0.122	0.189	0.407	0.705	0.222	1.09
Maximum   (µg B /g blood)	0.695	1.34	1.57	1.75	2.47	5.13

*Statistically significant (one tailed Studentt-test (P<0.05)

 

Correlation of blood boron concentrations on gestation day 20 with dietary intake and time of blood collection:

Maternal blood boron concentrations at termination showed a robust positive correlation with measured boron intake expressed as either the average daily intake for the entire exposure period (gestation day 0-20) or for the final 24 h (gestation day 19-20).

 

Correlation of selected developmental toxicity endpoints with blood boron concentration on gestation day 20:

Examples of affected and unaffected developmental toxicity endpoints were selected as response variables for regression analysis.

Three related exposure indices were used as the regressors, specifically nominal concentration of boric acid in feed (%), individual maternal daily intake (mg boron/kg body weight/d), and individual maternal blood boron concentrations (µg boron/g) on gestation day 20. The regression analyses for number of live foetuses per litter yielded R² values close to zero for all three indices of boron exposure. This is consistent with the finding that the number of live foetuses per litter was not affected by ingestion of diets containing 0 to 0.2% boric acid.

Three embryo/foetal endpoints were affected on gestation day 20 following exposure to ≥0.1% boric acid in the diet, specifically decreased foetal body weight and increased incidences of short rib and wavy rib. Data for the rib endpoints were not suitable for regression analysis, due to the large proportion of litters that exhibited no foetuses with either of these findings in most of the dose groups. Therefore, foetal body weight was the only affected embryo/foetal endpoint used for regression analysis. Regression analyses for foetal body weight indicated a significant, though not robust, correlation between average male or female body weight per litter and each of the three exposure indices. Because R² values were similar for male or female foetuses, the scatter plot for the female foetal body weight per litter versus maternal blood boron are provided to demonstrate the outcome of the regression analyses for foetal body weight. These results are consistent with the finding that average foetal body weight per litter on gestation day 20 (both sexes) was significantly reduced following exposure to 0.1% or 0.2% BA (94% or 88% of control foetal weight, respectively).

 

Table 2: Correlation of individual maternal blood boron (µg boron/g) with developmental toxicity endpoints

Response variable	Toxic effect	Regressor	R^2
No live foetuses/litter	No effect	Intake Blood Dose	-0.00554 -0.00525 -0.00612
Female foetal body wt (g)/litter	↓*	Intake Blood Dose	0.253 0.340 0.290
Male foetal body wt (g)/litter	↓*	Intake Blood Dose	0.239 0.343 0.273

*Mean foetal body weights (g/litter) were significantly reduced treatment groups fed 0.100% or 0.200% boric acid in the diet

Applicant's summary and conclusion

Executive summary:

Average concentration of boron in the blood increased with increased dietary exposure.

Concentrations in whole blood from the 0.075% and 0.1% exposure groups (1.27 and 1.53 µg B/g blood) coresponded to the NOAEL and LOAEL (10 and 13 mg B/kg bw/d respectively) reported previously