Registration Dossier

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

All of the data for L-threonine regarding toxicity to reproduction is from the public domain, summarizing the findings from an experiments conducted with a scientific background rather than gearing to registration requirements. Therefore, the study employed is not in compliance with standard methods and only partially cover endpoints which are analyzed in an up-to-date OECD guideline study.

However, conventional toxicology studies are considered to be inappropriate for testing essential dietary nutrients. In the case of such substances, there is a physiological concentration that is optimum for health and performance. Dietary intakes of such substances in quantities that lead to body levels significantly below or above optimum levels will cause a physiological imbalance and consequent adverse effects.

According to a publication from Matsueda and Niiyama (1982) feeding of a 6% casein diet containing 5% added L-threonine to pregnant SD rats from day 1 to day 14 or 21 of pregnancy resulted in significant lower fetal weight than in ad libitum or pair-fed controls but no change in litter size. Excess L-threonine produced a significant reduction in brain weight, DNA, RNA, and protein that was not produced by food restriction.

The study from Matsueda and Niiyama may indicate that 5% L-threonine in diet fed during pregnancy results in developmental/reproductive effects as the fetal growth was significantly affected. As mentioned above it has to be considered, that this scientific study was not performed according to common guidelines and the feeding conditions in this study are very artificial which by itself have significant influence on fetal growth. It is well known that restricted maternal protein supply perturbs fetal growth (e.g. Rees et al 1999). Offspring of pregnant rats fed on protein-deficient diets (like it is the case in the Matsueda and Niiyama study) are not only slightly smaller than controls fed on an adequate diet but also have permanent changes in the structure and function of their organs which result in reduced glucose tolerance and hypertension in adult life. Therefore, seen effects may be caused only by this extremely artificial situation of protein-restriction in combination with amino acid excess.Such situations are very artificial and unlikely for humans to occur.

A significant amount of L-threonine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Food consumption data indicate that 4 g L-threonine is consumed daily with a daily intake of 100 g protein. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated.

Exposure with L-threonine from uses which are covered by this registration would only marginally increase the total daily L-threonine dose which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis. Therefore it is highly unlikely that L-threonine taken up via any use covered by this registration would result in systemic effects.Several repeated dose toxicity studies consistently indicate the very low systemic toxicity of L-threonine. All repeated dose studies showed no effects on the reproductive organs.

Therefore it is highly unlikely that L-threonine taken up via any use covered by this registration would result in any effect on the reproductive system or the unborn life. Taking this into consideration and for animal welfare reasons it is not justified to do any further animal testing with regard to the toxicological endpoints reproductive toxicity and developmental toxicity/teratogenicity.

Reference:

Rees WD, Hay SM, Buchan V, Antipatis C, Palmer RM. (1999).The effects of maternal protein restriction on the growth of the rat fetus and its amino acid supply.Br J Nutr.; 81(3):243-50.

Short description of key information:
No evidence for effects on fertility.

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientific study not performed according to common guidelines. The feeding conditions in this study are very artificial which by itself might have significant influence on fetal growth.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Scientific study in which the effect of amino acid-excess diets on maintenance of pregnancy as well as fetal growth was examined.

GLP compliance:

not specified

Species:

rat

Strain:

Sprague-Dawley

Route of administration:

oral: feed

Analytical verification of doses or concentrations:

not specified

Remarks:

Doses / Concentrations:
5 %
Basis:
nominal in diet

No. of animals per sex per dose:

6 rats in the 5% L-threonine group
7 rats in the ad libitum control group
5 rats in the pair-fed control

Control animals:

other: 6% casein diet ad libitum... (see attached file)

Abnormalities:

not specified

Developmental effects observed:

not specified

Feeding of a 6% casein diet containing 5% added L-threonine to pregnant SD rats from day 1 to day 14 or 21 of pregnancy resulted in significant lower fetal weight than in ad libitum or pair-fed controls but no change in litter size. Excess L-threonine produced a significant reduction in brain weight, DNA, RNA, and protein that was not produced by food restriction. The maternal plasma concentration increased ca 13 -fold. Fetal brain concentration increased about 16 -fold.

Executive summary:

Feeding of a 6% casein diet containing 5% added L-threonine to pregnant SD rats from day 1 to day 14 or 21 of pregnancy resulted in significant lower fetal weight than in ad libitum or pair-fed controls but no change in litter size. Excess L-threonine produced a significant reduction in brain weight, DNA, RNA, and protein that was not produced by food restriction. The maternal plasma concentration of L-threonine increased ca 13 -fold. Fetal brain concentration increased about 16 -fold.

However, the study was not performed according to common guidelines and the food conditions in this study are very artificial which by itself have significant influence on fetal growth. It is well known that restricted maternal protein supply perturbs fetal growth. Offspring of pregnant rats fed on protein-deficient diets are not only slightly smaller than controls fed on an adequate diet but also have permanent changes in the structure and function of their organs which result in reduced glucose tolerance and hypertension in adult life. Therefore, seen effects may be caused only by this extremely artificial situation of protein-restriction in combination with amino acid excess. Such situations are very artificial and unlikely for humans to occur.

Endpoint conclusion:

adverse effect observed

Quality of whole database:

The artifically low protein diet may significantly contribute to the observed effects in this study.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

All of the data for L-threonine regarding toxicity to reproduction is from the public domain, summarizing the findings from an experiments conducted with a scientific background rather than gearing to registration requirements. Therefore, the study employed is not in compliance with standard methods and only partially cover endpoints which are analyzed in an up-to-date OECD guideline study.

However, conventional toxicology studies are considered to be inappropriate for testing essential dietary nutrients. In the case of such substances, there is a physiological concentration that is optimum for health and performance. Dietary intakes of such substances in quantities that lead to body levels significantly below or above optimum levels will cause a physiological imbalance and consequent adverse effects.

According to a publication from Matsueda and Niiyama (1982) feeding of a 6% casein diet containing 5% added L-threonine to pregnant SD rats from day 1 to day 14 or 21 of pregnancy resulted in significant lower fetal weight than in ad libitum or pair-fed controls but no change in litter size. Excess L-threonine produced a significant reduction in brain weight, DNA, RNA, and protein that was not produced by food restriction.

The study from Matsueda and Niiyama may indicate that 5% L-threonine in diet fed during pregnancy results in developmental/reproductive effects as the fetal growth was significantly affected. As mentioned above it has to be considered, that this scientific study was not performed according to common guidelines and the feeding conditions in this study are very artificial which by itself have significant influence on fetal growth. It is well known that restricted maternal protein supply perturbs fetal growth (e.g. Rees et al 1999). Offspring of pregnant rats fed on protein-deficient diets (like it is the case in the Matsueda and Niiyama study) are not only slightly smaller than controls fed on an adequate diet but also have permanent changes in the structure and function of their organs which result in reduced glucose tolerance and hypertension in adult life. Therefore, seen effects may be caused only by this extremely artificial situation of protein-restriction in combination with amino acid excess.Such situations are very artificial and unlikely for humans to occur.

A significant amount of L-threonine is usually taken up via the food. In usual diet, most amino acids are supplied as constituents of protein and not as free amino acid. Food consumption data indicate that 4 g L-threonine is consumed daily with a daily intake of 100 g protein. Protein intake clearly modifies plasma amino acid levels. However, amino acid concentrations are subject to homeostasis and the plasma concentrations vary within fixed limits and are tightly regulated.

Exposure with L-threonine from uses which are covered by this registration would only marginally increase the total daily L-threonine dose which is taken up via the food. Even if the plasma amino acid concentration would increase/vary by any use such fluctuations are physiological and subject to homeostasis. Therefore it is highly unlikely that L-threonine taken up via any use covered by this registration would result in systemic effects.Several repeated dose toxicity studies consistently indicate the very low systemic toxicity of L-threonine. All repeated dose studies showed no effects on the reproductive organs.

Therefore it is highly unlikely that L-threonine taken up via any use covered by this registration would result in any effect on the reproductive system or the unborn life. Taking this into consideration and for animal welfare reasons it is not justified to do any further animal testing with regard to the toxicological endpoints reproductive toxicity and developmental toxicity/teratogenicity.

Reference:

Rees WD, Hay SM, Buchan V, Antipatis C, Palmer RM. (1999).The effects of maternal protein restriction on the growth of the rat fetus and its amino acid supply.Br J Nutr.; 81(3):243-50.